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1
Bigal, Marcelo E. "NOS Inhibition." Headache Currents 1, no. 1 (July 2004): 23. http://dx.doi.org/10.1111/j.1743-5013.2004.10102d.x.
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Song, Michael Y., Charles F. Zwemer, Steven E. Whitesall, and Louis G. D'Alecy. "Acute and conditioned hypoxic tolerance augmented by endothelial nitric oxide synthase inhibition in mice." Journal of Applied Physiology 102, no. 2 (February 2007): 610–15. http://dx.doi.org/10.1152/japplphysiol.00894.2006.
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To identify a possible role for nitric oxide (NO) in acute hypoxic tolerance (HT) we measured hypoxic survival time (HST), effect of hypoxic conditioning (HC), and survival following hypoxic conditioning while blocking or mimicking the action of nitric oxide synthase (NOS). To inhibit NOS, CD-1 mice were given supplemental endogenous NOS inhibitor asymmetrical dimethylarginine (ADMA) or a synthetic NOS inhibitor Nω-nitro-l-arginine (l-NNA), both of which nonselectively inhibit three of the isoforms of NOS [inducible (iNOS), neuronal (nNOS), and endothelial NOS (eNOS)]. ADMA (10 mg/kg ip) or saline vehicle was given 5 min before HST testing. l-NNA was given orally at 1 g/l in drinking water with tap water as the control for 48 h before testing. Both ADMA and l-NNA significantly increased HST and augmented the HC effect on HST. Neither the nNOS selective inhibitor 7-nitroindazole (7-NI) nor the iNOS selective inhibitor N-{[3-(aminomethyl)phenyl]methyl}-enthanimidamide (1400W) had a statistically significant effect on HST or HT. The NO donor, 3-morpholinosydnoeimine, when given alone did not significantly decrease HT, but it did mitigate the increased HT effect of l-NNA. These data confirm that acute hypoxic conditioning increases HT and that NOS inhibition by endogenous (ADMA) and a synthetic NOS inhibitor (l-NNA) further increases HT, whereas iNOS and nNOS inhibition does not, suggesting that it is the inhibition of eNOS that mediates enhancement of HT.
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Wang, Xuemei, and William A. Cupples. "Brown Norway rats show impaired nNOS-mediated information transfer in renal autoregulationThis article is part of a Special Issue on Information Transfer in the Microcirculation." Canadian Journal of Physiology and Pharmacology 87, no. 1 (January 2009): 29–36. http://dx.doi.org/10.1139/y08-102.
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Nonselective inhibition of NO synthase (NOS) augments myogenic autoregulation of renal blood flow (RBF) and profoundly reduces RBF. Previously in Wistar rats, we showed that augmented autoregulation, but not vasoconstriction, is duplicated by intrarenal inhibition of neuronal NOS (nNOS), whereas intrarenal inhibition of inducible NOS (iNOS) has no effect on RBF or on RBF dynamics. Thus macula densa nNOS transfers information from tubuloglomerular feedback to the afferent arteriole. This information flow requires that macula densa nNOS can sufficiently alter ambient NO concentration, that is, that endothelial NOS (eNOS) and iNOS do not alter local NO concentration. Because the Brown Norway rat often shows exaggerated responses to NOS inhibition and has peculiarities of renal autoregulation that are related to NO, we used this strain to study systemic and renal vascular responses to NOS inhibition. The first experiment showed transient blood pressure reduction by bolus i.v. acetylcholine that was dose-dependent in both strains and substantially prolonged in Brown Norway rats. The depressor response decayed more rapidly after nonselective NOS inhibition and the difference between strains was lost, indicating a greater activity of eNOS in Brown Norway rats. In Brown Norway rats, selective inhibition of iNOS reduced RBF (–16% ± 7%) and augmented myogenic autoregulation, whereas nNOS inhibition reduced RBF (–25% ± 4%) and did not augment myogenic autoregulation. The significant responses to intrarenal iNOS inhibition, the reduced modulation of autoregulation by nNOS inhibition, and the enhanced endothelial depressor response suggest that physiological signalling by NO within the kidney is impaired in Brown Norway rats because of irrelevant or inappropriate input of NO by eNOS and iNOS.
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Niebauer, Josef, Andrew J. Maxwell, Patrick S. Lin, David Wang, Philip S. Tsao, and John P. Cooke. "NOS inhibition accelerates atherogenesis: reversal by exercise." American Journal of Physiology-Heart and Circulatory Physiology 285, no. 2 (August 2003): H535—H540. http://dx.doi.org/10.1152/ajpheart.00360.2001.
