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1
Widdop, R. E., S. M. Gardiner, P. A. Kemp, and T. Bennett. "Differential blockade of central effects of angiotensin II by AT2-receptor antagonists." American Journal of Physiology-Heart and Circulatory Physiology 265, no. 1 (July 1, 1993): H226—H231. http://dx.doi.org/10.1152/ajpheart.1993.265.1.h226.
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In conscious, chronically instrumented, male Long-Evans rats, we showed previously that central administration (intracerebroventricular) of the AT1-receptor antagonist EXP-3174 (1 microgram) caused a rapid-onset marked, but transient, blockade of the regional hemodynamic responses to intracerebroventricular angiotensin II (ANG II). In contrast, the AT2-receptor antagonist PD-123319 (80 micrograms) caused a slow-onset, but marked and persistent, antagonism of the effects of intracerebroventricular ANG II. In the present study we attempted to mimic the actions of PD-123319 by giving a supramaximal dose of EXP-3174 (10 micrograms), and we also assessed the effects of PD-123177 (80 micrograms), an AT2-receptor antagonist that differs from PD-123319 only by a dimethyl group. The higher dose of EXP-3174 did not exert prolonged antagonistic effects against responses to intracerebroventricular ANG II, and PD-123177 was without inhibitory effects in this model. The results indicate important functional differences between putative AT2-receptor antagonists, when assessed in vivo, that are not apparent from binding studies.
2
Louis, Sherif, Laura Saward, and Peter Zahradka. "Both AT1 and AT2 receptors mediate proliferation and migration of porcine vascular smooth muscle cells." American Journal of Physiology-Heart and Circulatory Physiology 301, no. 3 (September 2011): H746—H756. http://dx.doi.org/10.1152/ajpheart.00431.2010.
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Angiotensin receptor antagonists have shown clinical promise in modulating vascular disease, in part by limiting smooth muscle cell proliferation and migration. The majority of studies examining the contribution of these receptors have been undertaken in cells derived from rat aorta, which primarily express the ANG II type 1 (AT1) receptor. This investigation studied the relative contribution of AT1 and ANG II type 2 (AT2) receptors to the mitogenic program of porcine smooth muscle cells. Smooth muscle cells were derived from porcine coronary artery explants. The presence of both AT1 and AT2 receptors was demonstrated through ligand binding and RT-PCR analysis. Biochemical and cellular markers of proliferation were monitored in the presence of selective receptor antagonists. Smooth muscle cell migration was measured using both wound healing and Boyden chamber migration assays. Visualization of the AT1 and AT2 receptors in growing and quiescent porcine smooth muscle cells with epifluorescence microscopy demonstrated that their subcellular distribution varied with growth state. An examination with several growth assays revealed that both AT1-specific losartan and AT2-specific PD-123319 receptor antagonists inhibited ANG II-stimulated RNA and DNA synthesis, PCNA expression, and hyperplasia. ANG II induced both directional and nondirectional cell migration. AT1 receptor antagonist treatment significantly decreased ANG II-induced directional migration only, whereas AT2 receptor antagonist treatment significantly reduced both modes of migration. Interestingly, the focal adhesion kinase inhibitor PF-573228 also blocked migration but not proliferation. Furthermore, focal adhesion kinase activation in response to ANG II was prevented only by PD-123319, indicating that this activation is downstream of the AT2 receptor. The observed role of the AT2 receptor in ANG II-induced migration was confirmed with smooth muscle cells depleted of the AT2 receptor with short hairpin RNA treatment.
3
Le Noble, F. A., N. H. Schreurs, H. W. van Straaten, D. W. Slaaf, J. F. Smits, H. Rogg, and H. A. Struijker-Boudier. "Evidence for a novel angiotensin II receptor involved in angiogenesis in chick embryo chorioallantoic membrane." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 264, no. 2 (February 1, 1993): R460—R465. http://dx.doi.org/10.1152/ajpregu.1993.264.2.r460.
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Angiotensin II acts as a growth factor in the cardiovascular system and has been implicated in angiogenesis. The existence of at least two types of angiotensin II receptors, the AT1 and the AT2 receptors, has been suggested by ligand binding studies. We used three different AT receptor antagonists to study the receptor mediating angiotensin II-induced angiogenesis in the chorioallantoic membrane (CAM) of the chick embryo. Angiotensin II caused pronounced angiogenesis of pre- and postcapillary vessels of 30-40%. This response could only be blocked by adding the peptidergic AT2 antagonist CGP-42112A. The nonpeptidergic AT2 antagonist PD123319 and AT1 antagonist losartan (DuP 753) were not effective. In addition, we used radioligand binding studies with a range of ligands to define the nature of the receptor. Our results show a high density of specific single class AT receptor with a total number of binding sites of 1,190 fmol/mg protein and an affinity constant for angiotensin II of 2.7 nM. The inhibitory concentrations (IC50) for CGP-42112A, PD 123319 and losartan were 724, > 100,000, and 59,000 nM, respectively. Our studies suggest that these binding sites act as receptors for angiotensin II-induced angiogenesis. Both functional and radioligand binding studies suggest that the receptor is different from the classical mammalian AT1 and AT2 receptors.
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Naito, Takashi, Li-Jun Ma, Haichun Yang, Yiqin Zuo, Yiwei Tang, Jee Young Han, Valentina Kon, and Agnes B. Fogo. "Angiotensin type 2 receptor actions contribute to angiotensin type 1 receptor blocker effects on kidney fibrosis." American Journal of Physiology-Renal Physiology 298, no. 3 (March 2010): F683—F691. http://dx.doi.org/10.1152/ajprenal.00503.2009.
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Angiotensin type 1 (AT1) receptor blocker (ARB) ameliorates progression of chronic kidney disease. Whether this protection is due solely to blockade of AT1, or whether diversion of angiotensin II from the AT1 to the available AT2 receptor, thus potentially enhancing AT2 receptor effects, is not known. We therefore investigated the role of AT2 receptor in ARB-induced treatment effects in chronic kidney disease. Adult rats underwent 5/6 nephrectomy. Glomerulosclerosis was assessed by renal biopsy 8 wk later, and rats were divided into four groups with equivalent glomerulosclerosis: no further treatment, ARB, AT2 receptor antagonist, or combination. By week 12 after nephrectomy, systolic blood pressure was decreased in all treatment groups, but proteinuria was decreased only with ARB. Glomerulosclerosis increased significantly in AT2 receptor antagonist vs. ARB. Kidney cortical collagen content was decreased in ARB, but increased in untreated 5/6 nephrectomy, AT2 receptor antagonist, and combined groups. Glomerular cell proliferation increased in both untreated 5/6 nephrectomy and AT2 receptor antagonist vs. ARB, and phospho-Erk2 was increased by AT2 receptor antagonist. Plasminogen activator inhibitor-1 mRNA and protein were increased at 12 wk by AT2 receptor antagonist in contrast to decrease with ARB. Podocyte injury is a key component of glomerulosclerosis. We therefore assessed effects of AT1 vs. AT2 blockade on podocytes and interaction with plasminogen activator inhibitor-1. Cultured wild-type podocytes, but not plasminogen activator inhibitor-1 knockout, responded to angiotensin II with increased collagen, an effect that was completely blocked by ARB with lesser effect of AT2 receptor antagonist. We conclude that the benefical effects on glomerular injury achieved with ARB are contributed to not only by blockade of the AT1 receptor, but also by increasing angiotensin effects transduced through the AT2 receptor.
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Hakam, Amer C., and Tahir Hussain. "Angiotensin II AT2 receptors inhibit proximal tubular Na+-K+-ATPase activity via a NO/cGMP-dependent pathway." American Journal of Physiology-Renal Physiology 290, no. 6 (June 2006): F1430—F1436. http://dx.doi.org/10.1152/ajprenal.00218.2005.
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Angiotensin II AT2 receptors act as a functional antagonist for the AT1 receptors in various tissues. We previously reported that activation of the renal AT2 receptors promotes natriuresis and diuresis; however, the mechanism is not known. The present study was designed to investigate whether activation of AT2 receptors affects the activity of Na+-K+-ATPase (NKA), an active tubular sodium transporter, in the proximal tubules isolated from Sprague-Dawley rats. The AT2 receptor agonist CGP-42112 (10−10-10−7 M) produced a dose-dependent inhibition of NKA activity (9–38%); the inhibition was attenuated by the presence of the AT2 receptor antagonist PD-123319 (1 μM), suggesting the involvement of the AT2 receptors. The AT1 receptor antagonist losartan (1 μM) did not affect the CGP-42112 (100 nM)-induced inhibition of NKA activity. The presence of guanylyl cyclase inhibitor ODQ (10 μM) and the nitric oxide (NO) synthase inhibitor Nω-nitro-l-arginine methyl ester (l-NAME; 100 μM) abolished the CGP-42112 (100 nM)-induced NKA inhibition. ANG II (100 nM), in the presence of losartan, significantly inhibited NKA activity; the inhibition was attenuated by PD-123319. CGP-42112 also, in a dose-dependent manner, stimulated NO production (∼0–230%) and cGMP accumulation (∼25–100%). The CGP-42112 (100 nM)-induced NO and cGMP increases were abolished by the AT2 receptor antagonist PD-123319, ODQ, and l-NAME. The data suggest that the activation of the AT2 receptor via stimulation of the NO/cGMP pathway causes inhibition of NKA activity in the proximal tubules. This phenomenon provides a plausible mechanism responsible for the AT2 receptor-mediated natriuresis-diuresis in rodents.
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Johansson, Berndt, Mathias Holm, Sara Ewert, Anna Casselbrant, Anders Pettersson, and Lars Fändriks. "Angiotensin II type 2 receptor-mediated duodenal mucosal alkaline secretion in the rat." American Journal of Physiology-Gastrointestinal and Liver Physiology 280, no. 6 (June 1, 2001): G1254—G1260. http://dx.doi.org/10.1152/ajpgi.2001.280.6.g1254.
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The aims of this study were to elucidate the distribution of angiotensin receptors (AT1and AT2) in the duodenal wall and to investigate whether AT2 receptors are involved in the regulation of duodenal mucosal alkaline secretion, which is of importance for the mucosal defense against gastric acid. Immunohistochemistry was used to locate AT1 and AT2 receptors in chloralose-anesthetized rats. Duodenal mucosal alkaline output was measured by use of in situ pH-stat titration. Immunohistochemistry demonstrated a distinct staining for both AT1 and AT2 receptors in the lamina propria of the villi and also for AT1 receptors in the muscularis interna. When angiotensin II was infused in the presence of the AT1receptor antagonist losartan, mucosal alkaline secretion increased by ∼50%. This response was inhibited by the AT2 receptor antagonist PD-123319. The AT2 receptor agonist CGP-42112A increased mucosal alkaline secretion by ∼50%. This increase was absent in the presence of PD-123319 but not in the presence of losartan or the local anesthetic lidocaine. We conclude that angiotensin II stimulates duodenal mucosal alkaline secretion by activation of AT2 receptors located in the duodenal mucosa/submucosa.
