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1
Kiely, J., J. R. Hadcock, S. W. Bahouth та C. C. Malbon. "Glucocorticoids down-regulate β1-adrenergic-receptor expression by suppressing transcription of the receptor gene". Biochemical Journal 302, № 2 (1994): 397–403. http://dx.doi.org/10.1042/bj3020397.
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The expression of beta 2-adrenergic receptors is up-regulated by glucocorticoids. In contrast, beta 1-adrenergic receptors display glucocorticoid-induced down-regulation. In rat C6 glioma cells, which express both of these subtypes of beta-adrenergic receptors, the synthetic glucocorticoid dexamethasone stimulates no change in the total beta-adrenergic receptor content, but rather shifts the beta 1:beta 2 ratio from 80:20 to 50:50. Radioligand binding and immunoblotting demonstrate a sharp decline in beta 1-adrenergic receptor expression. Metabolic labelling of cells with [35S]-methionine in tandem with immunoprecipitation by beta 1-adrenergic-receptor-specific antibodies reveals a sharp decline in the synthesis of the receptor within 48 h for cells challenged with glucocorticoid. Steady-state levels of beta 1-adrenergic-receptor mRNA declined from 0.47 to 0.26 amol/microgram of total cellular RNA within 2 h of dexamethasone challenge, as measured by DNA-excess solution hybridization. The stability of receptor mRNA was not influenced by glucocorticoid; the half-lives of the beta 1- and beta 2-subtype mRNAs were 1.7 and 1.5 h respectively. Nuclear run-on assays revealed the basis for the down-regulation of receptor expression, i.e. a sharp decline in the relative rate of transcription for the beta 1-adrenergic-receptor gene in nuclei from dexamethasone-treated as compared with vehicle-treated cells. These data demonstrate transcriptional suppression as a molecular explanation for glucocorticoid-induced down-regulation of beta 1-adrenergic receptors.
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Gesek, F. A., and K. E. White. "Molecular and functional identification of beta-adrenergic receptors in distal convoluted tubule cells." American Journal of Physiology-Renal Physiology 272, no. 6 (1997): F712—F720. http://dx.doi.org/10.1152/ajprenal.1997.272.6.f712.
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Renal nerve stimulation or circulating catecholamines activate the beta-adrenergic receptors that mediate direct effects on tubular transport. Three subtypes of beta-adrenergic receptors have been characterized: beta 1, beta 2, and beta 3. beta-Adrenergic-receptor effects on Na+ and Ca2+ transport in distal convoluted tubules (DCT) have not been established. The focus of this study was to 1) identify the subtypes of beta-adrenergic receptors in DCT cells and 2) examine functional responses to beta-receptor activation on adenosine 3',5'-cyclic monophosphate (cAMP) formation and Na+ and Ca2+ entry. To determine the subtypes of beta-receptors present, RNA isolated from immortalized mouse DCT cells was reverse transcribed, and the cDNA was amplified using primers designed to reported sequences for beta 1-, beta 2-, and beta 3-receptor subtypes. Products of the appropriate sizes were obtained with beta 1- and beta 2-primers. No product was observed with primers to the beta 3 sequence. Receptor products were confirmed by sequencing and are identical to reported mouse beta 1- and beta 2-receptor sequence. Receptor binding of[3H]dihydroalprenolol was 123 +/- 13 fmol/mg protein, and a 3:1 ratio of beta 1- to beta 2-receptors was observed with DCT cell membranes. Isoproterenol, a beta-receptor agonist, increased cAMP formation 8.5-fold. Pretreatment with the antagonist propranolol abolished agonist-induced cAMP accumulation. Isoproterenol significantly increased 22Na+ uptake to 345 +/- 23 compared with a basal rate of 256 +/- 12 nmol.min-1.mg protein-1 and was blocked with propranolol and beta 1- and beta 2-selective antagonists. Isoproterenol had no effect on 45Ca2+ entry into DCT cells. In summary, DCT cells express three times more beta 1- than beta 2-receptors and express no detectable beta 3-adrenergic receptors. beta-Receptors couple to adenylyl cyclase, and activation of beta-adrenergic receptors increases Na+ but not Ca2+ entry in DCT cells.
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Maisel, A. S., H. J. Motulsky, M. G. Ziegler, and P. A. Insel. "Ischemia- and agonist-induced changes in alpha- and beta-adrenergic receptor traffic in guinea pig hearts." American Journal of Physiology-Heart and Circulatory Physiology 253, no. 5 (1987): H1159—H1166. http://dx.doi.org/10.1152/ajpheart.1987.253.5.h1159.
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We have used radioligand binding techniques and subcellular fractionation to assess whether changes in expression of myocardial alpha 1- and beta-adrenergic receptors are mediated by a redistribution of receptors between various membrane fractions. Three fractions were prepared from the left ventricles of guinea pigs that underwent either 1 h of ischemia or injection of epinephrine (0.25 mg/kg ip): a crude membrane, a purified sarcolemma, and a light vesicle fraction. In control animals alpha 1-adrenergic receptors ([3H]prazosin binding) in light vesicles was only 25% of the total alpha 1-receptor density found in sarcolemmal and light vesicle fractions as compared with 50% for beta-adrenergic receptors ([125I]iodocyanopindolol binding sites). Although ischemia was associated with a 53% decrease in the number of light vesicle beta-adrenergic receptors and a 42% increase in the number of sarcolemma beta-receptors (P less than 0.05), there was no change in the number of light vesicle alpha 1-receptors, even though the number of sarcolemmal alpha 1-receptors increased 34%. Epinephrine treatment promoted internalization of beta-adrenergic receptors; sarcolemma beta-receptors decreased 37% and light vesicle beta-receptors increased 28% (P less than 0.025). For alpha 1-receptors, epinephrine treatment decreased the number of sarcolemmal receptors 41% (P less than 0.025) but failed to increase the number of receptors in the light vesicle fraction. The changes in receptor binding to beta-adrenergic receptors in sarcolemmal fractions were mirrored by parallel changes in isoproterenol-stimulated adenylate cyclase activity. These results indicate that alpha 1- and beta-adrenergic receptors may undergo a different cellular itinerary in guinea pig myocardium.(ABSTRACT TRUNCATED AT 250 WORDS)
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Lechsner, Patrick, and Erika-Gyongyi Ban. "Alpha adrenergic receptors in clinical practice – Present and future." Acta Marisiensis - Seria Medica 68, no. 4 (2022): 145–49. http://dx.doi.org/10.2478/amma-2022-0030.
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Abstract In this review we discuss the adrenergic pathways for alpha 1 and alpha 2 receptors and the current as well as potential future medication targeting these receptors. Overall, there is ongoing research into a multitude of directions with a promising outlook for alpha 1 and alpha 2 adrenergic receptors. The alpha 1-adrenergic receptor subfamily is currently modulating only a modest number of nervous system functions due the fact, that only a relatively small number of selective commercial products are available. Chronic stress can affect the long-term depression of alpha 1 receptors. Recent studies are searching for new molecular targets which might act on these receptors. Presynaptic alpha 2 receptors play an important role in modulating release of several neurotransmitters in the central nervous system. The future of alpha 2 adrenergic receptors in clinical practice looks even more promising and versatile than that of alpha 1 adrenergic receptors. Alpha 2 adrenergic receptors show different responses, especially regarding hypertension and heart failure treatment, and current research suggests a genetic component as a cause, which is being explored further.
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Bahouth, S. W., та C. C. Malbon. "Human β-adrenergic receptors. Simultaneous purification of β1- and β2-adrenergic-receptor peptides". Biochemical Journal 248, № 2 (1987): 557–66. http://dx.doi.org/10.1042/bj2480557.
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Beta-Adrenergic receptors from basal membranes of human placenta were purified from digitonin extracts by sequential rounds of affinity chromatography, hydrophobic chromatography, ion-exchange chromatography and steric-exclusion h.p.l.c. Basal membranes display both beta 1- and beta 2-adrenergic receptors, in the ratio 65:35. Affinity chromatography, hydrophobic chromatography on heptylamine-Sepharose and ion-exchange chromatography on DEAE-Sephacel removed most of the contaminating proteins, and final purification of the receptor to apparent homogeneity was achieved by steric-exclusion h.p.l.c. The purified receptors showed Mr 67000 on SDS/polyacrylamide-gel electrophoresis under reducing conditions. Specific binding of radioligand to the purified beta-adrenergic receptors displayed stereoselectivity, and the agonist competition profiles demonstrated the presence of both beta 1- and beta 2-receptors. By using the subtype-selective ligands CGP-20712A (beta 1-selective) and ICI-118,551 (beta 2-selective), the purified Mr-67000 species was shown to be composed of equivalent amounts of beta 1- and beta 2-adrenergic receptors. Affinity chromatography on Sepharose-alprenolol and sequential elution with 1 microM-CGP-20712A followed by 100 microM(-)-alprenolol permitted beta 1-adrenergic receptors to be resolved from the mixture of beta 1-/beta 2-adrenergic receptors. The pharmacologically distinct human beta 1 and beta 2-adrenergic receptors are shown to be structurally very similar peptides.
6
Struthers, Allan D. "The alpha 1 adrenergic receptors." Clinica Chimica Acta 180, no. 1 (1989): 110. http://dx.doi.org/10.1016/0009-8981(89)90307-0.
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Docherty, Jim. "The Alpha-1 adrenergic receptors." Trends in Pharmacological Sciences 9, no. 7 (1988): 266–67. http://dx.doi.org/10.1016/0165-6147(88)90161-7.
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Raasmaja, A., та D. A. York. "α1- and β-adrenergic receptors in brown adipose tissue of lean (Fa/?) and obese (fa/fa) Zucker rats. Effects of cold-acclimation, sucrose feeding and adrenalectomy". Biochemical Journal 249, № 3 (1988): 831–38. http://dx.doi.org/10.1042/bj2490831.