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In this study, we assessed the effects of chronic exercise training (12 wk) on atherosclerotic lesion formation in hypercholesterolemic apolipoprotein E-deficient mice ( n = 31). At the age of 9 wk, mice were assigned to the following groups: sedentary (Sed; n = 9); exercise (Ex; n = 12); sedentary and oral NG-nitro-l-arginine (l-NNA, Sed-NA; n = 4), or exercise and oral l-NNA (Ex-NA; n = 6). Chronic exercise training was performed on a treadmill for 12 wk (6 times/wk and twice for 1 h/day) at a final speed of 22 m/min, and an 8° grade. l-NNA was discontinued 5 days before final treadmill testing. The farthest distance run to exhaustion was observed in Ex-NA mice (Sed: 306 ± 32 m; Ex: 640 ± 87; Sed-NA: 451 ± 109 m; Ex-NA: 820 ± 49 m; all P < 0.05). Lesion formation was assessed in the proximal ascending aorta by dissection microscopy after oil red O staining. The aortas of Sed-NA mice manifested a threefold increase in lesion formation compared with the other groups. This l-NNA-induced lesion formation was reduced by chronic exercise training (Sed, 786 ± 144; Ex, 780 ± 206; Sed-NA, 2,147 ± 522; Ex-NA, 851 ± 253; Sed-NA vs. all other groups: P < 0.001). In conclusion, treatment with oral l-NNA (an nitric oxide synthase antagonist) leads to accelerated atherogenesis in genetically determined hypercholesterolemic mice. This adverse effect can be overcome by chronic exercise training.
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O’Riordan, Edmond, Natalia Mendelev, Susann Patschan, Daniel Patschan, Jonathan Eskander, Leona Cohen-Gould, Praveen Chander, and Michael S. Goligorsky. "Chronic NOS inhibition actuates endothelial-mesenchymal transformation." American Journal of Physiology-Heart and Circulatory Physiology 292, no. 1 (January 2007): H285—H294. http://dx.doi.org/10.1152/ajpheart.00560.2006.
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Chronic kidney diseases are accompanied by the accumulation of substances like asymmetric dimethylarginine, phenylacetic acid, homocysteine, and advanced glycation end products, known to either inhibit endothelial nitric oxide synthase (eNOS) or uncouple it, consequently limiting the amount of available nitric oxide (NO). Reduced bioavailability of NO induces endothelial dysfunction. An early loss of peritubular capillaries in tubulointerstitial fibrotic areas and injury to endothelial cells have been linked to progressive renal disease. Screening endothelial genes in cells treated with NOS inhibitors showed upregulation of collagen XVIII, a precursor of a potent antiangiogenic substance, endostatin. This finding was confirmed at the level of mRNA and protein expression. Tie-2 promoter-driven green fluorescent protein mice treated with nonhypertensinogenic doses of a NOS inhibitor exhibited upregulation of collagen XVIII/endostatin and rarefaction of capillary profiles. This was accompanied by the increased expression of transforming growth factor-β and connective tissue growth factor in the kidney. Occasional endothelial cells expressed both the marker of endothelial lineage (green fluorescent protein) and mesenchymal marker (α-smooth muscle actin or calponin). In vitro studies of endothelial cells treated with asymmetric dimethylarginine showed decreased expression of eNOS and Flk-1 and enhanced expression of calponin and fibronectin, additional markers of smooth muscle and mesenchymal cells. These cells overexpressed transforming growth factor-β and connective tissue growth factor, as well as endostatin. In conclusion, data presented here 1) ascribe to NO deficiency in endothelial cells the function of a profibrotic stimulus associated with the expression of an antiangiogenic fragment of collagen XVIII (endostatin) and 2) provide evidence of endothelial-mesenchymal transdifferentiation in the course of inhibition of NOS by a pathophysiologically important antagonist, asymmetric dimethylarginine. Both mechanisms may account for microvascular rarefaction.
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Cholet, Nathalie, Jacques Seylaz, Pierre Lacombe, and Gilles Bonvento. "Local Uncoupling of the Cerebrovascular and Metabolic Responses to Somatosensory Stimulation after Neuronal Nitric Oxide Synthase Inhibition." Journal of Cerebral Blood Flow & Metabolism 17, no. 11 (November 1997): 1191–201. http://dx.doi.org/10.1097/00004647-199711000-00008.