7
Shimizu-Hirota, Ryoko, Hiroyuki Sasamura, Mizuo Mifune, Hideaki Nakaya, Mari Kuroda, Matsuhiko Hayashi, and Takao Saruta. "Regulation of Vascular Proteoglycan Synthesis by Angiotensin II Type 1 and Type 2 Receptors." Journal of the American Society of Nephrology 12, no. 12 (December 2001): 2609–15. http://dx.doi.org/10.1681/asn.v12122609.
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ABSTRACT. Recent studies have shown that proteoglycans play an important role in the development of vascular disease and renal failure. In this study, the effects of angiotensin II (AngII) type 1 (AT1) and type 2 (AT2) receptor stimulation on glycosaminoglycan and proteoglycan core protein synthesis in vascular smooth muscle cells (VSMC) were examined. Treatment of AT1 receptor-expressing VSMC with AngII resulted in a dose-dependent and time-dependent increase (2- to 4-fold) in 3H-glucosamine/35S-sulfate incorporation, which was abolished by pretreatment with the AT1 receptor antagonist, losartan. The effects of AngII were inhibited by the epidermal growth factor receptor inhibitor, AG1478, and the mitagen-activated protein kinase kinase inhibitor, PD98059, but not the protein kinase C inhibitors, chelerythrine and staurosporine. AngII treatment also resulted in significant increases in the mRNA of the core proteins, versican, biglycan, and perlecan. The effects of AT2 receptor stimulation were examined by retroviral transfection of VSMC with the AT2 receptor. Stimulation of the AT2 receptor in these VSMC-AT2 cells resulted in a significant (1.3-fold) increase in proteoglycan synthesis, which was abolished by the AT2 receptor antagonist, PD123319, and attenuated by pretreatment with pertussis toxin. These results implicate both AT1 and AT2 receptors in the regulation of proteoglycan synthesis and suggest the involvement of epidermal growth factor receptor-dependent tyrosine kinase pathways and Gαi/o-mediated mechanisms in the effects of the two receptors.
8
Vázquez, Erika, Israel Coronel, Rocio Bautista, Eunice Romo, Carlos M. Villalón, M. Carmen Avila-Casado, Virgilia Soto, and Bruno Escalante. "Angiotensin II-dependent induction of AT2 receptor expression after renal ablation." American Journal of Physiology-Renal Physiology 288, no. 1 (January 2005): F207—F213. http://dx.doi.org/10.1152/ajprenal.00216.2004.
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Angiotensin (ANG) II can be associated with gene expression regulation. Thus we studied the possible role of ANG II in the regulation of AT2 mRNA and protein expression. We utilized sham-operated renal ablation rats as well as renal ablation rats pretreated during the first 7 days of the development of renal damage with either the angiotensin-converting inhibitor ramipril, the AT1 receptor antagonist losartan, or the AT2 receptor antagonist PD-123319. Renal tissue was analyzed for histological changes and expression of AT2 receptor mRNA (by RT-PCR) and protein (by immunohistochemistry). To explore the physiological role of AT2 receptor overexpression in the development of renal damage, blood pressure, urinary protein excretion, and renal damage were evaluated. A time-dependent increase in the expression of AT2 receptor mRNA and protein was observed at 7, 15, and 30 days after renal ablation. Because these effects were already evident at day 7, the effects of ramipril, losartan, or PD-123319 were tested at this time. The ramipril group and the PD-123319-pretreated group showed inhibition of AT2 receptor expression, whereas the losartan-pretreated group showed a further increase in AT2 receptor expression. Inhibition of the AT2 receptor during renal ablation was associated with increased renal damage and a further increase in the blood pressure. This suggests that overexpression of AT2 receptors after renal ablation is modulated by ANG II through its own AT2 receptor and that functional expression of this effect may represent a counterregulatory mechanism to modulate the renal damage induced by renal ablation.
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Casselbrant, Anna, Anders Edebo, Peter Hallersund, Emma Spak, Herbert F. Helander, Claes Jönson, and Lars Fändriks. "Angiotensin II receptors are expressed and functional in human esophageal mucosa." American Journal of Physiology-Gastrointestinal and Liver Physiology 297, no. 5 (November 2009): G1019—G1027. http://dx.doi.org/10.1152/ajpgi.00255.2009.
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Only few studies have been devoted to the actions of the renin-angiotensin system (RAS) in the human gastrointestinal tract. The present study was undertaken to elucidate the expression and action of RAS in the human esophageal mucosa. Mucosal specimens with normal histological appearance were obtained from healthy subjects undergoing endoscopy and from patients undergoing esophagectomy due to neoplasm. Gene and protein expressions of angiotensin II (Ang II) receptor type 1 (AT1) and type 2 (AT2) and angiotensin-converting enzyme (ACE) were analyzed. In vivo functionality in healthy volunteers was reflected by assessing transmucosal potential difference (PD). Ussing chamber technique was used to analyze the different effects of Ang II on its AT1 and AT2 receptors. Immunoreactivity to AT1 and AT2 was localized to stratum superficiale and spinosum in the epithelium. ACE, AT1, and AT2 were found in blood vessel walls. Transmucosal PD in vivo increased following administration of the AT1 receptor antagonist candesartan. In Ussing preparations mean basal transmural PD was −6.4 mV, epithelial current ( Iep) 34 μA/cm2, and epithelial resistance ( Rep) 321 Ω·cm2. Serosal exposure to Ang II increased PD as a result of increased Iep, whereas Rep was constant. Ang II given together with the selective AT1-receptor antagonist losartan, or AT2 agonist C21 given alone, resulted in a similar effect. Ang II given in presence of the AT2-receptor antagonist PD123319 did not influence PD, but Iep decreased and Rep increased. In conclusion, Ang II receptors and ACE are expressed in the human esophageal epithelium. The results suggest that AT2-receptor stimulation increases epithelial ion transport, whereas the AT1 receptor inhibits ion transport and increases Rep.
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Mifune, Mizuo, Hiroyuki Sasamura, Hideaki Nakaya, Ryoko Shimizu-Hirota, Matsuhiko Hayashi, and Takao Saruta. "Effects of Angiotensin II Type 2 Receptor Stimulation on Collagen Synthesis in Vascular Smooth Muscle Cells." Hypertension 36, suppl_1 (October 2000): 709. http://dx.doi.org/10.1161/hyp.36.suppl_1.709.
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P84 Previously, we and others have shown that angiotensin II enhances vascular smooth muscle cell extracellular matrix synthesis via stimulation of the type 1 angiotensin (AT1) receptor. Recently, expression of the type 2 (AT2) receptor has been confirmed in the adult vasculature, but its role in vascular remodeling has not yet been fully defined. In particular, conflicting data from in vivo studies have reported that AT2 receptor inhibition may either attenuate or enhance vascular hypertrophy and fibrosis. The aim of this study was to clarify the effects of direct stimulation of AT2 receptors on collagen synthesis in vascular smooth muscle cells in vitro. Firstly, retroviral gene transfer was used to supplement adult vascular smooth muscle cells with AT2 receptors to mimic the vasculature in vivo. Treatment of these cells with the AT2 receptor agonist CGP42212A (10-7 mol/L) alone did not cause a significant change in p42/p44 MAP kinase activity, but caused a modest (33%) decrease in protein tyrosine phosphatase activity. Treatment with CGP42112A also caused a dose- and time-dependent increase in both cell-associated and secretory collagen synthesis (148+17% of control at 48 h, p<0.05) which was completely inhibited by the AT2 receptor antagonist PD123319, but unaffected by the AT1 receptor antagonist losartan. The AT2 receptor-mediated stimulation of collagen synthesis was unaffected by tyrosine phosphatase inhibitors sodium orthovanadate and okadaic acid, but attenuated by pretreatment with pertussis toxin or Galphai antisense oligonuclotides. These results suggest that direct AT2 receptor stimulation can increase rather than decrease collagen synthesis in vascular smooth muscle cells, and suggest a role for Galphai in the AT2 receptor-mediated effects.
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Duke, Lisa M., Roger G. Evans, and Robert E. Widdop. "AT2 receptors contribute to acute blood pressure-lowering and vasodilator effects of AT1 receptor antagonism in conscious normotensive but not hypertensive rats." American Journal of Physiology-Heart and Circulatory Physiology 288, no. 5 (May 2005): H2289—H2297. http://dx.doi.org/10.1152/ajpheart.01096.2004.
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The aims of this study were to determine the contribution of the AT2 receptor to the antihypertensive and regional vasodilatory effects of AT1 receptor blockade in adult spontaneously hypertensive rats (SHR), 2-kidney, 1-clip hypertensive (2K1C) rats, and sham-operated normotensive rats. Several studies have provided evidence to support the notion that the AT2 receptor may have opposing effects to those mediated by the AT1 receptor. We therefore tested the hypothesis that the depressor and vasodilator effects of acute AT1 receptor blockade are dependent on AT2 receptor activation. Heart rate, mean arterial pressure, and regional hemodynamics were measured over a 4-day protocol in rats that received the following treatments in randomized order: saline vehicle, the AT1 receptor antagonist candesartan (0.1 mg/kg iv bolus), the AT2 receptor antagonist PD-123319 (50 μg·kg−1·min−1), or both antagonists. Intravenous candesartan reduced mean arterial pressure in all groups of rats, and this was accompanied by renal and mesenteric vasodilation. Neither saline nor PD-123319 significantly affected these variables. Concomitant PD-123319 administration partially reversed the depressor and mesenteric vasodilator effects of candesartan in sham-operated normotensive rats but not in SHR or 2K1C rats. These data indicate that the AT2 receptor contributes to the blood pressure-lowering and mesenteric vasodilator effects of AT1 receptor blockade in the acute setting in conscious normotensive but not hypertensive rats.
12
Lambers, Donna S., Suzanne G. Greenberg, and Kenneth E. Clark. "Functional role of angiotensin II type 1 and 2 receptors in regulation of uterine blood flow in nonpregnant sheep." American Journal of Physiology-Heart and Circulatory Physiology 278, no. 2 (February 1, 2000): H353—H359. http://dx.doi.org/10.1152/ajpheart.2000.278.2.h353.
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The objective was to determine the receptor subtype of angiotensin II (ANG II) that is responsible for vasoconstriction in the nonpregnant ovine uterine and systemic vasculatures. Seven nonpregnant estrogenized ewes with indwelling uterine artery catheters and flow probes received bolus injections (0.1, 0.3 and 1 μg) of ANG II locally into the uterine artery followed by a systemic infusion of ANG II at 100 ng ⋅ kg−1 ⋅ min−1for 10 min to determine uterine vasoconstrictor responses. Uterine ANG II dose-response curves were repeated following administration of the ANG II type 2 receptor (AT2) antagonist PD-123319 and then repeated again in the presence of an ANG II type 1 receptor (AT1) antagonist L-158809. In a second experiment, designed to investigate the mechanism of ANG II potentiation that occurred in the presence of AT2 blockade, nonestrogenized sheep received a uterine artery infusion of L-158809 (3 mg/min for 5 min) prior to the infusion of 0.03 μg/min of ANG II for 10 min. ANG II produced dose-dependent decreases in uterine blood flow ( P < 0.03), which were potentiated in the presence of the AT2 antagonist ( P < 0.02). Addition of the AT1 antagonist abolished the uterine vascular responses and blocked ANG II-induced increases in systemic arterial pressure ( P < 0.01). Significant uterine vasodilation ( P < 0.01) was noted with AT1 blockade in the second experiment, which was reversed by administration of the AT2 antagonist or by the nitric oxide synthetase inhibitor N ω-nitro-l-arginine methyl ester. We conclude that the AT1- receptors mediate the systemic and uterine vasoconstrictor responses to ANG II in the nonpregnant ewe. AT2-receptor blockade resulted in a potentiation of the uterine vasoconstrictor response to ANG II, suggesting that the AT2-receptor subtype may modulate uterine vascular responses to ANG II potentially by release of nitric oxide.