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1. The populations of alpha 1- and beta-adrenergic receptors in brown adipose tissue (BAT) of genetically obese Zucker rats (fa/fa) were studied with [3H]prazosin and [3H]CGP-12177 respectively. 2. The density of alpha 1-adrenergic receptors in BAT was significantly lower in obese than in lean Zucker rats, both at 2-4 months of age and at 6 weeks of age. The density of beta-adrenergic receptors was identical in BAT of lean and obese 6-week-old Zucker rats. 3. Cold-acclimation increased the alpha 1-receptor density significantly in BAT of both lean and obese Zucker rats, and the number of beta-receptors was also somewhat increased. 4. Sucrose feeding did not affect the density of alpha 1-receptors in BAT of lean or obese Zucker rats, but it increased beta-receptor density. 5. Adrenalectomy restored the density of alpha 1-adrenergic receptors in BAT of obese Zucker rats to the value observed in lean rats. 6. It is concluded that there is a direct correlation between alpha 1-receptor density and tissue recruitment, and that alpha 1-receptor density is thus positively correlated with sympathetic activity. beta-Receptor density is apparently better correlated with feeding conditions.
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Scarpace, P. J., L. A. Baresi, and J. E. Morley. "Modulation of receptors and adenylate cyclase activity during sucrose feeding, food deprivation, and cold exposure." American Journal of Physiology-Endocrinology and Metabolism 253, no. 6 (1987): E629—E635. http://dx.doi.org/10.1152/ajpendo.1987.253.6.e629.
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Thermogenesis in brown adipose tissue (BAT) serves as a regulator of body temperature and weight maintenance. Thermogenesis can be stimulated by catecholamine activation of adenylate cyclase through the beta-adrenergic receptor. To investigate the effects of sucrose feeding, food deprivation, and cold exposure on the beta-adrenergic pathway, adenylate cyclase activity and beta-adrenergic receptors were assessed in rat BAT after 2 wk of sucrose feeding, 2 days of food deprivation, or 2 days of cold exposure. beta-Adrenergic receptors were identified in BAT using [125I]iodocyanopindolol. Binding sites had the characteristics of mixed beta 1- and beta 2-type adrenergic receptors at a ratio of 60/40. After sucrose feeding or cold exposure, there was the expected increase in BAT mitochondrial mass as measured by total cytochrome-c oxidase activity but a decrease in beta-adrenergic receptor density due to a loss of the beta 1-adrenergic subtype. This BAT beta-adrenergic receptor downregulation was tissue specific, since myocardial beta-adrenergic receptors were unchanged with either sucrose feeding or cold exposure. In contrast, food deprivation did not alter BAT beta-adrenergic receptor density. Forskolin-stimulated adenylate cyclase activity increased in BAT after sucrose feeding or cold exposure but not after food deprivation. The ratio of isoproterenol-stimulated to forskolin-stimulated adenylate cyclase activity decreased in the sucrose-fed and cold-exposed rats but not in the food-deprived rats. These data suggest that in BAT, sucrose feeding or cold exposure result in downregulation of beta-adrenergic receptors and that isoproterenol-stimulated adenylate cyclase activity was limited by receptor availability.
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Yoshizumi, Masaru, Kazumasa Matsumoto-Miyai, Akihiko Yonezawa та Masahito Kawatani. "Role of supraspinal and spinal α1-adrenergic receptor subtypes in micturition reflex in conscious rats". American Journal of Physiology-Renal Physiology 299, № 4 (2010): F785—F791. http://dx.doi.org/10.1152/ajprenal.00553.2009.
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α1-Adrenergic receptor subtypes are widely distributed in the central nervous system and are involved in autonomic functions such as micturition. We investigated the presence and the role of supraspinal and/or spinal α1-adrenergic receptors in modulating the micturition reflex in conscious female Wistar rats. The expression of α1-adrenergic receptor subtypes in rat brain and lumbosacral spinal cord was studied using RT-PCR. Continuous-infusion cystometrograms were obtained in conscious rats, and α1-adrenergic receptor antagonists were administered via intracerebroventricular or intrathecal routes. The mRNA expression of α1A-, α1B-, and α1D-adrenergic receptors was detected in rat brain (midbrain and pons) and lumbosacral spinal cord (dorsal and ventral parts of spinal cord). In addition, intracerebroventricular injection of the α1-adrenergic receptor antagonist tamsulosin (1–10 μg), the selective α1A-adrenergic receptor antagonist silodosin (1–10 μg), and the selective α1D-adrenergic receptor antagonist BMY 7378 (1–10 μg) significantly prolonged the intercontraction interval (ICI) but did not alter maximum voiding pressure (MVP). Although intrathecal injection of BMY 7378 (0.0001–10 μg) did not affect ICI, tamsulosin and silodosin prolonged ICI in a dose-dependent manner. MVP was significantly reduced by intrathecal injection of tamsulosin (10 μg) but not by silodosin or BMY 7378 (0.0001–10 μg). Supraspinal α1A- and α1D-adrenergic receptors are apparently important for the regulation of reflex-bladder activity in conscious rats. Noradrenergic projection from the brain stem to the lumbosacral spinal cord may promote the afferent limb rather than the efferent limb of the micturition reflex pathway via α1A-adrenergic receptors.
11
Beeler, J. F., та R. H. Cooper. "Regulation of hepatocyte plasma membrane α1-adrenergic receptors by 4β-phorbol 12-myristate 13-acetate". Biochemical Journal 305, № 1 (1995): 73–79. http://dx.doi.org/10.1042/bj3050073.
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The effect of phorbol 12-myristate 13-acetate (PMA) on hepatocyte alpha 1-adrenergic receptors was determined by [3H]prazosin binding to plasma membranes from control and PMA-treated hepatocytes. Membranes from hepatocytes incubated with PMA (1 microgram/ml) for 1 h exhibited a 40% decrease in alpha 1-adrenergic receptors (481 +/- 10 fmol/mg of protein; mean +/- S.E.M. for three separate experiments) relative to vehicle-treated (dimethylformamide) hepatocytes (802 +/- 91 fmol/mg of protein; n = 3), with no significant effect on the KD. The PMA-induced decrease in alpha 1-adrenergic receptors was maximal by 30 min and half-maximal inhibition of [3H]prazosin binding occurred with a PMA concentration of approx. 15 ng/ml. Pretreatment of hepatocytes with staurosporine (5 microM) blocked the effect of PMA, and 4 beta-phorbol 13-monoacetate was ineffective, suggesting the involvement of protein kinase C (PKC). Treatment of hepatocytes with primaquine (300 microM) for 15 min decreased hepatocyte plasma membrane alpha 1-adrenergic receptors by 34.0 +/- 2.4% (mean +/- S.E.M. of three experiments). Removal of primaquine allowed essentially complete recovery (98 +/- 4%; mean +/- S.E.M. for five separate experiments) of plasma membrane [3H]prazosin binding within 20 min, suggesting that the alpha 1-adrenergic receptor undergoes endocytotic recycling. Addition of PMA (1 microgram/ml) to hepatocytes immediately after removal of primaquine, completely inhibited the increase in plasma membrane alpha 1-adrenergic receptors relative to control cells, but had no effect on hepatocytes whose cell surface alpha 1-receptors remaining after primaquine treatment had been inactivated by alkylation. These observations suggested that activation of PKC may facilitate the internalization of the alpha 1-adrenergic receptor in hepatocytes.
12
Bonsignore, M. R., E. H. Jerome, and N. C. Staub. "Alpha-adrenergic agents have little effect during air embolism lung injury in awake sheep." Journal of Applied Physiology 62, no. 6 (1987): 2147–53. http://dx.doi.org/10.1152/jappl.1987.62.6.2147.
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Since it is not clear whether alpha-adrenergic receptors can modulate lung microvascular liquid and protein leakiness, we studied the effects of alpha-adrenergic receptor stimulation or blockade on lung filtration under base-line conditions and during the acute lung injury caused by a 4-h infusion of venous air emboli in six unanesthetized, chronically instrumented sheep with lung lymph fistulas. During the experiments we continuously infused the alpha-adrenergic receptor agonist phenylephrine hydrochloride (1.0 microgram X kg-1 X min-1 iv) or the alpha-adrenergic receptor antagonist phentolamine mesylate (1.0 mg X kg-1 X min-1 iv), and we measured pulmonary vascular pressures, cardiac output, lung lymph flow, and the lymph-to-plasma protein concentration ratio. During air embolism, alpha-receptor stimulation increased pulmonary vascular resistance and decreased lung lymph flow by 25%; alpha-receptor blockade had the opposite effects. During recovery, neither agent significantly affected pulmonary hemodynamics or lymph flow. Our results indicate that alpha-adrenergic receptors are active during air embolism and modulate pulmonary filtration by causing arteriolar constriction, which reduces the surface area or the perfusion pressure in the pulmonary microvascular bed. They may also affect venous smooth muscle tone. We found no evidence that alpha-adrenergic receptors modulate lung microvascular liquid or protein leakiness directly.
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ROMERO-ÁVILA, M. Teresa, C. Fabián FLORES-JASSO та J. Adolfo GARCÍA-SÁINZ. "α1B-Adrenergic receptor phosphorylation and desensitization induced by transforming growth factor-β". Biochemical Journal 368, № 2 (2002): 581–87. http://dx.doi.org/10.1042/bj20021052.
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Transforming growth factor-β (TGF-β) induced α1B-adrenergic receptor phosphorylation in Rat-1 fibroblasts stably expressing these adrenoceptors. This effect of TGF-β was rapid, reaching a maximum within 30min and decreasing thereafter, and concentration-dependent (EC50 0.3pM). The phosphoinositide 3-kinase inhibitors wortmannin and LY294002, and the protein kinase C inhibitors staurosporine, Ro 318220 and bisindolylmaleimide, blocked the effect of this growth factor. α1B-Adrenergic receptor phosphorylation was associated with desensitization, as indicated by a reduction in the adrenergic-mediated production of [3H]inositol phosphates. Phosphorylation of α1B-adrenergic receptors by TGF-β was also observed in Cos-1 cells transfected with the receptor. Co-transfection of the dominant-negative mutant of the regulatory subunit of phosphoinositide 3-kinase (Δp85) inhibited the phosphorylation of α1B-adrenergic receptors induced by TGF-β. Our results indicate that activation of TGF-β receptors induces α1B-adrenergic receptor phosphorylation and desensitization. The data suggest that phosphoinositide 3-kinase and protein kinase C play key roles in this effect of TGF-β.
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Meier, K. E., D. M. Sperling, and P. A. Insel. "Agonist-mediated regulation of alpha 1- and beta 2-adrenergic receptors in cloned MDCK cells." American Journal of Physiology-Cell Physiology 249, no. 1 (1985): C69—C77. http://dx.doi.org/10.1152/ajpcell.1985.249.1.c69.