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It has recently been shown, using either genetically engineered mutant mice (nitric oxide synthase [NOS] knockout) or specific pharmacological tools, that type I NOS (neuronal isoform of NOS, [nNOS]) participates in coupling cerebral blood flow to functional activation. However, it has not been clearly established whether the associated metabolic response was preserved under nNOS inhibition and whether this action was exerted homogeneously within the brain. To address these issues, we analyzed the combined circulatory and metabolic consequences of inhibiting the nNOS both at rest and during functional activation in the rat anesthetized with α-chloralose. Cerebral blood flow and cerebral glucose use (CGU) were measured autoradiographically using [14C]iodoantipyrine and [14C]2-deoxyglucose during trigeminal activation induced by unilateral whiskers stimulation in vehicle- and 7-nitroindazole-treated rats. Our data show that inhibition of nNOS globally decreased CBF without altering CGU, indicating that NO-releasing neurons play a significant role in maintaining a resting cerebrovascular tone in the whole brain. During whisker stimulation, nNOS inhibition totally abolished the cerebrovascular response only in the second order relay stations (thalamus and somatosensory cortex) of the trigeminal relay without altering the metabolic response. These findings provide evidence that the involvement of neurally-derived NO in coupling flow to somatosensory activation is region-dependent, and that under nNOS inhibition, CBF and CGU may vary independently during neuronal activation.
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Fujii, Naoto, Robert D. Meade, Lacy M. Alexander, Pegah Akbari, Imane Foudil-bey, Jeffrey C. Louie, Pierre Boulay, and Glen P. Kenny. "iNOS-dependent sweating and eNOS-dependent cutaneous vasodilation are evident in younger adults, but are diminished in older adults exercising in the heat." Journal of Applied Physiology 120, no. 3 (February 1, 2016): 318–27. http://dx.doi.org/10.1152/japplphysiol.00714.2015.
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Nitric oxide synthase (NOS) contributes to sweating and cutaneous vasodilation during exercise in younger adults. We hypothesized that endothelial NOS (eNOS) and neuronal NOS (nNOS) mediate NOS-dependent sweating, whereas eNOS induces NOS-dependent cutaneous vasodilation in younger adults exercising in the heat. Further, aging may upregulate inducible NOS (iNOS), which may attenuate sweating and cutaneous vasodilator responses. We hypothesized that iNOS inhibition would augment sweating and cutaneous vasodilation in exercising older adults. Physically active younger ( n = 12, 23 ± 4 yr) and older ( n = 12, 60 ± 6 yr) adults performed two 30-min bouts of cycling at a fixed rate of metabolic heat production (400 W) in the heat (35°C). Sweat rate and cutaneous vascular conductance (CVC) were evaluated at four intradermal microdialysis sites with: 1) lactated Ringer (control), 2) nNOS inhibitor (nNOS-I, NPLA), 3) iNOS inhibitor (iNOS-I, 1400W), or 4) eNOS inhibitor (eNOS-I, LNAA). In younger adults during both exercise bouts, all inhibitors decreased sweating relative to control, albeit a lower sweat rate was observed at iNOS-I compared with eNOS-I and nNOS-I sites (all P < 0.05). CVC at the eNOS-I site was lower than control in younger adults throughout the intermittent exercise protocol (all P < 0.05). In older adults, there were no differences between control and iNOS-I sites for sweating and CVC during both exercise bouts (all P > 0.05). We show that iNOS and eNOS are the main contributors to NOS-dependent sweating and cutaneous vasodilation, respectively, in physically active younger adults exercising in the heat, and that iNOS inhibition does not alter sweating or cutaneous vasodilation in exercising physically active older adults.
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Rudd, M. Audrey, George Toolan, Maria R. Trolliet, Timothy Cloutier, Karlene Maitland, and Joseph Loscalzo. "Short-Term NOS II Inhibition Leads to Long-Term Salt-Sensitivity in Dahl Salt-Resistant Rats." Hypertension 36, suppl_1 (October 2000): 713. http://dx.doi.org/10.1161/hyp.36.suppl_1.713-b.
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P111 We have previously shown that inhibition of inducible nitric oxide synthase (NOS II) evokes a salt-sensitive increase in blood pressure in Dahl salt-resistant rats when given a high salt (8% NaCl) diet for 7 days. To determine whether or not the effect of NOS II inhibition is short-lived, we continued the high salt diet for an additional 3 weeks following the discontinuation of the NOS II inhibitor. DR rats were given one of two NOS II selective inhibitors, AMT (300 nmoles/hr) and 1400W (35 nmoles/hr) for 2 weeks. A high salt diet was initiated after the first week of NOS II inhibition and continued for an additional 3 weeks for a total of 4 weeks of high salt treatment. Control DR rats received high salt alone for 4 weeks. Systolic blood pressure was taken at baseline and once weekly for the treatment period. Blood pressure significantly increased in DR rats after 1 week of high salt following NOS II inhibition. The blood pressure remained elevated throughout the 4-week period of high salt treatment despite the discontinuation of NOS II inhibitors 1 week following the initiation of the high salt diet. There was no significant change in blood pressure in DR rats on high salt diet alone. These data suggest that salt-sensitive hypertension can be evoked by transient NOS II inhibitor exposure. We conclude that tranisent NOS II inhibition may initiate events or processes that high salt maintains leading to sustained elevation in systolic blood pressure.