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Friederich-Persson, Malou, and Patrik Persson. "Mitochondrial angiotensin II receptors regulate oxygen consumption in kidney mitochondria from healthy and type 1 diabetic rats." American Journal of Physiology-Renal Physiology 318, no. 3 (March 1, 2020): F683—F688. http://dx.doi.org/10.1152/ajprenal.00417.2019.
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Exaggerated activation of the renin-angiotensin-aldosterone system (RAAS) is a key feature in diseases such as hypertension, diabetes, and chronic kidney disease. Recently, an intracellular RAAS was demonstrated with angiotensin II (ANG II) type 1 (AT1) and type 2 (AT2) receptors expressed in nuclei and mitochondria. Diabetes is associated with both mitochondrial dysfunction and increased intracellular ANG II concentration in the kidney cortex. The present study investigated the role of ANG II signaling in kidney cortex mitochondria isolated from control and streptozotocin-induced diabetic rats. Mitochondrial oxygen consumption was evaluated after addition of ANG II alone or after preincubation with candesartan (AT1 receptor antagonist), PD-123319 (AT2 receptor antagonist), or the two in combination. ANG II binds to only mitochondrial AT2 receptors in control rats and both AT1 receptors and AT2 receptors in diabetic rats. ANG II decreased oxygen consumption in mitochondria from both control and diabetic rats. ANG II response was reversed to increased oxygen consumption by the nitric oxide synthase inhibitor N-nitro-l-arginine methyl ester. AT1 receptor inhibition did not affect the response to ANG II, whereas AT2 receptor inhibition abolished the response in mitochondria from control rats and reversed the response to increased oxygen consumption through superoxide-induced mitochondrial uncoupling in mitochondria from diabetic rats. ANG II decrease mitochondrial respiration via AT2 receptor-mediated nitric oxide release in both control and diabetic rats. AT1 receptors do not regulate mitochondria function in control rats, whereas ANG II via AT1 receptors increase mitochondria leak respiration in diabetic animals.
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Gwathmey, TanYa M., Hossam A. Shaltout, Karl D. Pendergrass, Nancy T. Pirro, Jorge P. Figueroa, James C. Rose, Debra I. Diz, and Mark C. Chappell. "Nuclear angiotensin II type 2 (AT2) receptors are functionally linked to nitric oxide production." American Journal of Physiology-Renal Physiology 296, no. 6 (June 2009): F1484—F1493. http://dx.doi.org/10.1152/ajprenal.90766.2008.
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Expression of nuclear angiotensin II type 1 (AT1) receptors in rat kidney provides further support for the concept of an intracellular renin-angiotensin system. Thus we examined the cellular distribution of renal ANG II receptors in sheep to determine the existence and functional roles of intracellular ANG receptors in higher order species. Receptor binding was performed using the nonselective ANG II antagonist 125I-[Sar1,Thr8]-ANG II (125I-sarthran) with the AT1 antagonist losartan (LOS) or the AT2 antagonist PD123319 (PD) in isolated nuclei (NUC) and plasma membrane (PM) fractions obtained by differential centrifugation or density gradient separation. In both fetal and adult sheep kidney, PD competed for the majority of cortical NUC (≥70%) and PM (≥80%) sites while LOS competition predominated in medullary NUC (≥75%) and PM (≥70%). Immunodetection with an AT2 antibody revealed a single ∼42-kDa band in both NUC and PM extracts, suggesting a mature molecular form of the NUC receptor. Autoradiography for receptor subtypes localized AT2 in the tubulointerstitium, AT1 in the medulla and vasa recta, and both AT1 and AT2 in glomeruli. Loading of NUC with the fluorescent nitric oxide (NO) detector DAF showed increased NO production with ANG II (1 nM), which was abolished by PD and N-nitro-l-arginine methyl ester, but not LOS. Our studies demonstrate ANG II receptor subtypes are differentially expressed in ovine kidney, while nuclear AT2 receptors are functionally linked to NO production. These findings provide further evidence of a functional intracellular renin-angiotensin system within the kidney, which may represent a therapeutic target for the regulation of blood pressure.
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Morrissey, Jeremiah J., and Saulo Klahr. "Effect of AT2 receptor blockade on the pathogenesis of renal fibrosis." American Journal of Physiology-Renal Physiology 276, no. 1 (January 1, 1999): F39—F45. http://dx.doi.org/10.1152/ajprenal.1999.276.1.f39.
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Cellular and molecular events contributing to tubulointerstitial fibrosis of the kidney during obstructive nephropathy are driven in large part through increased angiotensin II levels in the obstructed kidney. Angiotensin converting enzyme inhibition or AT1 receptor antagonism have been shown to ameliorate the fibrosis of the kidney due to obstruction of the ureter. In this investigation, we determine the effects of the AT2 receptor antagonist PD-123319 on pathophysiological events within the kidneys of rats with unilateral ureteral obstruction. Treatment with PD-123319 was found to exacerbate the increase in interstitial volume and collagen IV matrix score of the ureteral obstructed kidney. Monocyte/macrophage infiltration of the injured kidney was no different between treated and untreated animals. The AT2 receptor antagonist did, however, inhibit apoptosis of tubular cells, α-smooth muscle actin expression within the interstitium, and p53 expression in the ureteral obstructed kidney. These results suggest that angiotensin II operating through the AT2 receptor exerts an antifibrotic effect on the kidney during obstructive nephropathy in opposition to the profibrotic effects of angiotensin II operating through the AT1 receptor.
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Zhu, Liping, Oscar A. Carretero, Jiang Xu, Pamela Harding, Nithya Ramadurai, Xiaosong Gu, Edward Peterson, and Xiao-Ping Yang. "Activation of angiotensin II type 2 receptor suppresses TNF-α-induced ICAM-1 via NF-кB: possible role of ACE2." American Journal of Physiology-Heart and Circulatory Physiology 309, no. 5 (September 2015): H827—H834. http://dx.doi.org/10.1152/ajpheart.00814.2014.
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ANG II type 2 receptor (AT2) and ANG I-converting enzyme 2 (ACE2) are important components of the renin-ANG system. Activation of AT2 and ACE2 reportedly counteracts proinflammatory effects of ANG II. However, the possible interaction between AT2 and ACE2 has never been established. We hypothesized that activation of AT2 increases ACE2 activity, thereby preventing TNF-α-stimulated ICAM-1 expression via inhibition of NF-κB signaling. Human coronary artery endothelial cells were pretreated with AT2 antagonist PD123319 (PD) or ACE2 inhibitor DX600 and then stimulated with TNF-α in the presence or absence of AT2 agonist CGP42112 (CGP). We found that AT2 agonist CGP increased both ACE2 protein expression and activity. This effect was blunted by AT2 antagonist PD. ICAM-1 expression was very low in untreated cells but greatly increased by TNF-α. Activation of AT2 with agonist CGP or with ANG II under concomitant AT1 antagonist reduced TNF-α-induced ICAM-1 expression, which was reversed by AT2 antagonist PD or ACE2 inhibitor DX600 or knockdown of ACE2 with small interfering RNA. AT2 activation also suppressed TNF-α-stimulated phosphorylation of inhibitory κB (p-IκB) and NF-κB activity. Inhibition of ACE2 reversed the inhibitory effect of AT2 on TNF-α-stimulated p-IκB and NF-κB activity. Our findings suggest that stimulation of AT2 reduces TNF-α-stimulated ICAM-1 expression, which is partly through ACE2-mediated inhibition of NF-κB signaling.
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Zimpelmann, Joseph, and Kevin D. Burns. "Angiotensin II AT2 receptors inhibit growth responses in proximal tubule cells." American Journal of Physiology-Renal Physiology 281, no. 2 (August 1, 2001): F300—F308. http://dx.doi.org/10.1152/ajprenal.2001.281.2.f300.
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Angiotensin II (ANG II) subtype 2 (AT2) receptors are expressed in the adult kidney, but the effects of AT2 receptor activation are unclear. The proximal tubule cell line LLC-PK1 was transfected with a plasmid containing cDNA for the rat AT2 receptor. In transfected cells, specific binding of 125I-labeled ANG II was detected (dissociation constant = 0.81 nM), with inhibition by the AT2 antagonist PD-123319, and no effect of the AT1 antagonist losartan. ANG II (10−7 M) significantly inhibited mitogen-activated protein kinase (MAPK) activity in transfected cells, associated with decreased phosphorylation of the extracellular signal-related kinases ERK1 and ERK2. ANG II stimulated phosphotyrosine phosphatase activity within 5 min, an effect blocked by PD-123319 and the phosphatase inhibitor vanadate. In transfected cells, ANG II inhibited epidermal growth factor-stimulated [3H]thymidine incorporation, an effect reversed by vanadate. In contrast, vanadate did not block ANG II-stimulated apoptosis of transfected cells. In summary, AT2 receptors in proximal tubule cells inhibit MAPK activity and stimulate phosphotyrosine phosphatase. AT2receptor-induced inhibition of mitogenesis is mediated by phosphatase activation, whereas effects on apoptosis are insensitive to phosphatase inhibition. The data suggest that AT2 receptors inhibit cell growth via distinct signaling pathways in the proximal tubule.
18
Rodrigues-Ferreira, Sylvie, Marina Morel, Rosana I. Reis, Françoise Cormier, Véronique Baud, Claudio M. Costa-Neto, and Clara Nahmias. "A Novel Cellular Model to Study Angiotensin II AT2 Receptor Function in Breast Cancer Cells." International Journal of Peptides 2012 (December 6, 2012): 1–6. http://dx.doi.org/10.1155/2012/745027.
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Recent studies have highlighted the AT1 receptor as a potential therapeutic target in breast cancer, while the role of the AT2 subtype in this disease has remained largely neglected. The present study describes the generation and characterization of a new cellular model of human invasive breast cancer cells (D3H2LN-AT2) stably expressing high levels of Flag-tagged human AT2 receptor (Flag-hAT2). These cells exhibit high-affinity binding sites for AngII, and total binding can be displaced by the AT2-selective antagonist PD123319 but not by the AT1-selective antagonist losartan. Of interest, high levels of expression of luciferase and green fluorescent protein make these cells suitable for bioluminescence and fluorescence studies in vitro and in vivo. We provide here a novel tool to investigate the AT2 receptor functions in breast cancer cells, independently of AT1 receptor activation.