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Chronic exposure of cells to neurotransmitters and hormones can result in a decrease in receptor number (down-regulation). We asked whether two different types of receptors on the same cell that can both respond to a particular hormone are identically regulated. For this study we used MDCK-D-1, a cloned renal epithelial cell line that coexpresses alpha 1- and beta 2-adrenergic receptors, as a model system in which to examine the effects of an adrenergic agonist on the expression and function of these receptors. MDCK-D-1 cells retain differentiated features of renal tubular epithelium with respect to morphology and hormonal responsiveness. When MDCK-D-1 cells were incubated for 21 h with 100 microM epinephrine, alpha 1- and beta 2-receptor numbers decreased by 81 and 90%, respectively. The down-regulation of beta 2-receptors proceeded more rapidly than that of alpha 1-receptors. Down-regulated cells showed a greater than 80% loss of both alpha 1- and beta 2-adrenergic responses (alpha 1: stimulation of prostaglandin E2 release; beta 2: elevation of adenosine 3',5'-cyclic monophosphate levels). We conclude that in renal epithelial cells chronic exposure to a catecholamine agonist can result in a profound decrease in the number of alpha 1- and beta 2-receptors, this down-regulation is accompanied by a loss of adrenergic response, and the kinetics of receptor loss are different for alpha 1- and beta 2-receptors.
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Frey, M. J., D. Mancini, D. Fischberg, J. R. Wilson, and P. B. Molinoff. "Effect of exercise duration on density and coupling of beta-adrenergic receptors on human mononuclear cells." Journal of Applied Physiology 66, no. 3 (1989): 1494–500. http://dx.doi.org/10.1152/jappl.1989.66.3.1494.
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The effect of maximal exercise on lymphocyte beta-adrenergic receptors was examined in 26 normal subjects. Exercise increased O2 consumption (Vo2) from 5 +/- 1 to 50 +/- 4 ml.min-1.kg-1, plasma norepinephrine level from 188 +/- 28 to 2,682 +/- 160 pg/ml, and plasma epinephrine level from 94 +/- 72 to 857 +/- 180 pg/ml. The density of beta-adrenergic receptors on lymphocytes obtained at rest was 31 +/- 3.7 fmol/mg protein; exercise increased the density of receptors by 86 +/- 33% (range 0–257%) to 58.3 +/- 1.5 fmol/mg protein but did not alter the affinity of the receptor for [125I]iodopindolol or the coupling of the receptor to the guanine nucleotide-binding regulatory protein. The density of beta-adrenergic receptors increased progressively throughout exercise and paralleled the increase in heart rate. The magnitude of the change in the density of beta-adrenergic receptors did not correlate with the magnitude of the increase in heart rate, Vo2, or plasma levels of catecholamines. The density of receptors was still elevated 15 min after completion of exercise but fell below base line 1 h after peak exercise to 18.2 +/- 6.7 fmol/mg protein (P less than 0.05 vs. base-line levels). These results demonstrate that exhaustive exercise results in a progressive increase in the number of beta-adrenergic receptors on lymphocyte membranes, followed by a reduction in the density of receptors during the recovery phase of exercise. Despite a significant increase in the level of plasma catecholamines, the receptor remains coupled to the guanine nucleotide-binding regulatory protein.
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Doshi, R., E. Strandness, and D. Bernstein. "Regulation of atrial autonomic receptors in experimental cyanotic heart disease." American Journal of Physiology-Heart and Circulatory Physiology 261, no. 4 (1991): H1135—H1140. http://dx.doi.org/10.1152/ajpheart.1991.261.4.h1135.
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During chronic hypoxemia, left ventricular beta-adrenergic receptor density is decreased and a dissociation occurs between increased chronotropic and decreased inotropic responses to chronically elevated sympathetic tone. To determine whether this dissociation was related to alterations in autonomic receptor populations in the right atrium, we studied right atrial cholinergic and beta-adrenergic receptors in chronically hypoxemic newborn lambs and in normoxemic controls. Heart rate response was determined by infusing isoproterenol at 0.1 or 0.5 microgram.kg-1.min-1. Muscarinic receptors were quantified with [3H]quinuclidinyl benzilate and beta-adrenergic receptors with [125I]iodocyanopindolol. Competition with ICI 118,551 was used to determine beta 1- vs. beta 2-receptor subtypes. In the hypoxemic lambs, isoproterenol resulted in a lesser percentage increase in heart rate (hypoxemic, 46 +/- 6% vs. control, 89 +/- 17%, P less than 0.05); however, because baseline heart rate was higher in the hypoxemic lambs (213 +/- 7 vs. 177 +/- 12 beats/min, P less than 0.05), maximal heart rate responses were similar (310 +/- 7 vs. 326 +/- 6 beats/min, NS). There was no change in receptor density or affinity of either muscarinic or beta-adrenergic receptors and no change in the proportion of beta 1- vs. beta 2-receptor subtypes. Thus the dissociation between the chronotropic and inotropic responses to chronic hypoxemia may be in part secondary to a differential regulation of beta-adrenergic receptors between the left ventricle and the right atrium.
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Schwinn, Debra A. "IL-8 α1-Adrenergic Receptors and LUTS". Japanese Journal of Urology 98, № 2 (2007): 61. http://dx.doi.org/10.5980/jpnjurol.98.61.
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Sundaresan, P. R., T. L. Fortin, and S. L. Kelvie. "Alpha- and beta-adrenergic receptors in proximal tubules of rat kidney." American Journal of Physiology-Renal Physiology 253, no. 5 (1987): F848—F856. http://dx.doi.org/10.1152/ajprenal.1987.253.5.f848.
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Proximal tubules were isolated from the rat kidney by collagenase digestion of the cortical tissue followed by Percoll gradient centrifugation. Microscopic and hormone-stimulated adenylate cyclase activity studies proved the purity of the preparation. [3H]Prazosin, [3H]rauwolscine, and [125I]iodocyanopindolol were used to identify and quantitate respectively the alpha 1-, alpha 2- and beta-adrenergic receptors. Proximal tubular (F4) particulate fraction was compared against other cortical nephron segment (F1, F2) fractions and the total collagenase-digested cortex particulate suspension (Ft). Proximal tubules were enriched in alpha 1- and alpha 2-adrenergic receptors compared with Ft (alpha 1-receptor, 100.4 +/- 4.5 vs. 87.4 +/- 4.9; alpha 2-receptor, 250 +/- 16.2 vs. 185.1 +/- 12 fmol/mg protein). The fractions enriched in glomeruli and distal tubular segments (F1, F2) had relatively low concentrations of alpha 1- and alpha 2-adrenergic receptors. In contrast, beta-adrenergic receptor concentration in the proximal tubules was approximately 25% of that in the Ft fraction and approximately 10% of that in the F1 fraction. Isoproterenol-stimulated adenylate cyclase activities in the different fractions corroborated well with the pattern suggested by the [125I]iodocyanopindolol binding studies. Our results suggest that whole-cortex preparation radioligand binding studies may reflect proximal tubular alpha 1- and alpha 2-adrenergic receptor changes quite well. They may, however, miss or give erroneous impressions about beta-adrenergic receptor changes occurring in different cortical nephron segments.
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Kagiya, T., M. Hori, K. Iwakura, et al. "Role of increased alpha 1-adrenergic activity in cardiomyopathic Syrian hamster." American Journal of Physiology-Heart and Circulatory Physiology 260, no. 1 (1991): H80—H88. http://dx.doi.org/10.1152/ajpheart.1991.260.1.h80.
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We investigated serial changes in myocardial norepinephrine content and myocardial adrenergic receptors during the development of cardiomyopathy in Syrian hamsters (Bio 14.6) and their age-matched healthy controls. We also examined phosphatidylinositide hydrolysis after alpha 1-adrenergic stimulation and the effects of alpha 1-blockade. We found that in the prehypertrophic stage, myocardial norepinephrine content and densities of alpha 1- and beta-adrenergic receptors were significantly higher in the cardiomyopathic hamsters than in the controls. However, in the early heart failure stage, beta-receptor density was 28% lower than that of the age-matched controls, although alpha 1-receptor density remained 55% higher. Norepinephrine-stimulated phosphatidylinositide hydrolysis in the cardiomyopathic hamster in the hypertrophic stage was twice that in the controls, indicating that the increase in alpha 1-adrenergic receptors is coupled with the intracellular signal transduction. Furthermore, selective alpha 1-adrenoceptor blockade by bunazosin in the cardiomyopathic hamsters from 70 to 170 days of age reduced myocardial hypertrophy and focal myocardial necrosis. Thus we conclude that increased alpha 1-adrenergic activity plays an important role in progression of cardiac hypertrophy is cardiomyopathic Syrian hamsters.
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Wang, H. Y., M. Berrios та C. C. Malbon. "Localization of β-adrenergic receptors in A431 cells in situ. Effect of chronic exposure to agonist". Biochemical Journal 263, № 2 (1989): 533–38. http://dx.doi.org/10.1042/bj2630533.
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The status of beta-adrenergic receptors was investigated in A431 cells exposed to chronic stimulation by the beta-adrenergic agonist, (-)-isoproterenol. Specific binding of beta-adrenergic antagonist (-)-[125I]iodocyanopindolol declined to 60-80% below control values within 12 h of agonist treatment. This decline in ligand binding was also observed in high-speed membrane fractions prepared from agonist-treated cells. Immunoblots probed with anti-receptor antibodies revealed both that beta-adrenergic receptors from untreated and treated cells migrated as 65,000-Mr peptides and that the cellular complement of receptor was unchanged. Indirect immunofluorescence localization of beta-adrenergic receptors was comparable in control (untreated) cells and cells challenged with (-)-isoproterenol for 1, 12, or 24 h. Thus receptor complement, migration on SDS/polyacrylamide-gel electrophoresis, and localization in situ are largely unaffected by agonist stimulation. Receptor binding of antagonist radioligands, in contrast, is markedly down-regulated in cells stimulated chronically with beta-adrenergic agonists. These data argue in favour of agonist-induced alteration(s) in the conformation of the receptor that preclude radioligand binding rather than agonist-induced receptor sequestration and/or degradation.
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Studer, R. K., and L. Ganas. "Hepatic sexual dimorphism: ontogeny and influence of adult gonadectomy." American Journal of Physiology-Endocrinology and Metabolism 256, no. 3 (1989): E392—E400. http://dx.doi.org/10.1152/ajpendo.1989.256.3.e392.
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The ontogeny of alpha 1- and beta-adrenergic receptors and their relative stimulation of phosphorylase alpha activity in hepatic tissue from male and female rats were compared. A decrease in beta-adrenergic receptor concentration and 4-(t-butylamino-2-hydroxypropoxy)-[5,7-3H]benzimidazol-2-one HCl affinity for these sites was found in males and females, when data from membranes of 20- to 22-day animals was compared with that from neonates. No subsequent decline in receptor concentration was noted in the female; however, the beta-mediated phosphorylase activation was further diminished by 49-56 days, suggesting maturational changes beyond the receptor-adenylate cyclase system. Although high-affinity beta-adrenergic receptors were documented in membranes from pubertal males, they were not identified on the intact cells, and activation of phosphorylase alpha via the beta-pathway was minimal. This suggests the majority of the beta-receptors are sequestered in cellular sites not accessible to the hydrophilic ligand or epinephrine in the sexually mature male. Ontogeny of the alpha 1-adrenergic receptors was similar in males and females. Gonadectomy of mature males and females did not eliminate the sexual differences in adrenergic response. However, the ovariectomized females developed an enhanced basal and alpha-adrenergic stimulated phosphorylase activity. The rise in cytosolic free calcium in response to epinephrine was increased in the ovariectomized females to values seen in the intact male, whereas the response in the castrate male was depressed. The results suggest the dimorphism in alpha 1- and beta-adrenergic receptor function is determined by factors other than the ambient concentration of sex steroids in the adult.(ABSTRACT TRUNCATED AT 250 WORDS)
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Plato, Craig F. "α-2 And β-adrenergic receptors mediate NE's biphasic effects on rat thick ascending limb chloride flux". American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 281, № 3 (2001): R979—R986. http://dx.doi.org/10.1152/ajpregu.2001.281.3.r979.
Full textAbstract:
The sympathetic neurotransmitter norepinephrine (NE) influences renal sodium excretion via activation of adrenergic receptors. The thick ascending limb (THAL) possesses both α-2 and β-adrenergic receptors. However, the role(s) different adrenergic receptors play in how isolated THALs respond to NE are unclear. We tested the hypothesis that both α-2 and β-adrenergic receptors are responsive to NE in the isolated THAL, with α-2 receptors inhibiting and β-receptors stimulating chloride flux ( J Cl). THALs from male Sprague-Dawley rats were perfused in vitro, and the effects of 1) incremental NE, 2) the α-2 agonist clonidine, and 3) the β-agonist isoproterenol on J Cl were measured. Low concentrations (0.1 nM) of NE decreased J Clfrom a rate of 114.2 ± 8.1 to 93.5 ± 14.6 pmol · mm−1 · min−1( P < 0.05), with the nadir occurring at 1 nM (67.7 ± 8.8 pmol · mm−1 · min−1; P < 0.05). In contrast, greater concentrations of NE significantly increased J Cl from the nadir to a maximal rate of 131.0 ± 28.5 pmol · mm−1 · min−1 at 10 μM ( P < 0.05). To evaluate the adrenergic receptors mediating these responses, the THAL J Cl response to NE was measured in the presence of selective antagonists of β- and α-2 receptors. A concentration of NE (1 μM), which alone tended to increase J Cl, decreased THAL J Cl (from 148.9 ± 16.4 to 76.2 ± 13.6 pmol · mm−1 · min−1; P < 0.01) in the presence of the β-antagonist propranolol. In contrast, a concentration of NE (0.1 μM), which alone tended to decrease J Cl, increased THAL J Cl (from 85.5 ± 20.1 to 111.8 ± 20.1 pmol · mm−1 · min−1; P < 0.05) in the presence of the α-2 antagonist rauwolscine. To further clarify the role of different adrenergic receptors, selective adrenergic agonists were used. The α-2 agonist clonidine decreased J Cl from 102.4 ± 9.9 to 54.0 ± 15.7 pmol · mm−1 · min−1, a reduction of 49.1 ± 11.0% ( P < 0.02). In contrast, the β-agonist isoproterenol stimulated J Cl from 95.3 ± 11.6 to 144.1 ± 15.0 pmol · mm−1 · min−1, an increase of 56 ± 14% ( P < 0.01). We conclude that 1) the sympathetic neurotransmitter NE exerts concentration-dependent effects on J Cl in the isolated rat THAL, 2) selective α-2 receptor activation inhibits THAL J Cl, and 3) selective β-receptor activation stimulates THAL J Cl. These data indicate the response elicited by the isolated rat THAL to NE is dependent on the neurotransmitter concentration, such that application of NE in vitro biphasically modulates J Cl via differential activation of α-2 and β-adrenergic receptors in a concentration-dependent manner.
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Baglole, Carolyn J., Joseph S. Davison, and Jonathan B. Meddings. "Epithelial distribution of neural receptors in the guinea pig small intestine." Canadian Journal of Physiology and Pharmacology 83, no. 5 (2005): 389–95. http://dx.doi.org/10.1139/y05-024.
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Neural and paracrine agents, such as dopamine, epinephrine, and histamine, affect intestinal epithelial function, but it is unclear if these agents act on receptors directly at the enterocyte level. The cellular localization and villus-crypt distribution of adrenergic, dopamine, and histamine receptors within the intestinal epithelium is obscure and needs to be identified. Single cell populations of villus or crypt epithelial cells were isolated from the jejunum of adult guinea pigs. Enterocytes were separated from intraepithelial lymphocytes by flow cytometry and specific binding was determined using fluorescent probes. α1-adrenergic receptors were located on villus and crypt intraepithelial lymphocytes and enterocytes. β-adrenergic receptors were found on villus and crypt enterocytes. Dopamine receptors were found on all cell types examined, whereas histamine receptors were not detected (<10% for each cell population). These studies demonstrated that (1) receptors for epinephrine and dopamine exist on epithelial cells of the guinea pig jejunum, (2) β-adrenergic receptors are found primarily on villus and crypt enterocytes and (3) intraepithelial lymphocytes contain α1-adrenergic, but have few β-adrenergic, receptors. The presence of neural receptors suggests that these agents are acting, at least in part, at the enterocyte or intraepithelial lymphocyte levels to modulate intestinal and immune function.Key words: enterocyte, receptor, intestine, epithelium.
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Mauduit, P., G. Herman, and B. Rossignol. "Protein secretion in lacrimal gland: alpha 1-beta-adrenergic synergism." American Journal of Physiology-Cell Physiology 250, no. 5 (1986): C704—C712. http://dx.doi.org/10.1152/ajpcell.1986.250.5.c704.
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We have shown the existence of a homogeneous population of specific binding sites for [3H]prazosin in membranes from rat lacrimal glands. The value of the equilibrium dissociation constant was 0.186 +/- 0.07 nM, and the density of specific binding sites was 20.4 +/- 1 fmol/mg protein. Taking into account the potency sequences for adrenergic agonists and antagonists for competition with these [3H]prazosin binding sites, we identified them as alpha 1-adrenergic receptors. Moreover, we have demonstrated that the stimulation of protein discharge evoked by epinephrine could be partly attributed to the occupation of this alpha-adrenergic receptor subtype. However, the inhibition pattern of the epinephrine effect by a beta-adrenergic antagonist, 1-propranolol, and the characteristics of the secretory response observed when selectively stimulating the alpha 1- and beta-adrenergic receptors, either separately or simultaneously, suggest that 1) a simultaneous activation of both receptors is necessary to produce a maximal secretory response to catecholamines; and 2) a synergism may exist between these two routes of stimulation, leading to an amount of protein discharge higher than that expected in the case of additive effects.
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Feldstein, J. B., R. A. Gonzales, S. P. Baker, C. Sumners, F. T. Crews, and M. K. Raizada. "Decreased alpha 1-adrenergic receptor-mediated inositide hydrolysis in neurons from hypertensive rat brain." American Journal of Physiology-Cell Physiology 251, no. 2 (1986): C230—C237. http://dx.doi.org/10.1152/ajpcell.1986.251.2.c230.
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The expression of alpha 1-adrenergic receptors and norepinephrine (NE)-stimulated hydrolysis of inositol phospholipid has been studied in neuronal cultures from the brains of normotensive (Wistar-Kyoto, WKY) and spontaneously hypertensive (SH) rats. Binding of 125I-2-[beta-(4-hydroxyphenyl)-ethyl-aminomethyl] tetralone (HEAT) to neuronal membranes was 68-85% specific and was rapid. Competition-inhibition experiments with various agonists and antagonists suggested that 125I-HEAT bound selectively to alpha 1-adrenergic receptors. Specific binding of 125I-HEAT to neuronal membranes from SH rat brain cultures was 30-45% higher compared with binding in WKY normotensive controls. This increase was attributed to an increase in the number of alpha 1-adrenergic receptors on SH rat brain neurons. Incubation of neuronal cultures of rat brain from both strains with NE resulted in a concentration-dependent stimulation of release of inositol phosphates, although neurons from SH rat brains were 40% less responsive compared with WKY controls. The decrease in responsiveness of SH rat brain neurons to NE, even though the alpha 1-adrenergic receptors are increased, does not appear to be due to a general defect in membrane receptors and postreceptor signal transduction mechanisms. This is because neither the number of muscarinic-cholinergic receptors nor the carbachol-stimulated release of inositol phosphates is different in neuronal cultures from the brains of SH rats compared with neuronal cultures from the brains of WKY rats. These observations suggest that the increased expression of alpha 1-adrenergic receptors does not parallel the receptor-mediated inositol phosphate hydrolysis in neuronal cultures from SH rat brain.
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Terman, B. I., J. F. Reece, R. D. Brown та P. A. Insel. "The oligosaccharide component of α 1-adrenergic receptors from BC3H1 and DDT1 muscle cells. Studies with glycosidases and photoaffinity labelling of intact cells". Biochemical Journal 253, № 2 (1988): 363–70. http://dx.doi.org/10.1042/bj2530363.