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Cook, M. D., M. I. Phillips, V. I. Cook, B. Kimura, and C. S. Wilcox. "Angiotensin II receptor subtypes on adrenal adenoma in primary hyperaldosteronism." Journal of the American Society of Nephrology 4, no. 1 (July 1993): 111–16. http://dx.doi.org/10.1681/asn.v41111.
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Patients with an aldosterone-producing adenoma (APA) characteristically fail to show an increase in plasma aldosterone (PA) concentration with maneuvers that increase angiotensin II (Ang II), yet they retain a brisk response of PA to adrenocorticotrophic hormone. Therefore, adrenal Ang II receptor binding was characterized in a patient with APA who had a blocked PA response to Ang II infusion before adrenalectomy. The binding of [125I]Sar1,IIe5-Ang II in adrenal gland and tumor was fully displaced by excess Ang II. In the tumor, 98% of [125I]Sar1,IIe5-Ang II binding was displaced by the AT, receptor antagonist losartan, yet only 5% was displaced by the AT2 receptor antagonist PD-123,319. Autoradiography of the adrenal gland itself showed a predominance of AT1 receptors in the cortex and AT2 receptors in the medulla. The tumor showed a predominance of AT1 receptors, but there was some evidence of a limited population of AT2 receptors. The tumor and adjacent adrenal contained high concentrations of Ang II. In conclusion, a defect in Ang II-stimulated aldosterone secretion in APA occurs despite high concentrations of Ang II in the adrenal and the presence of specific, high-affinity Ang II receptor binding sites.
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Lucius, Ralph, Stefan Gallinat, Philip Rosenstiel, Thomas Herdegen, Jobst Sievers, and Thomas Unger. "The Angiotensin II Type 2 (AT2) Receptor Promotes Axonal Regeneration in the Optic Nerve of Adult Rats." Journal of Experimental Medicine 188, no. 4 (August 17, 1998): 661–70. http://dx.doi.org/10.1084/jem.188.4.661.
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The renin-angiotensin system (RAS) has been traditionally linked to blood pressure and volume regulation mediated through the angiotensin II (ANG II) type 1 (AT1) receptor. Here we report that ANG II via its ANG II type 2 (AT2) receptor promotes the axonal elongation of postnatal rat retinal explants (postnatal day 11) and dorsal root ganglia neurons in vitro, and, moreover, axonal regeneration of retinal ganglion cells after optic nerve crush in vivo. In retinal explants, ANG II (10−7–10−5 M) induced neurite elongation via its AT2 receptor, since the effects were mimicked by the AT2 receptor agonist CGP 42112 (10−5 M) and were entirely abolished by costimulation with the AT2 receptor antagonist PD 123177 (10−5 M), but not by the AT1 receptor antagonist losartan (10−5 M). To investigate whether ANG II is able to promote axonal regeneration in vivo, we performed optic nerve crush experiments in the adult rats. After ANG II treatment (0.6 nmol), an increased number of growth-associated protein (GAP)-43–positive fibers was detected and the regenerating fibers regularly crossed the lesion site (1.6 mm). Cotreatment with the AT2 receptor antagonist PD 123177 (6 nmol), but not with the AT1 receptor antagonist losartan (6 nmol), completely abolished the ANG II–induced axonal regeneration, providing for the first time direct evidence for receptor-specific neurotrophic action of ANG II in the central nervous system of adult mammals and revealing a hitherto unknown function of the RAS.
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Ytterberg, Hoa, and Lars Edvinsson. "Characterisation of angiotensin II receptors in isolated human subcutaneous resistance arteries." Journal of the Renin-Angiotensin-Aldosterone System 2, no. 1_suppl (March 2001): S37—S41. http://dx.doi.org/10.1177/14703203010020010601.
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Subcutaneous arteries have been used as a model for resistance arteries, which are potentially involved in enhanced blood pressure (BP) regulation in man. Angiotensin II (Ang II) is an important regulator of tone, acting via type 1 (AT1-) and type 2 (AT2-) receptor subtypes. The aim of this study was to characterise the Ang II receptors in isolated human subcutaneous arteries, using pharmacological and molecular methods. Subcutaneous arteries were obtained from patients undergoing elective gut surgery and were carefully dissected from the abdominal wall. Cylindrical segments were mounted on two L-shaped metal prongs, one of which was connected to a force-displacement transducer for continuous recording of isometric tension. Concentration-response curves to Ang II were constructed in the presence and absence of various selective AT1-receptor antagonists, candesartan, EXP3174, irbesartan and losartan, and the AT2-receptor antagonist, PD 123319. Responses to Ang II were measured as increases in force (mN) and expressed as a percentage of the response to 60 mM of KCl. Ang II caused a concentration-dependent contraction (pEC50=9.45±0.48, Emax=120±13%). Candesartan and EXP3174 caused concentration-dependent depression of the Emax of Ang II without any major shift of pEC50. Losartan and irbesartan caused a significant, dose-dependent rightward shift of the Ang II contraction-response curve in human subcutaneous arteries. The results show that contractile responses of human subcutaneous arteries are mediated via the AT1-receptor. The AT1-receptor antagonists, candesartan and EXP3174, acted in an insurmountable manner, while losartan and irbesartan were surmountable AT1-receptor antagonists. The AT2-receptor antagonist, PD 123319, (10, 100 nM) had no effect on Ang II-induced contraction. This is supported by the positive identification of mRNA for the human AT 1-receptor by RT-PCR.
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Tatarciuc, Diana, Decebal Vasincu, Gabriela Stoleriu, Roxana Irina Iancu, and Marcel Costuleanu. "Biochemical Effects of Intraliposomal Angiotensins on Isolated Vascular Smooth Muscle Cells." Revista de Chimie 69, no. 5 (June 15, 2018): 1187–90. http://dx.doi.org/10.37358/rc.18.5.6285.
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The intracellular renin-angiotensin effectors (peptides, enzymes, receptors) and their effects are intriguing for a lot of systems. That�s why we aimed the effects of intracellularly-administered angiotensins (angiotensin II, angiotensin III, angiotensin IV, angiotensin fragment 1-7), angiotensinogen, CGP-42112A, apelin, and angiotensin receptors blockers (losartan, PD123319), by the means of liposomes, on apoptosis of cultured isolated rat aortic vascular smooth muscle cells. We evidenced that CGP-42112A (a potent AT2 angiotensin II receptor agonist), administered intracellularly, induced the apoptosis of the cultured isolated vascular smooth muscle cells in a much higher proportion than other agonists and antagonists of angiotensin system: CGP-42112A ] angiotensin II] angiotensin III@ angiotensinogen. Moreover, losartan (an AT1 angiotensin II receptor antagonist), administered intracellularly, induced an important degree of apoptosis of cultured isolated vascular smooth muscle cells. Losartan, administered as concomitant treatment for other angiotensin peptides and CGP-42112A, did not significantly modified the apoptotic effects of these peptides. On the other hand, PD123319 (an AT2 angiotensin II receptor antagonist) was able to significantly reduce the losartan effects when administered as co-treatment for 24 h. The same effects were obtained when LY294002, a PI3K/Akt signaling inhibitor, was administered as a co-treatment. We can conclude an involvement of an AT2 angiotensin II receptor and PI3K/Akt signaling in these apoptotic effects induced by some angiotensin peptides and losartan on cultured isolated rat aortic vascular smooth muscle cells.
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Nostramo, Regina, Andrej Tillinger, Juan M. Saavedra, Ashok Kumar, Varunkumar Pandey, Lidia Serova, Richard Kvetnansky, and Esther L. Sabban. "Regulation of angiotensin II type 2 receptor gene expression in the adrenal medulla by acute and repeated immobilization stress." Journal of Endocrinology 215, no. 2 (August 21, 2012): 291–301. http://dx.doi.org/10.1530/joe-12-0181.
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While the renin–angiotensin system is important for adrenomedullary responses to stress, the involvement of specific angiotensin II (Ang II) receptor subtypes is unclear. We examined gene expression changes of angiotensin II type 1A (AT1A) and type 2 (AT2) receptors in rat adrenal medulla in response to immobilization stress (IMO). AT2 receptor mRNA levels decreased immediately after a single 2-h IMO. Repeated IMO also decreased AT2 receptor mRNA levels, but the decline was more transient. AT1A receptor mRNA levels were unaltered with either single or repeated IMO, although binding was increased following repeated IMO. These effects of stress on Ang II receptor expression may alter catecholamine biosynthesis, as tyrosine hydroxylase and dopamine β-hydroxylase mRNA levels in PC12 cells are decreased with Ang II treatment in the presence of ZD7155 (AT1 receptor antagonist) or with CGP42112 (AT2 receptor agonist) treatment. Involvement of stress-triggered activation of the hypothalamic–pituitary–adrenocortical or sympathoadrenal axis in AT2 receptor downregulation was examined. Cultured cells treated with the synthetic glucocorticoid dexamethasone displayed a transcriptionally mediated decrease in AT2 receptor mRNA levels. However, glucocorticoids are not required for the immediate stress-triggered decrease in AT2 receptor gene expression, as demonstrated in corticotropin-releasing hormone knockout (Crh KO) mice and hypophysectomized rats, although they can regulate basal gene expression. cAMP and pituitary adenylate cyclase-activating polypeptide also reduced AT2 receptor gene expression and may mediate this response. Overall, the effects of stress on adrenomedullary AT1A and AT2 receptor expression may contribute to allostatic changes, such as regulation of catecholamine biosynthesis.
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Gibson, R. E., H. H. Thorpe, M. E. Cartwright, J. D. Frank, T. W. Schorn, P. B. Bunting, and P. K. Siegl. "Angiotensin II receptor subtypes in renal cortex of rats and rhesus monkeys." American Journal of Physiology-Renal Physiology 261, no. 3 (September 1, 1991): F512—F518. http://dx.doi.org/10.1152/ajprenal.1991.261.3.f512.
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The angiotensin II (ANG II) receptor has recently been shown to exhibit subtypes with respect to antagonist binding. Of particular interest are the potent nonpeptide antagonists, DUP 753 and PD 121981, which exhibit selectivity for the subtype 1 (AT1) and subtype 2 (AT2) receptors, respectively. We used these high-affinity antagonists in competition with 125I-[Sar1,Ile8]ANG II to determine autoradiographically the distribution of these ANG II-receptor subtypes in the renal cortex of rats and rhesus monkeys. Binding of the radioligand to receptor in sections of rat renal cortex was inhibited by DUP 753; inhibition by PD 121981 was not detected. By contrast, AT1 and AT2 receptors are present in the renal cortex of rhesus monkeys in regionally distinct structures. DUP 753 inhibited binding to the ANG II receptor in glomeruli. PD 121981 inhibited binding to arterial smooth muscle and the juxtaglomerular (JG) apparatus. The JG apparatus also exhibits radioligand binding, which is inhibited by DUP 753. The effect of DUP 753 and PD 123177 (a more water-soluble analogue of PD 121981) on changes in plasma renin activity was examined to determine if one or both of these subtypes participate in the ANG II-mediated negative feedback of control of renin release. Although DUP 753 increased plasma renin activity to the same extent as the angiotensin-converting enzyme inhibitor, enalaprilat, in rats and rhesus monkeys, the AT2 antagonists did not affect renin release in either species. Thus both subtypes of ANG II receptor are present in rhesus monkey cortex, but a function for only the AT1 subtype was demonstrated.
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Ernsberger, P., J. Zhou, T. H. Damon, and J. G. Douglas. "Angiotensin II receptor subtypes in cultured rat renal mesangial cells." American Journal of Physiology-Renal Physiology 263, no. 3 (September 1, 1992): F411—F416. http://dx.doi.org/10.1152/ajprenal.1992.263.3.f411.
Full textAbstract:
The selective angiotensin (ANG II) antagonists losartan (DuP 753) and PD 123319 have been shown to bind selectively to AT1 and AT2 subtypes, respectively. To characterize ANG II receptor subtypes in mesangial cells, washed membranes were incubated with 0.1 to 0.5 nM 125I-ANG II and increasing concentrations of competitors. The inhibition of 125I-ANG II binding by losartan and PD 123319 was biphasic, and LIGAND curve-fitting analysis revealed two populations of specific binding sites. One subpopulation comprised 86% of the total and showed high affinity for ANG II and losartan, but low affinity for the AT2 antagonists PD 123319 and CGP42112A, and thus appear identical to the recently cloned AT1 subtype. The remaining 14% of the sites showed nearly 100-fold lower affinity for losartan and 10,000-fold higher affinity for PD 123319 relative to AT1 sites. However, another AT2-selective antagonist, CGP42112A, showed little affinity for these sites. Both classes of binding sites were inhibited by guanosine 5'-O-(3-thiophosphate) and pertussis toxin treatment. We propose that there are two distinct G protein-coupled ANG II receptor subtypes (AT1A and AT1B) present in renal mesangial cells.
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Champion, Hunter C., Marc A. Czapla, and Philip J. Kadowitz. "Responses to angiotensin peptides are mediated by AT1 receptors in the rat." American Journal of Physiology-Endocrinology and Metabolism 274, no. 1 (January 1, 1998): E115—E123. http://dx.doi.org/10.1152/ajpendo.1998.274.1.e115.
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The effects of the angiotensin AT1 and AT2 receptor antagonists candesartan and PD-123,319 on hemodynamic responses to angiotensin peptides were investigated in the anesthetized rat. Injections of angiotensin II and III caused dose-related increases in systemic arterial and in hindquarters perfusion pressure that were reduced in an insurmountable manner by candesartan. Pressor responses to angiotensin IV were also attenuated, and a vasodepressor or vasodilator response to the angiotensin peptides was not unmasked by the AT1 receptor antagonists candesartan or losartan. The AT2receptor antagonist PD-123,319 had no significant effect on increases in systemic arterial and hindquarters perfusion pressure in response to the angiotensin peptides. Pressor responses to angiotensin peptides were not altered by adrenergic nerve terminal and α-receptor blocking agents or by the cyclooxygenase inhibitor sodium meclofenamate but were increased by an inhibitor of nitric oxide synthase. The present results suggest that pressor responses to the angiotensin peptides are mediated by the activation of AT1 receptors and that AT2 receptors, the adrenergic system, or cyclooxygenase products do not appear to modulate hemodynamic responses to the angiotensin peptides in the anesthetized rat.
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Nahmias, C., S. M. Cazaubon, M. M. Briend-Sutren, D. Lazard, P. Villageois, and A. D. Strosberg. "Angiotensin II AT2 receptors are functionally coupled to protein tyrosine dephosphorylation in N1E-115 neuroblastoma cells." Biochemical Journal 306, no. 1 (February 15, 1995): 87–92. http://dx.doi.org/10.1042/bj3060087.
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Murine N1E-115 neuroblastoma cells are shown to express a single class of angiotensin II (Ang II) receptors that display all the pharmacological properties defining the Ang II receptor subtype 2 (AT2): high affinity for 125I-labelled AT2-selective agonist CGP 42112 (Kd 91 +/- 19 pM); expected rank order of potency (CGP 42112 = (Sar1,Ile8)Ang II > or = Ang II > PD 123319 >> DUP 753) for several Ang II analogues; increased binding in the presence of the reducing reagent dithiothreitol (DTT); and insensitivity to analogues of GTP. Molecular cloning of cDNA encoding AT2 receptors from N1E-115 cells reveals nucleotide sequence identity with the AT2 subtype expressed in fetal tissue. Murine AT2 receptors transiently expressed in COS cells display the same pharmacological profile as endogenous Ang II receptors of N1E-115 cells. Taken together, these data reveal the exclusive presence of the AT2 receptor subtype in N1E-115 cells. Incubation of N1E-115 cells with Ang II leads to a marked decrease in the level of tyrosine phosphorylation of several proteins with apparent molecular masses of 80, 97, 120, 150 and 180 kDa respectively. Tyrosine dephosphorylation of the same set of proteins is observed after treatment with the AT2-specific agonist CGP 42112. The response to both effectors is rapid and transient, showing a maximum between 5 and 10 min, and returning to basal levels after 20-30 min. In both cases, tyrosine dephosphorylation can be prevented by co-incubation with an excess of the antagonist Sarile. These data thus establish that AT2 receptor activation leads to protein tyrosine dephosphorylation in N1E-115 cells, and support a possible role for AT2 receptors in the negative regulation of cell proliferation.
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Montiel, M., S. Barker, G. P. Vinson, and E. Jiménez. "Angiotensin II receptor isoforms in the rat adrenal gland: studies with the selective subtype antagonists DuP 753 and CGP42112A." Journal of Molecular Endocrinology 11, no. 1 (August 1993): 69–75. http://dx.doi.org/10.1677/jme.0.0110069.
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ABSTRACT The angiotensin II (Ang II)-binding sites in rat adrenal gland membranes were characterized using 125I-radiolabelled Ang II. While Scatchard analysis identified a single population of Ang II receptor sites, isoelectric focusing (IEF) on polyacrylamide gels revealed four peaks of specific Ang II binding which migrated to isoelectric points (pI values) 6·8, 6·7, 6·5 and 6·3. In binding assays in the presence of an excess of the Ang II receptor AT1 subtype antagonist DuP 753, a monophasic dose-dependent displacement of 125I-labelled Ang II binding by the Ang II receptor AT2 subtype antagonist CGP42112A was observed, and vice versa. In this system, reduction of disulphide bridges using 1 mmol dithiothreitol (DTT)/l markedly increased the number of binding sites in the adrenal zona glomerulosa without affecting receptor affinity. Using IEF, it was found that both DuP 753 and CGP42112A were able to reduce specific binding of each of the four peaks to some extent. However, the predominant effect of DuP 753 was to reduce the labelling of the isoform at pI 6·7 substantially, while CGP42112A significantly inhibited the specific 125I-labelled Ang II binding to the pI 6·3 isoform. When DuP 753 and CGP42112A were used together, specific binding of 125I-labelled Ang II to the isoforms of pI values 6·8, 6·7 and 6·3 was completely eliminated. These data suggest that the four peaks of specific binding found may be composed of different isoforms of both AT1 and AT2 receptor subtypes and that the Ang II receptor isoforms which migrated to pI 6·7 and pI 6·3 are predominantly composed of AT1 and AT2 receptor subtypes respectively. Interestingly, in the presence of both antagonists, 8·7 ± 0·9% of the specific binding migrating at pI 6·5 remained unaffected. This finding suggests the presence of an additional subtype, which is neither AT1 nor AT2, in the rat adrenal zona glomerulosa. In further studies, pretreatment with DTT was found to increase the specific 125I-labelled Ang II binding of all four isoforms. Moreover, DTT also produced a further specific binding component between pI 6·5 and pI 6·7 which exhibited AT2 subtype pharmacology in DTT-treated preparations. Since DTT has been reported to enhance only AT2 subtype binding this also suggests that the different isoforms may contain components related to both AT1 and AT2 receptor subtypes.
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Souza, Álvaro P. S., Deny B. S. Sobrinho, Jônathas F. Q. Almeida, Gisele M. M. Alves, Larissa M. Macedo, Juliana E. Porto, Eneida F. Vêncio, et al. "Angiotensin II type 1 receptor blockade restores angiotensin-(1–7)-induced coronary vasodilation in hypertrophic rat hearts." Clinical Science 125, no. 9 (July 8, 2013): 449–59. http://dx.doi.org/10.1042/cs20120519.
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The aim of the present study was to investigate the coronary effects of Ang-(1–7) [angiotensin-(1–7)] in hypertrophic rat hearts. Heart hypertrophy was induced by abdominal aorta CoA (coarctation). Ang-(1–7) and AVE 0991, a non-peptide Mas-receptor agonist, at picomolar concentration, induced a significant vasodilation in hearts from sham-operated rats. These effects were blocked by the Mas receptor antagonist A-779. Pre-treatment with L-NAME (NG-nitro-L-arginine methyl ester) or ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinozalin-1-one) [NOS (NO synthase) and soluble guanylate cyclase inhibitors respectively] also abolished the effect of Ang-(1–7) in control hearts. The coronary vasodilation produced by Ang-(1–7) and AVE 0991 was completely blunted in hypertrophic hearts. Chronic oral administration of losartan in CoA rats restored the coronary vasodilation effect of Ang-(1–7). This effect was blocked by A-779 and AT2 receptor (angiotensin II type 2 receptor) antagonist PD123319. Acute pre-incubation with losartan also restored the Ang-(1–7)-induced, but not BK (bradykinin)-induced, coronary vasodilation in hypertrophic hearts. This effect was inhibited by A-779, PD123319 and L-NAME. Chronic treatment with losartan did not change the protein expression of Mas and AT2 receptor and ACE (angiotensin-converting enzyme) and ACE2 in coronary arteries from CoA rats, but induced a slight increase in AT2 receptor in aorta of these animals. Ang-(1–7)-induced relaxation in aortas from sham-operated rats was absent in aortas from CoA rats. In vitro pre-treatment with losartan restored the Ang-(1–7)-induced relaxation in aortic rings of CoA rats, which was blocked by the Mas antagonist A-779 and L-NAME. These data demonstrate that Mas is strongly involved in coronary vasodilation and that AT1 receptor (angiotensin II type 1 receptor) blockade potentiates the vasodilatory effects of Ang-(1–7) in the coronary beds of pressure-overloaded rat hearts through NO-related AT2- and Mas-receptor-dependent mechanisms. These data suggest the association of Ang-(1–7) and AT1 receptor antagonists as a potential therapeutic avenue for coronary artery diseases.
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Jacques, Danielle, Nelly A. Abdel Malak, Sawsan Sader, and Claudine Perreault. "Angiotensin II and its receptors in human endocardial endothelial cells: role in modulating intracellular calcium." Canadian Journal of Physiology and Pharmacology 81, no. 3 (March 1, 2003): 259–66. http://dx.doi.org/10.1139/y03-046.