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In this study, we clarify the structural aspects of the oligosaccharides associated with the alpha 1-adrenergic receptor in two muscle cell lines. Photoaffinity labelling of intact BC3H1 or DDT1 muscle cells with 2-[4-(4-azido-3-[125I]iodobenzoyl)piperazin-1-yl]-4-amino-6, 7-dimethoxyquinazoline ([125I]azidoprazosin) followed by SDS/polyacrylamide-gel electrophoresis (PAGE) and autoradiography revealed specifically labelled proteins of molecular mass = 87,000 and 81,000, respectively. Treatment of photoaffinity-labelled receptors in DDT1 cells with 33 u. of endoglycosidase F/ml for 24 h resulted in the loss of the 81 kDa receptor and the appearance of a 52.5 kDa protein. When lower concentrations of glycosidase or shorter incubation times were used, the 81 kDa receptor was converted to a 66 kDa protein. Treatment of the photoaffinity-labelled BC3H1 receptor with endoglycosidase F resulted in the appearance of a 50.5 kDa protein. Neither alpha-mannosidase nor endoglycosidase H had an effect on the photoaffinity labelling patterns of the receptor from the two cell types. alpha 1-Adrenergic receptors, solubilized from membranes prepared from BC3H1 and DDT1 cells, bound to wheat germ agglutinin-Sepharose and were displaced by N-acetylglucosamine. Taken together, these results indicate that alpha 1-adrenergic receptors in BC3H1 and DDT1 cells contain complex, but not high, mannose oligosaccharide chains; differences in the composition or number of chains partially accounts for the different molecular mass of the receptor in the two cell lines. The results further indicate that the oligosaccharide chains contribute substantially to the apparent molecular mass of alpha 1-adrenergic receptors, as detected by SDS/PAGE, and that the protein backbone of these receptors is likely to be approximately 50 kDa.
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Tithof, Patricia K., Mona Elgayyar, Hildegard M. Schuller, Maryann Barnhill, and Richard Andrews. "4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone, a nicotine derivative, induces apoptosis of endothelial cells." American Journal of Physiology-Heart and Circulatory Physiology 281, no. 5 (2001): H1946—H1954. http://dx.doi.org/10.1152/ajpheart.2001.281.5.h1946.
Full textAbstract:
Smoking causes endothelial cell (EC) injury; however, neither the components of cigarette smoke nor the mechanisms responsible for this injury are understood. The nitrosated derivative of nicotine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), has been implicated in the carcinogenic effects of tobacco; however, the effects of NNK on the cardiovascular system are largely unknown. NNK binds to β1- and β2-adrenergic receptors. Because β-adrenergic receptor activation causes arachidonic acid (AA) release and cellular injury, we postulated that NNK causes EC injury by a mechanism that involves β-adrenergic-mediated release of AA. NNK stimulated [3H]AA release from ECs, and this effect was mediated by both β1- and β2-adrenergic receptors because pretreatment with atenolol or ICI 118,551 inhibited the response. NNK also induced EC apoptosis, as measured by terminal deoxyribonucleotide transferase-mediated dUTP nick-end labeling and annexin V staining. NNK-mediated apoptosis was attenuated by pretreatment with atenolol or ICI 118,551. Furthermore, depletion of cellular AA by incubation with eicosapentaenoic acid abolished the apoptotic effect of NNK. These data suggest that NNK causes EC apoptosis by a mechanism that involves β1- and β2-adrenergic receptor-mediated release of AA.
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Vatner, D. E., K. Kiuchi, W. T. Manders, and S. F. Vatner. "Effects of coronary arterial reperfusion on beta-adrenergic receptor-adenylyl cyclase coupling." American Journal of Physiology-Heart and Circulatory Physiology 264, no. 1 (1993): H196—H204. http://dx.doi.org/10.1152/ajpheart.1993.264.1.h196.
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The effects of 1 h of coronary arterial occlusion (CAO) followed by 15 min reperfusion (CAR) were examined in nine conscious dogs. Ischemia was verified by decreased regional blood flow (radioactive microspheres) and loss of systolic regional wall motion in the ischemic zone. beta-Adrenergic receptor density assessed by 125I-labeled cyanopindolol binding in a crude membrane fraction tended to decrease but was not significantly different. However, adenylyl cyclase activity and the guanine nucleotide stimulatory protein (Gs) were reduced in ischemic subendocardium compared with nonischemic subendocardium. The fraction of beta-adrenergic receptors binding agonist with high affinity increased in ischemic subendocardial and subepicardial layers. Compared with prior data in experiments with 1 h CAO without CAR, the increase in beta-adrenergic receptor density that occurs with myocardial ischemia is rapidly reversed with CAR of 15 min duration, while the decreased fraction of receptors binding agonist with high affinity was reversed to an increase in high-affinity receptors. The global decreases in adenylyl cyclase and Gs, which have been observed with simple CAO, persist but are observed selectively in the previously ischemic subendocardium after CAR. Thus both CAO and CAR affect beta-adrenergic receptors and adenylyl cyclase differently. During CAR, increased numbers of beta-adrenergic receptors binding agonist with high affinity occur potentially as a compensatory mechanism in the face of persistent reductions in adenylyl cyclase activity and Gs.
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Fortin, T. L., and P. R. Sundaresan. "Reserpine but not surgical denervation regulates rat renal beta-adrenergic receptors." American Journal of Physiology-Renal Physiology 256, no. 4 (1989): F532—F539. http://dx.doi.org/10.1152/ajprenal.1989.256.4.f532.
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The effects of unilateral surgical denervation or reserpine administration on renal beta-adrenergic receptors were examined in rat kidney cortex. The specific binding of [125I]iodocyanopindolol was used to quantitate the beta-adrenoceptors. Denervation had no significant effect on beta-adrenoceptor concentration in denervated compared with contralateral control kidney, 7 days postsurgery. In contrast, reserpine treatment increased beta-adrenoceptor concentration 30% compared with control (P less than 0.05). Tissue norepinephrine levels were depleted to a significant extent with both manipulations. The reserpine effect was investigated further. Reserpine increased both beta 1- and beta 2-adrenergic receptor subtypes to the same extent. The effect of reserpine was primarily on tubular beta-adrenoceptors including those in the proximal tubules; glomerular beta-adrenoceptors were minimally affected by reserpine. Other adrenergic receptor subtypes (alpha 1- and alpha 2-) were also significantly increased by reserpine; however, angiotensin II receptors were not altered, indicating that the reserpine effect was not a general one affecting all membrane receptors. Reserpine treatment increased beta-adrenergic receptor-stimulated adenosine 3',5'-cyclic monophosphate (cAMP) accumulation by 49% over control in the renal cortex. Denervation had no significant effect on cAMP accumulation. Overall, our results suggest that, in addition to sympathetic nerve terminal norepinephrine, other factors may be involved in the regulation of renal beta-adrenergic receptors.
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Dillon, Patrick F., Robert S. Root-Bernstein, and Charles M. Lieder. "Ascorbate enhancement of H1 histamine receptor sensitivity coincides with ascorbate oxidation inhibition by histamine receptors." American Journal of Physiology-Cell Physiology 291, no. 5 (2006): C977—C984. http://dx.doi.org/10.1152/ajpcell.00613.2005.
Full textAbstract:
Ascorbate has previously been shown to enhance both α1- and β2-adrenergic activity. This activity is mediated by ascorbate binding to the extracellular domain of the adrenergic receptor, which also decreases the oxidation rate of ascorbate. H1 histamine receptors have extracellular agonist or ascorbate binding sites with strong similarities to α1- and β2-adrenergic receptors. Physiological concentrations of ascorbate (50 μM) significantly enhanced histamine contractions of rabbit aorta on the lower half of the histamine dose-response curve, increasing contractions of 0.1, 0.2, and 0.3 μM histamine by two- to threefold. Increases in ascorbate concentration significantly enhanced 0.2 μM histamine (5–500 μM ascorbate) and 0.3 μM histamine (15–500 μM ascorbate) in a dose-dependent manner. Histamine does not measurably oxidize over 20 h in oxygenated PSS at 37°C. Thus the ascorbate enhancement is independent of ascorbate's antioxidant effects. Ascorbate in solution oxidizes rapidly. Transfected histamine receptor membrane suspension with protein concentration at >3.1 μg/ml (56 nM maximum histamine receptor) decreases the oxidation rate of 392 μM ascorbate, and virtually no ascorbate oxidation occurs at >0.0004 mol histamine receptor/mol ascorbate. Histamine receptor membrane had an initial ascorbate oxidation inhibition rate of 0.094 min·μg protein−1·ml−1, compared with rates for transfected ANG II membrane (0.055 min·μg protein−1·ml−1), untransfected membrane (0.052 min·μg protein−1·ml−1), creatine kinase (0.0082 min·μg protein−1·ml−1), keyhole limpet hemocyanin (0.00092 min·μg protein−1·ml−1), and osmotically lysed aortic rings (0.00057 min·μg wet weight−1·ml−1). Ascorbate enhancement of seven-transmembrane-spanning membrane receptor activity occurs in both adrenergic and histaminergic receptors. These receptors may play a significant role in maintaining extracellular ascorbate in a reduced state.
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Liggett, S. B., S. D. Shah, and P. E. Cryer. "Characterization of beta-adrenergic receptors of human skeletal muscle obtained by needle biopsy." American Journal of Physiology-Endocrinology and Metabolism 254, no. 6 (1988): E795—E798. http://dx.doi.org/10.1152/ajpendo.1988.254.6.e795.
Full textAbstract:
Human skeletal muscle beta-adrenergic receptors were characterized by 125I-iodopindolol radioligand-binding studies of homogenates prepared from small muscle samples obtained by percutaneous needle biopsy from the gastrocnemius of six normal subjects. Binding was saturable, reversible, and stereospecific, with typical kinetics and a rank-order potency characteristic of a beta-adrenergic receptor. In saturation-binding studies, the receptor density was 9.7 +/- 1.9 fmol/mg protein, with a dissociation constant of 24 +/- 2.2 pM. Competition studies with selective antagonists revealed a population of receptors exclusively of the beta 2-subtype. Basal and isoproterenol-stimulated adenylate cyclase activities were 79 +/- 22 and 150 +/- 60 pmol adenosine 3',5'-cyclic monophosphate.min-1.mg protein-1, respectively. These results support pharmacological observations of beta-adrenergic receptor-mediated cellular responses in mammalian skeletal muscle. By use of these methods, small quantities of skeletal muscle obtained in this manner can be used to study in vivo beta-adrenergic receptor regulatory phenomena in humans.