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he aims of the present study are to investigate the presence and distribution of angiotensin II (Ang II), as well as AT1 and AT2 receptors, in endocardial endothelial cells (EECs) and to determine if the effect of Ang II on intracellular calcium in these cells is mediated via the AT1 or the AT2 receptor. Immunofluorescence and 3D confocal microscopy techniques were used on 20-week-old fetal human EECs. Our results showed that Ang II and its receptors, the AT1 and the AT2 types, are present and exhibit a different distribution in human EECs. Ang II labelling is found throughout the cell with a fluorescence signal higher in the cytosol when compared with the nucleus. Like Ang II, the AT1 receptor fluorescence signal is also homogeneously distributed in human EECs but with a preferential labelling at the level of the nucleus, while the AT2 receptor labelling is solely present in the nucleus. Using fluo-3 and 3D confocal microscopy technique, superfusion of human EECs with increasing concentration of Ang II induced a dose-dependent sustained increase in free cytosolic and nuclear Ca2+ levels. This effect of Ang II on human EEC's intra cellular Ca2+ ([Ca2+]i) was completely prevented by losartan, an AT1 receptor antagonist. Our results suggest that Ang II, as well as AT1 and AT2 receptors, is present but differentially distributed in EECs of 20-week-old fetal human hearts, and that the AT1 receptor mediates the effects of Ang II on [Ca2+]i in these cells.Key words: angiotensin II, nuclear receptors, endocardial endothelial cells, Ang II receptors, intracellular calcium.
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Messerli, Franz H., and Simbo M. Chiadika. "Stroke Prevention: Not all Antihypertensive Drugs are Created Equal." Journal of the Renin-Angiotensin-Aldosterone System 6, no. 1_suppl (March 2005): S4—S7. http://dx.doi.org/10.1177/14703203050060010201.
Full textAbstract:
Reductions in blood pressure (BP) through intervention can significantly reduce the risk of cardiovascular events in hypertensive patients. However, a number of trials indicate that beta-blockers, despite lowering BP, do not reduce the risk of stroke. A recent meta-analysis suggested that, over and beyond BP reduction, angiotensin-converting enzyme (ACE) inhibitors appear superior to calcium channel blockers for prevention of coronary heart disease whereas calcium channel blockers appear superior to ACE inhibitors for prevention of stroke. Indeed, in the Syst-EUR study a 42% reduction in strokes was achieved in the calcium antagonist arm when compared to the placebo arm.It is hypothesised that antihypertensive agents that stimulate the AT2-receptor (thiazide diuretics, dihydropyridine calcium antagonists and angiotensin receptor blockers) are more cerebroprotective than drug classes that do not stimulate the AT2-receptor (beta-blockers and ACE inhibitors).The angiotensin receptor blockers are the only drug class that have a dual mechanism of action that could be helpful in preventing strokes in that they not only inhibit the AT1-receptor but also allow stimulation of the AT2-receptor. Not surprisingly therefore, in trials such as LIFE, VALUE and MOSES, angiotensin receptor blockers showed excellent cerebroprotection.
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Helou, Claudia M. B., Martine Imbert-Teboul, Alain Doucet, Rabary Rajerison, Catherine Chollet, François Alhenc-Gelas, and Jeannine Marchetti. "Angiotensin receptor subtypes in thin and muscular juxtamedullary efferent arterioles of rat kidney." American Journal of Physiology-Renal Physiology 285, no. 3 (September 2003): F507—F514. http://dx.doi.org/10.1152/ajprenal.00430.2002.
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ANG II controls the vascular tone of pre- and postglomerular arterioles, and thereby glomerular filtration, through binding to either AT1A, AT1B, or AT2 receptors. AT1 receptors, which are coupled to intracellular Ca2+ signaling, have vasoconstricting effects, whereas AT2 receptors, whose signaling mechanism is unknown, induce vasodilatation. The angiotensin receptors have been characterized in afferent arterioles, which express the three types of receptors, but not in efferent arterioles. Two subpopulations of juxtamedullary efferent arterioles, muscular ones which terminate as vasa rectae and thin ones which terminate as peritubular capillaries, have been described. They display functional heterogeneity with regard to the ANG II response. To evaluate whether these differences are associated with differential expression of ANG II receptors, we examined the expression pattern of AT1A, AT1B, and AT2 receptor mRNAs by RT-PCR in these arterioles and studied the effect of valsartan, a specific AT1-receptor antagonist. Results indicate that muscular arterioles express AT1A, AT1B, and AT2 receptors, whereas thin arterioles only express the AT1A and AT2 types, and at a much lower level. Valsartan fully inhibited ANG II-induced increases in intracellular Ca2+ in both arteriolar types, but with different kinetics. In muscular arterioles, inhibition was monoexponential, whereas it displayed a marked positive cooperativity in thin arterioles. Finally, the apparent affinity for valsartan was higher in muscular than in thin arterioles. In conclusion, this study further documents the differences between muscular and thin efferent arterioles with regard to ANG II signalization in the rat kidney.
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Blume, Annegret, Christian Undeutsch, Yi Zhao, Elena Kaschina, Juraj Culman, and Thomas Unger. "ANG III induces expression of inducible transcription factors of AP-1 and Krox families in rat brain." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 289, no. 3 (September 2005): R845—R850. http://dx.doi.org/10.1152/ajpregu.00672.2004.
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In addition to rapid responses comprising increases in blood pressure, drinking, and stimulation of natriuresis, ANG II induces the expression of transcription factors (TF) in the central nervous system. The ANG II metabolite ANG III (ANG 2–8) has been demonstrated to exert physiological effects similar to those of ANG II. We aimed to determine 1) whether ANG III induces TF expression in the brain, 2) which ANG II (AT) receptor subtype is involved, and 3) whether the two peptides, ANG II and ANG III, differ in their efficacy to stimulate TF expression. ANG II (100 pmol), ANG III (100 pmol), or vehicle was injected into the lateral brain ventricle of conscious rats alone or in combination with the AT1 receptor antagonist losartan (10 nmol), the AT2 receptor antagonist PD-123319 (5 nmol), or the aminopeptidase inhibitor amastatin (10 nmol). Similar to ANG II, ANG III induced the expression of c-Fos, c-Jun, and Krox-24 in four brain regions, subfornical organ, median preoptic area, paraventricular nucleus, and supraoptic nucleus of the hypothalamus, with the same efficacy. This effect was AT1 receptor mediated. Pretreatment with amastatin reduced the expression of TF in response to ANG II, indicating that this expression is partly mediated by ANG III. Interestingly, the AT2 receptor antagonist PD-123319 alone slightly enhanced the expression of c-Fos, c-Jun, and Krox-24 in different populations of neurons of the paraventricular nucleus. These data indicate that different populations of neurons in the paraventricular nucleus are tonically inhibited by AT2 receptors under physiological conditions.
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Baranov, Dimitry, and William M. Armstead. "Selective Blockade of AT1 Receptor Attenuates Impairment of Hypotensive Autoregulation and Improves Cerebral Blood Flow after Brain Injury in the Newborn Pig." Anesthesiology 99, no. 5 (November 1, 2003): 1118–24. http://dx.doi.org/10.1097/00000542-200311000-00018.
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Background Fluid percussion injury (FPI) in piglets produces vasoconstriction of pial arteries (PAs), decreases in cerebral blood flow (CBF), and impairment of hypotensive autoregulation. Two types of angiotensin II receptors, AT1 and AT2, have been identified in the brain. This study characterized the effect of pretreatment with AT1- and AT2-selective antagonists on CBF and hypotensive autoregulation after FPI. Methods Fluid percussion injury was induced in chloralose-anesthetized newborn pigs equipped with closed cranial windows. CBF was determined by the radiolabeled microsphere technique. Results Moderate and severe hypotension (71 +/- 3, 53 +/- 2, and 40 +/- 1 mmHg for normotension, moderate hypotension, and severe hypotension, respectively) elicited PA dilation without changes in CBF in sham control piglets. The AT1 antagonist ZD 7155 partially restored impaired hypotension-induced PA dilation after FPI (19 +/- 1 and 34 +/- 1 vs. 5 +/- 1 and 7 +/- 1 vs. 12 +/- 1 and 20 +/- 3% for PA dilation during moderate and severe hypotension in sham control, FPI, and FPI + ZD 7155 animals, respectively). ZD 7155 also blunted the reductions in CBF during normotension and hypotension observed in untreated animals (43 +/- 4, 38 +/- 5, and 55 +/- 3 vs. 32 +/- 4, 19 +/- 2, and 27 +/- 5% CBF reductions during normotension, moderate hypotension, and severe hypotension in untreated and pretreated animals, respectively). The AT2 selective antagonist PD 123,319 did not restore hypotension-induced PA dilation and did not prevent decreases in CBF observed during normotension and moderate and severe hypotension after FPI. Conclusion These data indicate that blockade of the AT1 and not the AT2 receptor diminished the reduction in hypotensive PA dilation after FPI. AT1 blockade also blunted the decrease in CBF during normotension as well as the further decrease in CBF observed during hypotension after FPI. These data suggest that AT1 receptor activation by angiotensin II contributes to cerebrovascular dysregulation during hypotension after FPI.
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Yusof, Mozow, Kazuhiro Kamada, F. Spencer Gaskin, and Ronald J. Korthuis. "Angiotensin II mediates postischemic leukocyte-endothelial interactions: role of calcitonin gene-related peptide." American Journal of Physiology-Heart and Circulatory Physiology 292, no. 6 (June 2007): H3032—H3037. http://dx.doi.org/10.1152/ajpheart.01210.2006.
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Vascular inflammation and enhanced production of angiotensin II (ANG II) are involved in the pathogenesis of hypertension and diabetes, disease states that predispose the afflicted individuals to ischemic disorders. In light of these observations, we postulated that ANG II may play a role in promoting leukocyte rolling (LR) and adhesion (LA) in postcapillary venules after exposure of the small intestine to ischemia-reperfusion (I/R). Using an intravital microscopic approach in C57BL/6J mice, we showed that ANG II type I (AT1) or type II (AT2) receptor antagonism (with valsartan or PD-123319, respectively), inhibition of angiotensin-converting enzyme (ACE) with captopril, or calcitonin gene-related peptide (CGRP) receptor blockade (CGRP8-37) prevented postischemic LR but did not influence I/R-induced LA. However, both postischemic LR and LA were largely abolished by concomitant AT1 and AT2 receptor blockade or chymase inhibition (with Y-40079). Additionally, exogenously administered ANG II increased LR and LA, effects that were attenuated by pretreatment with a CGRP receptor antagonist or an NADPH oxidase inhibitor (apocynin). Our work suggests that ANG II, formed by the enzymatic activity of ACE and chymase, plays an important role in inducing postischemic LR and LA, effects that involve the engagement of both AT1 and AT2 receptors and may be mediated by CGRP and NADPH oxidase.
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Pechlivanova, Daniela M., and Alexander G. Stoynev. "Effect of chronic treatment with angiotensin receptor ligands on water-salt balance in wistar and spontaneously hypertensive rats." Folia Medica 55, no. 3-4 (September 1, 2013): 63–69. http://dx.doi.org/10.2478/folmed-2013-0029.
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ABSTRACT The renin-angiotensin system plays a crucial role in the regulation of cardiovascular function and maintenance of water-electrolyte balance. The two major receptor types of the system, AT1 and AT2, have different, often opposite effects on these functions. AIM: To elucidate the impact of long term treatment with selective angiotensin receptor antagonists and an agonist on water-salt balance in normotensive Wistar and spontaneously hypertensive rats (SHRs). MATERIALS AND METHODS: 12-week-old male Wistar rats and SHRs were individually housed in metabolic cages and 24-h food and water intake and urine and electrolyte excretion were measured. Urinary sodium (UNa), potassium (UK) and chlorine (UCl) were determined by a flame photometer. Losartan, a selective AT1 receptor antagonist, was administered in the Wistar rats and SHRs at a dose of 10 mg/kg/day subcutaneously (sc). Wistar rats were also given the AT2 receptor antagonist, PD123319, subcutaneously at a dose of 10 mg/kg/ day. CGP 42112A, an AT2 receptor agonist, was administered intracerebroventricularly in Wistar rats at a dose of 12 μg/rat/day. The drugs were infused continuously for 14 days through osmotic minipumps. RESULTS: Losartan selectively increased sodium excretion in both rat strains and decreased weight gain in SHRs. PD123319 increased potassium excretion and decreased weight gain in Wistar rats. CGP 42112A increased food and water intake, urine output and UNa+ and UK+ excretion and decreased weight gain in normotensive Wistar rats. CONCLUSIONS: Chronic treatment with selective angiotensin receptor ligands modifies water- salt balance in rats through changes both in renal excretory function and ingestive behaviors.
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Angelis, Ekaterini, M. Yat Tse, Michael A. Adams, and Stephen C. Pang. "Effect of AT2 blockade on cardiac hypertrophy as induced by high dietary salt in the proatrial natriuretic peptide (ANP) gene-disrupted mouse." Canadian Journal of Physiology and Pharmacology 84, no. 6 (June 2006): 625–34. http://dx.doi.org/10.1139/y06-016.
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The role of the angiotensin II type 2 receptor (AT2) during alterations in cardiac size remains largely unclear. Through employment of an AT2 antagonist, the present study explored a possible involvement of the AT2 receptor during salt-induced cardiac hypertrophy in the proatrial natriuretic peptide gene-disrupted mouse (ANP−/−). ANP−/− mice received either saline solution or the AT2 antagonist, PD123319, and were then placed on a high salt diet (8.0% NaCl) for 3 weeks. Cardiac and pulmonary size, expression of the renin–angiotensin system (RAS), and the behaviour of various hypertrophy marker genes were assessed. PD123319 caused enhanced expression of the systemic RAS, yet the cardiac RAS was largely unaffected. Although AT2 blockade did not alter whole cardiac mass, right ventricle mass, as well as pulmonary mass-to-body mass ratios were significantly decreased. Collagen type I was decreased in the latter tissues, likely contributing to the regression in mass. Several players essential in the maintenance of myocardial extracellular matrix homeostasis including B-type natriuretic peptide, matrix metalloproteinase-2, tumour necrosis factor, and transforming growth factor were also significantly altered by PD123319. These data suggest that AT2 blockade is involved in significant changes in myocardial extracellular matrix components translating into decreases in tissue mass in the salt-sensitive ANP−/− animal.
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Chang, Raymond S. L., Victor J. Lotti, Tsing-Bau Chen, Stacey S. O'Malley, Robert J. Bendesky, Paul J. Kling, Salah D. Kivlighn, et al. "In vitro pharmacology of an angiotensin AT1 receptor antagonist with balanced affinity for AT2 receptors." European Journal of Pharmacology 294, no. 2-3 (December 1995): 429–37. http://dx.doi.org/10.1016/0014-2999(95)00563-3.
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Hakam, Amer C., Athar H. Siddiqui, and Tahir Hussain. "Renal angiotensin II AT2 receptors promote natriuresis in streptozotocin-induced diabetic rats." American Journal of Physiology-Renal Physiology 290, no. 2 (February 2006): F503—F508. http://dx.doi.org/10.1152/ajprenal.00092.2005.
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Angiotensin II AT2 receptors have been implicated to play a role in the regulation of renal/cardiovascular functions under pathological conditions. The present study is designed to investigate the function of the AT2 receptors on renal sodium excretion and AT2 receptor expression in the cortical membranes of streptozotocin (STZ)-induced diabetic rats. The STZ treatment led to a significant weight loss, hyperglycemia, and decrease in plasma insulin levels compared with control rats. STZ-induced diabetic rats had significantly elevated basal urine flow, urinary sodium excretion rate (UNaV), urinary fractional sodium excretion, and urinary cGMP compared with control rats. Infusion of PD-123319, an AT2 receptor antagonist, caused a significant decrease in UNaV (μmol/min) in STZ-induced diabetic rats (1 ± 0.09 vs. 0.45 ± 0.1) but not in control rats (0.35 ± 0.05 vs. 0.4 ± 0.07). The decrease in UNaV was associated with a significant decrease in urinary cGMP levels (pmol/min) in STZ-induced diabetic rats (21 ± 2 vs. 10 ± 0.8) but not in control rats (11.75 ± 3 vs. 12.6 ± 2). The infusion of PD-123319 did not alter glomerular filtration rate (STZ: 0.3 ± 0.02 vs. 0.25 ± 0.03; control: 1.4 ± 0.05 vs. 1.5 ± 0.09 ml/min) or mean arterial pressure (STZ: 82 ± 3 vs. 79 ± 3.5; control: 90 ± 4 vs. 89 ± 4 mmHg), suggesting a tubular effect of the drug. Western blot analysis using an AT2 receptor antibody revealed a significantly enhanced expression of the AT2 receptor protein (∼45 kDa) in brush-border (∼50-fold) and basolateral membranes (∼80-fold) of STZ-induced diabetic compared with control rats. In conclusion, our data suggest that the tubular AT2 receptors in diabetic rats are profoundly enhanced and possibly via a cGMP pathway promote sodium excretion in this model of diabetes.
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Oishi, Yoshihiko, Ryoji Ozono, Masao Yoshizumi, Masahiro Akishita, Masatsugu Horiuchi, and Tetsuya Oshima. "AT2 receptor mediates the cardioprotective effects of AT1 receptor antagonist in post-myocardial infarction remodeling." Life Sciences 80, no. 1 (December 2006): 82–88. http://dx.doi.org/10.1016/j.lfs.2006.08.033.
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Höhle, Susanne, Heidi Spitznagel, Wolfgang Rascher, Juraj Culman, and Thomas Unger. "Angiotensin AT1 receptor-mediated vasopressin release and drinking are potentiated by an AT2 receptor antagonist." European Journal of Pharmacology 275, no. 3 (March 1995): 277–82. http://dx.doi.org/10.1016/0014-2999(95)00005-6.
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Kaiser, Jeffrey R., Blair E. Cox, Timothy A. Roy, and Charles R. Rosenfeld. "Differential development of umbilical and systemic arteries. I. ANG II receptor subtype expression." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 274, no. 3 (March 1, 1998): R797—R807. http://dx.doi.org/10.1152/ajpregu.1998.274.3.r797.
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In fetal sheep umbilical responses to angiotensin II (ANG II) exceed those by systemic vasculature. Two ANG II receptors (AT) exist, AT1 and AT2, but only AT1 mediates vasoconstriction in adult tissues. Thus differences in reactivity could reflect differences in subtype expression. Using competitive radioligand binding assays, we demonstrated AT1 predominance in umbilical arteries and AT2 in femoral arteries. Steady-state responses to intravenous ANG II (0.229–1.72 μg/min) were studied in 16 fetuses with umbilical and/or femoral artery flow probes without and with local AT1 (L-158,809) or AT2 (PD-123319) blockade. ANG II dose dependently ( P < 0.001) increased umbilical resistance more than arterial pressure (MAP) while decreasing umbilical blood flow. Femoral vascular resistance also increased dose dependently ( P = 0.02), but responses were less than umbilical ( P = 0.0001) and paralleled increases in MAP; blood flow was unaffected. Cumulative local doses of L-158,809 (125 μg) inhibited all responses ( P< 0.001); however, 1,000 μg of the AT2 antagonist had no effect. Plasma renin activity (PRA) was unaltered by local AT1 blockade, whereas PRA doubled ( P = 0.001) after systemic infusion of only 50 μg of the AT1 antagonist and remained elevated. Differences in umbilical and femoral vascular responses to ANG II are in large part due to differences in AT subtype expression. Furthermore, in fetal sheep the ANG II negative feedback on PRA is mediated by AT1 receptors, and it is substantially more sensitive to receptor blockade than the vasculature.
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Weisinger, R. S., J. R. Blair-West, D. A. Denton, and E. Tarjan. "Role of brain angiotensin II in thirst and sodium appetite of sheep." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 273, no. 1 (July 1, 1997): R187—R196. http://dx.doi.org/10.1152/ajpregu.1997.273.1.r187.
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The contribution of brain angiotensin II (ANG II) to thirst and Na+ appetite of sheep was evaluated. Thirst was stimulated by water deprivation, intracarotid or intracerebroventricular infusion of ANG II, or intracarotid or intracerebroventricular infusion of hypertonic solution. Intracerebroventricular infusion, over 1-3 h, of the ANG II type 1 (AT1) receptor antagonist, losartan, decreased or abolished water intake caused by all of the stimuli tested. Intracerebroventricular infusion of ZD-7155, another AT1-receptor antagonist, blocked ANG II-induced water intake. Neither losartan nor ZD-7155 infused intracerebroventricularly altered the Na+ appetite of Na(+)-depleted sheep. Intracerebroventricular infusion of losartan over 3 h, however, did block the increase in water intake and the decrease in Na+ intake caused by intracerebroventricular infusion of hypertonic NaCl in Na(+)-depleted sheep. Intracerebroventricular infusion of the ANG II type 2 (AT2) receptor antagonist, PD-123319, over 1-3 h, did not alter ANG II-induced water intake or Na+ depletion-induced Na+ intake. These results are consistent with the proposition that brain ANG II, working via AT1 receptors, is involved in the neural system controlling some aspects of physiological thirst and Na+ appetite. A role for AT2 receptors in physiological thirst or Na+ appetite is not supported by the present results.
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Widdop, R. E., S. M. Gardiner, P. A. Kemp, and T. Bennett. "Central administration of PD 123319 or EXP-3174 inhibits effects of angiotensin II." American Journal of Physiology-Heart and Circulatory Physiology 264, no. 1 (January 1, 1993): H117—H125. http://dx.doi.org/10.1152/ajpheart.1993.264.1.h117.
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Cardiovascular responses to intracerebroventricular angiotensin II (ANG II) were measured in conscious rats, chronically instrumented for the measurement of regional hemodynamics, over 4 consecutive days in the absence and presence of either the AT2 receptor antagonist, PD 123319 (experiment 1), or the AT1 receptor antagonist, EXP-3174 (experiment 2). Intracerebroventricular ANG II had pressor and bradycardic effects, which were associated with marked mesenteric and hindquarters vasoconstriction, and a small transient renal vasoconstriction. Both PD 123319 and EXP-3174, given intracerebroventricularly, abolished the cardiovascular response to intracerebroventricular ANG II, although the profiles of activity of the compounds were different. PD 123319 caused a slowly developing, but remarkably prolonged (1-2 days) inhibition of the effects of ANG II, whereas EXP-3174 caused an immediate inhibition of the effects of ANG II, although responses to ANG II had returned to control levels by the following day. These data suggest that the hemodynamic effects of ANG II may involve concurrent, and interdependent, activation of AT1 and AT2 receptors or that PD 123319 undergoes a unique biotransformation in the brain to some product(s) with AT1 receptor antagonist activity.