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Haddad, E. B., J. C. Mak, M. G. Belvisi, M. Nishikawa, J. Rousell, and P. J. Barnes. "Muscarinic and beta-adrenergic receptor expression in peripheral lung from normal and asthmatic patients." American Journal of Physiology-Lung Cellular and Molecular Physiology 270, no. 6 (1996): L947—L953. http://dx.doi.org/10.1152/ajplung.1996.270.6.l947.
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We used human peripheral lung from 8 mildly asthmatic patients and 11 normal donors to study the expression of muscarinic and beta-adrenergic receptors in asthma. There was no significant difference in the affinity or the density of muscarinic (labeled with [N-methyl-3H]scopolamine) and beta 1- and beta 2-adrenergic receptors (labeled with [125I]iodocyanopindolol) in peripheral lung from asthmatics compared with nonasthmatics. Only the muscarinic m1 receptor mRNA was detected in human lung using Northern blot analysis. Additionally, peripheral lung cellular mRNA hybridized to human beta 1 and beta 2 cDNA probes, giving 3.2- and 2.2-kb hands corresponding to beta 1 and beta 2-adrenergic receptors mRNA, respectively. Densitometric scanning of the autoradiograms suggests that there was no significant difference in the relative abundance of muscarinic m1 and beta 1- and beta 2-adrenergic receptor mRNA in asthmatic compared with nonasthmatic lungs. Functional experiments obtained in trachea suggest that there was an increase in the cholinergic neural response evoked by electrical field stimulation in asthmatic compared with nonasthmatic tissues which was not due to a reduction in inhibitory noncholinergic nonadrenergic relaxations.
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Frielle, T., M. G. Caron, and R. J. Lefkowitz. "Properties of the beta 1- and beta 2-adrenergic receptor subtypes revealed by molecular cloning." Clinical Chemistry 35, no. 5 (1989): 721–25. http://dx.doi.org/10.1093/clinchem/35.5.721.
Full textAbstract:
Abstract The beta 1- and beta 2-adrenergic receptor subtypes are biochemically and functionally similar, because both receptors mediate the catecholamine-dependent activation of adenylate cyclase through the GTP-binding protein, Gs. Pharmacologically, the two receptors can be distinguished on the basis of their relative affinities for the agonists epinephrine and norepinephrine as well as their affinities for several selective antagonists. The primary structures of the human beta 1- and beta 2-adrenergic receptors have recently been deduced from the cloning of their genes and (or) cDNAs, revealing high sequence homology and a membrane topography of seven putative transmembrane regions similar to that of rhodopsin. Chimeric beta 1/beta 2-adrenergic receptor cDNAs have been constructed by site-directed mutagenesis and the chimeric RNA transcripts expressed in Xenopus laevis oocytes. The pharmacological properties of the expressed chimeric receptor proteins were assessed by radioligand binding utilizing subtype-selective agonists and antagonists. Apparently, several of the putative transmembrane regions contribute significantly to the determination of subtype selectivity, presumably by formation of a ligand-binding pocket, with determinants for agonist and antagonist binding being distinguishable.
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Jasper, J. R., H. J. Motulsky, L. C. Mahan, and P. A. Insel. "Beta-adrenoceptor metabolism in wild-type, Gs, and protein kinase A-variant S49 cells." American Journal of Physiology-Cell Physiology 259, no. 1 (1990): C41—C46. http://dx.doi.org/10.1152/ajpcell.1990.259.1.c41.
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To determine the role of the stimulatory guanine nucleotide-binding protein, Gs, and adenosine 3',5'-cyclic monophosphate (cAMP)-dependent protein kinase in the basal metabolism of beta-adrenergic receptors in S49 lymphoma cells, we measured the return of receptor number and function after irreversible blockade of receptors. After inactivation of receptors with the irreversible ligand N8-(bromoacetyl)-N'-[3-(4-indolyoxy)-2-hydroxypropyl]-(2)-1,8-diam ino-p- methane (BIM), beta-adrenergic receptors (defined as [125I]iodocyanopindolol binding sites) reappeared in a biphasic manner, the faster phase having a half-time (t 1/2) of 3-8 h (approximately 50% of the sites) and the slower phase greater than 40 h. Although the slow phase is not readily explained, recovery of binding sites during the first 10 h matched recovery of receptor function after BIM treatment (as measured by stimulation of cAMP accumulation) and recovery of receptor sites after downregulation induced by the agonist isoproterenol. Thus quantifying receptor recovery during the first 10 h after BIM treatment appears to be a reasonable method for examining basal receptor metabolism in S49 cells. Measured in this way, metabolism of beta-adrenergic receptors is very similar in wild-type S49 and the following variant clones: cyc- (absent Gs alpha), UNC and H21a (defective Gs alpha), and kin- (lacking cAMP-dependent protein kinase activity). Although previous data have demonstrated that agonist-promoted downregulation of beta-adrenergic receptors requires functional receptor-Gs coupling, the current data suggest that neither Gs nor cAMP-dependent protein kinase activity plays an important role in the regulation of basal metabolism of beta-adrenergic receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
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Levy, F. O., X. Zhu, A. J. Kaumann, and L. Birnbaumer. "Efficacy of beta 1-adrenergic receptors is lower than that of beta 2-adrenergic receptors." Proceedings of the National Academy of Sciences 90, no. 22 (1993): 10798–802. http://dx.doi.org/10.1073/pnas.90.22.10798.
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Feldman, R. D., J. P. Christy, S. T. Paul, and D. G. Harrison. "Beta-adrenergic receptors on canine coronary collateral vessels: characterization and function." American Journal of Physiology-Heart and Circulatory Physiology 257, no. 5 (1989): H1634—H1639. http://dx.doi.org/10.1152/ajpheart.1989.257.5.h1634.
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The present studies were performed to examine the role of beta-adrenergic receptors in modulating smooth muscle tone in mature coronary collaterals. To examine the beta-adrenergic receptor population present, radioligand binding-cover slip autoradiographic studies were performed on sections of native canine coronary vessels and sections of coronary collaterals developed after placement of Ameroid constrictors. Specific binding of the nonselective beta-adrenergic antagonist [125I]iodopindolol to vascular smooth muscle in segments of both collaterals and native coronary arteries was saturable and stereospecific. Maximal binding and the potency of beta-adrenergic subtype-selective antagonists were similar in all segments. Beta-adrenergic relaxation of native coronary vessels and collateral vessels were studied in isolated organ chambers after preconstriction with prostaglandin F2 alpha. Both native coronary arteries and collateral segments demonstrated beta-adrenergic-mediated relaxation with affinities for both agonists and antagonists compatible with a mixed population of beta 1- and beta 2-adrenergic receptors. These studies indicate that during development, the new collateral vascular smooth muscle expresses a functional population of beta-adrenergic receptors, comparable to that in native vessels.
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Schwinn, Debra A. "Transcriptional regulation of alpha-1 adrenergic receptors." Frontiers in Bioscience 3, no. 4 (1998): d348–353. http://dx.doi.org/10.2741/a279.
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Jensen, Brian C., Timothy D. OʼConnell, and Paul C. Simpson. "Alpha-1–Adrenergic Receptors in Heart Failure." Journal of Cardiovascular Pharmacology 63, no. 4 (2014): 291–301. http://dx.doi.org/10.1097/fjc.0000000000000032.
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Culp, D. J., R. K. McBride, L. A. Graham, and M. G. Marin. "Alpha-adrenergic regulation of secretion by tracheal glands." American Journal of Physiology-Lung Cellular and Molecular Physiology 259, no. 4 (1990): L198—L205. http://dx.doi.org/10.1152/ajplung.1990.259.4.l198.
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The purpose of the present study was to begin to characterize, pharmacologically, the alpha-adrenergic regulation of glycoconjugate secretion from airway glands. Using isolated gland cells from cat trachea, we determined the binding characteristics of [3H]dihydroergocryptine ([3H]DHE), an alpha-adrenergic antagonist, with equal affinities for alpha 1- and alpha 2-adrenergic receptors. Specific binding of [3H]DHE to gland cell homogenates was saturable, of high affinity (KDapp = 4.2 nM) and inhibited with greater efficacy by epinephrine much greater than isoproterenol. Competition experiments with alpha 1- and alpha 2-adrenergic selective antagonists (prazosin and yohimbine, respectively) demonstrated high- and low-affinity sites for each antagonist, indicating the presence of both receptor subtypes. In studies of glycoconjugate secretion by cat tracheal explants, secretion was stimulated by adrenergic agonists with the rank potency: norepinephrine greater than or equal to phenylephrine greater than epinephrine much greater than clonidine. alpha-Adrenergic-stimulated secretion (epinephrine + propranolol) was inhibited by low concentrations of prazosin, but was unaffected by 100 nM yohimbine. The alpha 2-adrenergic agonists, clonidine and UK-14,304, each markedly inhibited beta-adrenergic-stimulated secretion. Collectively, these results demonstrate alpha 1-adrenergic regulation of glandular glycoconjugate secretion and suggest alpha 2-adrenergic receptors may modulate beta-adrenergic-stimulated secretion.
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DiCarlo, S. E., R. W. Blair, V. S. Bishop, and H. L. Stone. "Role of beta 2-adrenergic receptors on coronary resistance during exercise." Journal of Applied Physiology 64, no. 6 (1988): 2287–93. http://dx.doi.org/10.1152/jappl.1988.64.6.2287.
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The effects of regional alpha- and specific beta 2-adrenergic receptor blockade on measurements of late diastolic coronary resistance (LDCR) and mean coronary blood flow velocity (CBFV) during exercise were examined in 14 conscious adult mongrel dogs. Specific beta 2-adrenergic receptor blockade (ICI 118.551) significantly decreased CBFV and increased LDCR by blockade of beta 2-vasodilator tone independent of alpha-adrenergic receptor-mediated tone and independent of altering myocardial metabolism. alpha-Adrenergic receptor blockade (phentolamine, 1 mg) significantly increased CBFV and decreased LDCR by blocking sympathetically mediated vasoconstrictor tone. There was no significant difference in the magnitude of response between alpha- and beta 2-adrenergic receptor blockade. These results demonstrate that alpha- and beta 2-adrenergic receptors have a significant and evidently equal influence on CBFV and LDCR during exercise. Four weeks of daily exercise and left stellate ganglionectomy (LSGx) prevented phentolamine-induced vasodilation but not ICI 118.551-induced vasoconstriction. This suggests that daily exercise and LSGx significantly decreased the alpha-adrenergic receptor-mediated vasoconstrictor tone on the coronary circulation, resulting in an apparently greater role for the coronary vascular beta 2-adrenergic receptor on the control of CBFV and LDCR during exercise.
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WEISS, H. Markus, Winfried HAASE, Hartmut MICHEL та Helmut REILÄNDER. "Comparative biochemical and pharmacological characterization of the mouse 5HT5A 5-hydroxytryptamine receptor and the human β2-adrenergic receptor produced in the methylotrophic yeast Pichia pastoris". Biochemical Journal 330, № 3 (1998): 1137–47. http://dx.doi.org/10.1042/bj3301137.
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Over the last few years, Pichia pastoris has been developed into a powerful expression system for a multitude of foreign genes. Here, we demonstrate that the P. pastoris expression system has similar power to the baculovirus expression system in high-level production of two G-protein-coupled receptors, the mouse 5HT5A 5-hydroxtryptamine receptor and the human β2-adrenergic receptor. Different expression plasmids were constructed in which the cDNAs of the two receptors were cloned under the transcriptional control of the highly inducible promoter of the P. pastoris alcohol oxidase 1 (AOX1) gene. In three expression plasmids, the receptors were fused to the Saccharomyces cerevisiae α-factor prepropeptide and also to the c-myc tag or the FLAG tag to permit immunological detection of the receptors. After transformation into P. pastoris strains KM71 and SMD 1163, recombinant clones were selected and tested for the production of the 5HT5A receptor and the β2-adrenergic receptor by radioligand binding using [N-methyl-3H]lysergic acid diethylamide and [5,7-3H](-)CGP-12177 respectively. The production level of the 5HT5A receptor was improved by a factor of three by fusion with the α-factor prepropeptide. Also, the higher gene dosage resulting from multiple insertions of the expression cassette led to an improvement in production by a factor of two for both receptors. The addition of the adrenergic antagonist alprenolol to the culture medium had a positive effect on the number of specific binding sites detectable in clones producing the β2-adrenergic receptor. For the 5HT5A receptor the addition of yohimbine resulted in a similar but smaller effect. Binding assays revealed that approx. 25 pmol of β2-adrenergic receptor and approx. 40 pmol of 5HT5A receptor per mg of membrane protein in crude membrane preparations were produced. The pharmacological profiles for the heterologously produced receptors, estimated by ligand-displacement analysis using certain adrenergic and serotoninergic agonists and antagonists, were comparable with those reported for the receptors expressed in mammalian systems. Immunoblot analysis of the 5HT5A receptor revealed an apparent molecular mass about 20 kDa higher than expected from the amino acid sequence. Here, the Kex2 endopeptidase failed to process the α-factor leader correctly. Blocking glycosylation in vivo by tunicamycin or in vitro deglycosylation of membranes by endoglycosidase H resulted in correct processing. In contrast, the β2-adrenergic receptor fusion to the α-factor leader was correctly processed by the internal Kex2 endopeptidase. The Kex2-processed β2-adrenergic receptor was not glycosylated. In conclusion, the high-level production of the two receptors in P. pastoris will allow their purification in quantities sufficient for subsequent biophysical and structural studies.
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Ventimiglia, Maria S., Myrian R. Rodriguez, Vanina P. Morales, et al. "Endothelins participate in the central and peripheral regulation of submandibular gland secretion in the rat." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 300, no. 1 (2011): R109—R120. http://dx.doi.org/10.1152/ajpregu.00041.2010.
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We previously reported that endothelins (ETs) are involved in the rat central and peripheral regulation of bile secretion. In this study we sought to establish whether ET-1 and ET-3 modulated submandibular gland secretion when locally or centrally applied. Animals were prepared with gland duct cannulation to collect saliva samples and jugular cannulation to administer sialogogues. ETs were given either into the submandibular gland or brain lateral ventricle. Intraglandularly administered ETs failed to elicit salivation per se. However, ET-1, but not ET-3, potentiated both cholinergic- and adrenergic-evoked salivation through ETA receptors. ET-1 decreased cAMP content but increased phosphoinositide hydrolysis, whereas ET-3 attenuated both intracellular pathways. The expression of ETA and ETB receptor mRNAs as well as that of ETs was revealed in the submandibular gland by RT-PCR. Immunohistochemical studies showed that ETA receptor staining was localized around the interlobular ducts and acini, compatible with the myoepithelial cells' location, whereas ETB receptor staining was restricted to small blood vessels. When applied to the brain, both ETs induced no salivation but enhanced cholinergic- and adrenergic-evoked salivary secretion through parasympathetic pathways. ET-1 response was mediated by brain ETA receptors, whereas that of ET-3 was presumably through nonconventional ET receptors. Present findings show that ETs are involved in the brain regulation of cholinergic- and adrenergic-stimulated submandibular gland secretion through the activation of distinct brain ET receptors and parasympathetic pathways. However, when ETs were administered into the gland, only ET-1 enhanced cholinergic and adrenergic salivation likely through myopithelial cell contraction by activating ETA receptors coupled to phospholipase C. The presence of ETs and ET receptors suggests the existence of an endothelinergic system in the submandibular gland.
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Khabibrakhmanov, Insaf Ilkhamovich, Anna Mihailovna Kuptsova, Nafisa Ilgizovna Ziyatdinova, Nur Mansur, and Timur Lvovich Zefirov. "ALPHA(1)-ADRENOCEPTORS ACTIVATION DECREASES MYOCARDIAL CONTRACTILITY IN NEWBORN RATS." Journal of Experimental Biology and Agricultural Sciences 8, Spl-2-AABAS (2020): S322—S326. http://dx.doi.org/10.18006/2020.8(spl-2-aabas).s322.s326.
Full textAbstract:
Alpha(1)-adrenergic receptors (α1-AR) are found in cardiomyocytes, endothelial cells, and smooth muscle cells of humans and animals. Despite the fact that α1-AR make up 10% of the total number of adrenergic receptors, these receptors also involved in the regulation of inotropic and chronotropic functions of the heart. According to some scientists, the effects of α1-AR activation are not required for the basal contractile function of the heart while other group of researchers believe that α1-AR can be considered as cardioprotective targets; in particular, it is postulated that the α1A-subtype of adrenergic receptors can provide significant inotropic support in cardiac pathologies. This study was carried out on 6-7-day-old outbred newborn rat pups to evaluate the effect of alpha(1)-adrenoceptors activation on the myocardial contractility in newborn rats. For this, Alpha1-adrenergic receptors were stimulated by the pharmacological drug methoxamine at concentrations of 10-9-10-6 mol and the reaction of the contractile force of the strips of myocardium ventricles and heart atria in response to the agonist was investigated. Results of study revealed that stimulation of alpha1-adrenergic receptors, regardless of the methoxamine concentration, led to a negative inotropic reaction of the myocardium of atria and ventricles of newborn rat pups. This study showed unidirectional inotropic responses on rat atrial and ventricular myocardium in response to α1-adrenergic receptors stimulation. Methoxamine smoothly reduces the contractile force of the strips of myocardium atria and ventricles. At the same time, the concentration dependence on the inotropic reaction of the myocardium was observed. Results of study suggested that probably α1-adrenergic receptors along with the main regulators β-adrenergic receptors carry out fine tuning of the heart activity.
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Dicker, A., A. Raasmaja, B. Cannon, and J. Nedergaard. "Increased alpha 1-adrenoceptor density in brown adipose tissue indicates recruitment drive in hypothyroid rats." American Journal of Physiology-Endocrinology and Metabolism 263, no. 4 (1992): E654—E662. http://dx.doi.org/10.1152/ajpendo.1992.263.4.e654.
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The effects of hypothyroidism on whole body thermogenesis, brown adipose tissue recruitment state, and alpha 1-adrenergic receptor density were investigated. Treatment of rats with methimazole for 4-5 wk led, as expected, to reduction of growth and resting metabolic rate. The thermogenic response to norepinephrine injection was practically abolished. Generally, only small effects of hypothyroidism on brown adipose tissue were observed: total protein content, mitochondrial GDP binding capacity, and total content of the uncoupling protein thermogenin were not altered. The density of beta-adrenergic receptors (estimated with [3H]CGP-12177 as a ligand) was also unchanged. However, the density of alpha 1-adrenergic receptors (estimated with [3H]prazosin) was markedly increased; in other physiological conditions, such an increase has been associated with an increased degree of recruitment of the tissue. These data indicate that brown adipose tissue in the subthermoneutral hypothyroid animal, probably due to homeostatic mechanisms, is exposed to an increased sympathetic stimulation, leading to an increased alpha 1-adrenoceptor density. However, other features of recruitment are only poorly induced, probably due to attenuation of the beta-adrenergic signaling mechanism. The increased alpha 1-adrenergic receptor density may be responsible for certain altered features of brown adipose tissue in hypothyroid animals, such as peroxisomal recruitment and perhaps also for maintenance of the thermogenin content. The results also indicate that the increased alpha 1-adrenergic density generally seen in recruitment would not result from chronic beta-adrenergic stimulation of the tissue but may be controlled via another regulatory pathway, e.g., via the alpha 1-adrenergic pathway itself.
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Kubes, P., M. Melinyshyn, K. Nesbitt, S. M. Cain, and C. K. Chapler. "Participation of alpha 2-adrenergic receptors in neural vascular tone of canine skeletal muscle." American Journal of Physiology-Heart and Circulatory Physiology 262, no. 6 (1992): H1705—H1710. http://dx.doi.org/10.1152/ajpheart.1992.262.6.h1705.