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Raffai, Gábor, Matthew J. Durand, and Julian H. Lombard. "Acute and chronic angiotensin-(1–7) restores vasodilation and reduces oxidative stress in mesenteric arteries of salt-fed rats." American Journal of Physiology-Heart and Circulatory Physiology 301, no. 4 (October 2011): H1341—H1352. http://dx.doi.org/10.1152/ajpheart.00202.2011.
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This study determined the effect of ANG-(1–7) on salt-induced suppression of endothelium-dependent vasodilatation in the mesenteric arteries of male Sprague-Dawley rats. Chronic intravenous infusion of ANG-(1–7), oral administration of the nonpeptide mas receptor agonist AVE-0991, and acute preincubation of the arteries with ANG-(1–7) and AVE-0991 all restored vasodilator responses to both ACh and histamine that were absent in the arteries of rats fed a high-salt (4% NaCl) diet. The protective effects of ANG-(1–7) and AVE-0991 were inhibited by acute or chronic administration of the mas receptor antagonist A-779, the ANG II type 2 (AT2) receptor blocker PD-123319, or N-nitro-l-arginine methyl ester, but not the ANG II type 1 receptor antagonist losartan. Preincubation with the antioxidant tempol or the nitric oxide (NO) donor diethylenetriamine NONOate and acute and chronic administration of the AT2 receptor agonist CGP-42112 mimicked the protective effect of ANG-(1–7) to restore vascular relaxation. Acute preincubation with ANG-(1–7) and chronic infusion of ANG-(1–7) ameliorated the elevated superoxide levels in rats fed a high-salt diet, but the expression of Cu/Zn SOD and Mn SOD enzyme proteins in the vessel wall was unaffected by ANG-(1–7) infusion. These results indicate that both acute and chronic systemic administration of ANG-(1–7) or AVE-0991 restore endothelium-dependent vascular relaxation in salt-fed Sprague-Dawley rats by reducing vascular oxidant stress and enhancing NO availability via mas and AT2 receptors. These findings suggest a therapeutic potential for mas/AT2 receptor activation in preventing the vascular oxidant stress and endothelial dysfunction associated with elevated dietary salt intake.
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Schuijt, Martin P., Munesh Basdew, Richard van Veghel, René de Vries, Pramod R. Saxena, Regien G. Schoemaker, and A. H. Jan Danser. "AT2 receptor-mediated vasodilation in the heart: effect of myocardial infarction." American Journal of Physiology-Heart and Circulatory Physiology 281, no. 6 (December 1, 2001): H2590—H2596. http://dx.doi.org/10.1152/ajpheart.2001.281.6.h2590.
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To investigate the functional consequences of postinfarct cardiac angiotensin (ANG) type 2 (AT2) receptor upregulation, rats underwent coronary artery ligation or sham operation and were infused with ANG II 3–4 wk later, when scar formation is complete. ANG II increased mean arterial pressure (MAP) more modestly in infarcted animals than in sham animals. The AT1 receptor antagonist irbesartan, but not the AT2 receptor antagonist PD123319, decreased MAP and antagonized the ANG II-mediated systemic hemodynamic effects. Myocardial (MVC) but not renal vascular conductance (RVC) was diminished in infarcted versus sham rats. ANG II did not affect MVC and reduced RVC in all rats. MVC was unaffected by irbesartan and PD123319 in all animals. However, with PD123319, ANG II reduced MVC in sham but not infarcted animals, and, with irbesartan, ANG II increased MVC in infarcted but not sham animals. Irbesartan increased RVC and antagonized the ANG II-mediated renal effects in all animals. RVC, at baseline or with ANG II, was not affected by PD123319 in infarcted and sham animals. In conclusion, coronary but not renal AT2 receptor stimulation results in vasodilation, and this effect is enhanced in infarcted rats.
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Deliu, Elena, Andrei A. Tica, Dana Motoc, G. Cristina Brailoiu, and Eugen Brailoiu. "Intracellular angiotensin II activates rat myometrium." American Journal of Physiology-Cell Physiology 301, no. 3 (September 2011): C559—C565. http://dx.doi.org/10.1152/ajpcell.00123.2011.
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Angiotensin II is a modulator of myometrial activity; both AT1 and AT2 receptors are expressed in myometrium. Since in other tissues angiotensin II has been reported to activate intracellular receptors, we assessed the effects of intracellular administration of angiotensin II via microinjection on myometrium, using calcium imaging. Intracellular injection of angiotensin II increased cytosolic Ca2+ concentration ([Ca2+]i) in myometrial cells in a dose-dependent manner. The effect was abolished by the AT1 receptor antagonist losartan but not by the AT2 receptor antagonist PD-123319. Disruption of the endo-lysosomal system, but not that of Golgi apparatus, prevented the angiotensin II-induced increase in [Ca2+]i. Blockade of AT1 receptor internalization had no effect, whereas blockade of microautophagy abolished the increase in [Ca2+]i produced by intracellular injection of angiotensin II; this indicates that microautophagy is a critical step in transporting the peptide into the endo-lysosomes lumenum. The response to angiotensin II was slightly reduced in Ca2+-free saline, indicating a major involvement of Ca2+ release from internal stores. Blockade of inositol 1,4,5-trisphosphate (IP3) receptors with heparin and xestospongin C or inhibition of phospholipase C (PLC) with U-73122 abolished the response to angiotensin II, supporting the involvement of PLC-IP3 pathway. Angiotensin II-induced increase in [Ca2+]i was slightly reduced by antagonism of ryanodine receptors. Taken together, our results indicate for the first time that in myometrial cells, intracellular angiotensin II activates AT1-like receptors on lysosomes and activates PLC-IP3-dependent Ca2+ release from endoplasmic reticulum; the response is further augmented by a Ca2+-induced Ca2+ release mechanism via ryanodine receptors activation.
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Kilian, Peter, Shirley Campbell, Lyne Bilodeau, Marie-Odile Guimond, Claude Roberge, Nicole Gallo-Payet, and Marcel Daniel Payet. "Angiotensin II Type 2 Receptor Stimulation Increases the Rate of NG108–15 Cell Migration via Actin Depolymerization." Endocrinology 149, no. 6 (March 6, 2008): 2923–33. http://dx.doi.org/10.1210/en.2007-0313.
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Angiotensin II (Ang II) has been reported to induce migration in neuronal cell types. Using time-lapse microscopy, we show here that Ang II induces acceleration in NG108–15 cell migration. This effect was antagonized by PD123319, a selective AT2 receptor antagonist, but not by DUP753, a selective AT1 receptor antagonist, and was mimicked by the specific AT2 receptor agonist CGP42112. This Ang II-induced acceleration was not sensitive to the inhibition of previously described signaling pathways of the AT2 receptor, guanylyl cyclase/cyclic GMP or p42/p44mapk cascades, but was abolished by pertussis toxin treatment and involved PP2A activation. Immunofluorescence studies indicate that Ang II or CGP42112 decreased the amount of filamentous actin at the leading edge of the cells. This decrease was accompanied by a concomitant increase in globular actin levels. Regulation of actin turnover in actin-based motile systems is known to be mainly under the control of the actin depolymerizing factor and cofilin. Basal migration speed decreased by 77.2% in cofilin-1 small interfering RNA-transfected NG108–15 cells, along with suppression of the effect of Ang II. In addition, the Ang II-induced increase in cell velocity was abrogated in serum-free medium as well as by genistein or okadaic acid treatment in a serum-containing medium. Such results indicate that the AT2 receptor increases the migration speed of NG108–15 cells and involves a tyrosine kinase activity, followed by phosphatase activation, which may be of the PP2A type. Therefore, the present study identifies actin depolymerization and cofilin as new targets of AT2 receptor action, in the context of cellular migration.
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Rowland, N. E., B. H. Li, A. K. Rozelle, and G. C. Smith. "Comparison of fos-like immunoreactivity induced in rat brain by central injection of angiotensin II and carbachol." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 267, no. 3 (September 1, 1994): R792—R798. http://dx.doi.org/10.1152/ajpregu.1994.267.3.r792.
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Rats were given intracerebroventricular injections of either angiotensin II (ANG II) or the cholinomimetic carbachol. Some rats received cotreatment with ANG II antagonists selective for either angiotensin receptor AT1 (losartan) or AT2 (PD-123319, CGP-42112A). One hour later, the rats were killed and the brains processed for immunocytochemical detection of Fos-like immunoreactivity (FLI). ANG II treatment induced strong FLI in the anterior subfornical organ (SFO), median preoptic nucleus (MnPO), organum vasculosum laminae terminalis (OVLT), and supraoptic and paraventricular hypothalamic nuclei (SON, PVH). The AT1 antagonist abolished FLI in all regions normally stimulated by ANG II. The AT2 antagonist PD-123319 reduced FLI in SON and PVH, but CGP-42112A was less effective. Carbachol induced strong FLI in SON, PVH, and MnPO and only moderate FLI in SFO and OVLT. The AT1 antagonist prevented carbachol-induced FLI in the MnPO only. The distributions of FLI are compared between these central dipsogens and with that previously reported after peripheral infusion of ANG II, and their implications for mapping central thirst pathways are discussed.
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Marchi-Coelho, Camila, Willian Costa-Ferreira, Lilian L. Reis-Silva, and Carlos C. Crestani. "Angiotensinergic Neurotransmissions in the Medial Amygdala Nucleus Modulate Behavioral Changes in the Forced Swimming Test Evoked by Acute Restraint Stress in Rats." Cells 10, no. 5 (May 17, 2021): 1217. http://dx.doi.org/10.3390/cells10051217.
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We investigated the role of angiotensin II type 1 (AT1 receptor) and type 2 (AT2 receptor) and MAS receptors present in the medial amygdaloid nucleus (MeA) in behavioral changes in the forced swimming test (FST) evoked by acute restraint stress in male rats. For this, rats received bilateral microinjection of either the selective AT1 receptor antagonist losartan, the selective AT2 receptor antagonist PD123319, the selective MAS receptor antagonist A-779, or vehicle 10 min before a 60 min restraint session. Then, behavior in the FST was evaluated immediately after the restraint (15 min session) and 24 h later (5 min session). The behavior in the FST of a non-stressed group was also evaluated. We observed that acute restraint stress decreased immobility during both sessions of the FST in animals treated with vehicle in the MeA. The decreased immobility during the first session was inhibited by intra-MeA administration of PD123319, whereas the effect during the second session was not identified in animals treated with A-779 into the MeA. Microinjection of PD123319 into the MeA also affected the pattern of active behaviors (i.e., swimming and climbing) during the second session of the FST. Taken together, these results indicate an involvement of angiotensinergic neurotransmissions within the MeA in behavioral changes in the FST evoked by stress.