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Studies were carried out in anesthetized, paralyzed, and ventilated dogs to determine whether postsynaptic alpha 2-adrenergic receptors participated in neurally mediated vascular tone in skeletal muscle. Hindlimb skeletal muscle resistance (RL) and blood flow (QL) were determined before, during, and after reversible cold block of the sciatic nerve. This sequence of observations was repeated 30 min after blockade of alpha 1-adrenergic receptors with prazosin. Then the alpha 2-adrenergic receptors were blocked with yohimbine, and the nerve cold block was repeated. When the sciatic nerve was cold blocked before alpha 1-adrenergic blockade, RL decreased approximately 50% and QL increased 75% (P less than 0.05) and then returned to control when the nerve was rewarmed. After alpha 1-block 76% of neural tone remained as assessed by nerve cooling (P less than 0.05). This phenomenon occurred despite effective alpha 1-adrenergic blockade as assessed by the alpha 1-receptor agonist methoxamine. With alpha 1- plus alpha 2-block no change in RL or QL was seen with nerve cold block. The same protocol was repeated in a second series of animals, but mean arterial pressure, which fell after alpha 1-block in the group above, was maintained by dextran infusion at normotensive levels. In these animals, 40% of neural tone remained after alpha 1-block. Both alpha 1- and alpha 2-adrenergic blockers were again needed to abolish the QL and RL response to nerve cold block. In another series of animals, yohimbine was administered before prazosin. In this series, alpha 2-adrenergic blockade greatly reduced neural tone as assessed by nerve cooling.(ABSTRACT TRUNCATED AT 250 WORDS)
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Howard, M. J., M. D. Mullen, and P. A. Insel. "Amiloride interacts with renal alpha- and beta-adrenergic receptors." American Journal of Physiology-Renal Physiology 253, no. 1 (1987): F21—F25. http://dx.doi.org/10.1152/ajprenal.1987.253.1.f21.
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We have used radioligand binding techniques to assess whether amiloride and certain analogues of amiloride (ethylisopropyl amiloride and benzamil) can bind to adrenergic receptors in the kidney. We found that amiloride could compete for [3H]rauwolscine (alpha 2-adrenergic receptors), [3H]prazosin (alpha 1-adrenergic receptors), and [125I]iodocyanopindolol (beta-adrenergic receptors) binding in rat renal cortical membranes with inhibitor constants of 13.6 +/- 5.7, 24.4 +/- 7.4, and 83.6 +/- 13.5 microM, respectively. Ethylisopropyl amiloride and benzamil were from 2- to 25-fold more potent than amiloride in competing for radioligand binding sites in studies with these membranes. In addition, amiloride and the two analogues competed for [3H]prazosin sites on intact Madin-Darby canine kidney cells and amiloride blocked epinephrine-stimulated prostaglandin E2 production in these cells. We conclude that amiloride competes for binding to several classes of renal adrenergic receptors with a rank order of potency of alpha 2 greater than alpha 1 greater than beta. Binding to, and antagonism of, adrenergic receptors occurs at concentrations of amiloride that are lower than previously observed “nonspecific” interactions of this agent.
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BENGTSSON, Tore, Barbara CANNON та Jan NEDERGAARD. "Differential adrenergic regulation of the gene expression of the β-adrenoceptor subtypes β1, β2 and β3 in brown adipocytes". Biochemical Journal 347, № 3 (2000): 643–51. http://dx.doi.org/10.1042/bj3470643.
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In brown adipocytes, fundamental cellular processes (cell proliferation, differentiation and apoptosis) are regulated by adrenergic stimulation, notably through β-adrenergic receptors. The presence of all three β-receptor subtypes has been demonstrated in brown adipose tissue. Due to the significance of the action of these receptors and indications that the subtypes govern different processes, the adrenergic regulation of the expression of the β1-, β2- and β3-adrenoceptor genes was examined in murine brown-fat primary cell cultures. Moderate levels of β1-receptor mRNA, absence of β2-receptor mRNA and high levels of β3-receptor mRNA were observed in mature brown adipocytes (day 6 in culture). Noradrenaline (norepinephrine) addition led to diametrically opposite effects on β1- (markedly enhanced expression) and β3-gene expression (full cessation of expression, as previously shown). β2-Gene expression was induced by noradrenaline, but only transiently (< 1 h). The apparent affinities (EC50) of noradrenaline were clearly different (7 nM for the β1-gene and≤ 1 nM for the β3-gene), as were the mediation pathways (solely via β3-receptors and cAMP for the β1-gene and via β3-receptors and cAMP, as well as via α1-receptors and protein kinase C, for the β3-gene). The half-lives of the corresponding mRNA species were very short but different (17 min for β1-mRNA and 27 min for β3-mRNA), and these degradation rates were not affected by noradrenaline, implying that the mRNA levels were controlled by transcription. Inhibition of protein synthesis also led to diametrically opposite effects on β1- and β3-gene expression, but - notably - these effects were congruent with the noradrenaline effects, implying that a common factor regulating β1-gene expression negatively and β3-gene expression positively could be envisaged. In conclusion, very divergent effects of adrenergic stimulation on the expression of the different β-receptor genes were found within one cell type, and no unifying concept of adrenergic control of β-receptor gene expression can be formulated, either concerning different cell types, or concerning the different β-receptor subtype genes.
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Laffon, M., L. N. Lu, K. Modelska, M. A. Matthay та J. F. Pittet. "α-Adrenergic blockade restores normal fluid transport capacity of alveolar epithelium after hemorrhagic shock". American Journal of Physiology-Lung Cellular and Molecular Physiology 277, № 4 (1999): L760—L768. http://dx.doi.org/10.1152/ajplung.1999.277.4.l760.
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Activation of β-adrenergic receptors in the lung is an important mechanism that can prevent alveolar flooding after brief but severe hemorrhagic shock. However, a neutrophil-dependent oxidant injury to the alveolar epithelium prevents the normal upregulation of alveolar fluid clearance by catecholamines after prolonged hemorrhagic shock. Because hemorrhage increases proinflammatory cytokine expression in the lung partly through the activation of α-adrenergic receptors, the objective of this study was to determine whether α-adrenergic blockade would restore the normal fluid transport capacity of the alveolar epithelium after hemorrhagic shock. Hemorrhagic shock was associated with a significant increase of interleukin-1β (IL-1β) concentration in the lung and a failure of the alveolar epithelium to respond to β-adrenergic agonists, with the upregulation of vectorial fluid transport despite intra-alveolar administration of exogenous catecholamines. In contrast, catecholamine-mediated upregulation of alveolar liquid clearance was restored by pretreatment with phentolamine, an α-adrenergic-receptor antagonist. Phentolamine pretreatment also significantly attenuated the shock-mediated increase of IL-1β concentration in the lung. Additional experiments demonstrated that the inhibition of IL-1β binding to its receptor by the administration of IL-1-receptor antagonist restored the normal fluid transport capacity of the alveolar epithelium after hemorrhagic shock. In summary, the results of these studies indicate that the activation of α-adrenergic receptors after hemorrhagic shock prevents the β-adrenergic-dependent upregulation of alveolar fluid clearance by modulating the severity of the pulmonary inflammatory response.
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Chen, Yanmin, Bujing Guo, Hongda Zhang, Lihong Hu та Jue Wang. "Higenamine, a Dual Agonist for β 1- and β 2-Adrenergic Receptors Identified by Screening a Traditional Chinese Medicine Library". Planta Medica 85, № 09/10 (2019): 738–44. http://dx.doi.org/10.1055/a-0942-4502.
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AbstractChronic heart failure is the terminal stage of various cardiovascular diseases. Despite the availability of several classes of drugs, there is still an unmet need for effective treatment. Based on bench work during the past two decades, we have proposed that enhancement of β 2-adrenergic receptor signaling in combination with the presently preferred β 1-adrenergic receptor blockade would be a promising strategy. Chinese herbal medicines have been shown to be effective in the treatment of heart failure, although the mechanisms largely remain unknown. In the present study, we screened an herbal medicine compound/extract library for β-adrenergic receptor ligands to determine the target of certain effective botanical remedies and seek a leading compound(s) for chronic heart failure treatment. Using a high-throughput screening assay, we identified higenamine, which has a long history in chronic heart failure treatment in traditional Chinese medicine, to be a potent β-adrenergic receptor agonist. Further experiments using specific inhibitors showed that higenamine activated both β 1-adrenergic receptor and β 2-adrenergic receptor. Inhibition of its action by pertussis toxin (a Gi inhibitor) indicated that it is a β 2-adrenergic receptor Gs/Gi dual agonist. Contractility experiments demonstrated a positive inotropic effect of higenamine. In conclusion, we found an herbal compound, higenamine, to be a dual agonist for β 1/β 2-adrenergic receptors with no preference in stimulating the Gs and Gi pathways in β 2-adrenergic receptor signaling. Our results elucidated not only the target of higenamine to explain its pharmacological effect in treating chronic heart failure, but also the mechanisms of its cardiac toxicity.
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Thunhorst, Robert L., Connie L. Grobe, Terry G. Beltz та Alan Kim Johnson. "Effects of β-adrenergic receptor agonists on drinking and arterial blood pressure in young and old rats". American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 300, № 4 (2011): R1001—R1008. http://dx.doi.org/10.1152/ajpregu.00737.2010.
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These experiments examined water-drinking and arterial blood pressure responses to β-adrenergic receptor activation in young (4 mo), “middle-aged” adult (12 mo), and old (29 mo) male rats of the Brown-Norway strain. We used isoproterenol to simultaneously activate β1- and β2-adrenergic receptors, salbutamol to selectively activate β2-adrenergic receptors, and the combination of isoproterenol and the β2-adrenergic receptor antagonist ICI 118,551 to stimulate only β1-adrenergic receptors. Animals received one of the drug treatments, and water drinking was measured for 90 min. About 1 wk later, animals received the same drug treatment for measurement of arterial blood pressure responses for 90 min. In some rats, levels of renin and aldosterone secretion in response to isoproterenol or salbutamol were measured in additional tests. Old and middle-aged rats drank significantly less after isoproterenol than did young rats and also had greater reductions in arterial blood pressure. Old and middle-aged rats drank significantly less after salbutamol than did young rats, although reductions in arterial blood pressure were equivalent across the ages. The β2-adrenergic antagonist ICI 118,551 abolished drinking after isoproterenol and prevented most of the observed hypotension. Renin secretion after isoproterenol and salbutamol was greater in young rats than in middle-aged rats, and wholly absent in old rats. Aldosterone secretion was reduced in old rats compared with young and middle-aged rats after treatment with isoproterenol, but not after treatment with salbutamol. In conclusion, there are age-related differences in β-adrenergic receptor-mediated drinking that can be explained only in part by age-related differences in renin secretion after β-adrenergic receptor stimulation.