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Otterson, Mary F., Shawn C. Leming, Xiaoqi Liu, and John E. Moulder. "NOS inhibition reduces the contractile response to irradiation." Gastroenterology 118, no. 4 (April 2000): A411. http://dx.doi.org/10.1016/s0016-5085(00)83755-5.
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Nevoral, J., T. Krejčová, J. Petr, P. Melicharová, A. Vyskočilová, M. Dvořáková, I. Weingartová, et al. "The role of nitric oxide synthase isoforms in aged porcine oocytes." Czech Journal of Animal Science 58, No. 10 (September 27, 2013): 453–59. http://dx.doi.org/10.17221/6994-cjas.
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In the sphere of reproductive biotechnologies, the demand for sufficient numbers of high-quality oocytes is still increasing. In some cases, this obstacle is overcome by in vitro prolonged cultivation. However, a prolonged oocyte culture is accompanied by changes called ageing. Ageing is manifested by spontaneous parthenogenetic activation, programmed cell death or lysis. Various substances, such as caffeine or dithiothreitol, have been tested for ageing suppression. In this respect, research into gasotransmitters (hydrogen sulphide, carbon monoxide, and nitric oxide) has currently been intensified. The objectives of the present study were to localize nitric oxide synthases (NOS) and to evaluate NOS inhibition of aged porcine oocytes. We demonstrated the presence of NOS isoforms in oocyte cultivation prolonged by 24, 48, and 72 h. After 72 h of prolonged cultivation, NOS inhibition by the non-specific inhibitor L-NAME or the specific inhibitor aminoguanidine caused suppression both of programmed cell death and lysis. Although NOS amount rapidly decreased after the 72-h cultivation, changes induced by NOS inhibition were statistically significant. We can presume that NOS play an important physiological role in porcine oocyte ageing.
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Vaughan, David J., Thomas V. Brogan, Mark E. Kerr, Steven Deem, Daniel L. Luchtel, and Erik R. Swenson. "Contributions of nitric oxide synthase isozymes to exhaled nitric oxide and hypoxic pulmonary vasoconstriction in rabbit lungs." American Journal of Physiology-Lung Cellular and Molecular Physiology 284, no. 5 (May 1, 2003): L834—L843. http://dx.doi.org/10.1152/ajplung.00341.2002.
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We investigated the source(s) for exhaled nitric oxide (NO) in isolated, perfused rabbits lungs by using isozyme-specific nitric oxide synthase (NOS) inhibitors and antibodies. Each inhibitor was studied under normoxia and hypoxia. Only nitro-l-arginine methyl ester (l-NAME, a nonselective NOS inhibitor) reduced exhaled NO and increased hypoxic pulmonary vasoconstriction (HPV), in contrast to 1400W, an inhibitor of inducible NOS (iNOS), and 7-nitroindazole, an inhibitor of neuronal NOS (nNOS). Acetylcholine-mediated stimulation of vascular endothelial NOS (eNOS) increased exhaled NO and could only be inhibited by l-NAME. Selective inhibition of airway and alveolar epithelial NO production by nebulized l-NAME decreased exhaled NO and increased hypoxic pulmonary artery pressure. Immunohistochemistry demonstrated extensive staining for eNOS in the epithelia, vasculature, and lymphatic tissue. There was no staining for iNOS but moderate staining for nNOS in the ciliated cells of the epithelia, lymphoid tissue, and cartilage cells. Our findings show virtually all exhaled NO in the rabbit lung is produced by eNOS, which is present throughout the airways, alveoli, and vessels. Both vascular and epithelial-derived NO modulate HPV.
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Fujii, Naoto, Sheila Dervis, Ronald J. Sigal, and Glen P. Kenny. "Type 1 diabetes modulates cyclooxygenase- and nitric oxide-dependent mechanisms governing sweating but not cutaneous vasodilation during exercise in the heat." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 311, no. 6 (December 1, 2016): R1076—R1084. http://dx.doi.org/10.1152/ajpregu.00376.2016.
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Both cyclooxygenase (COX) and nitric oxide synthase (NOS) contribute to sweating, whereas NOS alone contributes to cutaneous vasodilation during exercise in the heat. Here, we evaluated if Type 1 diabetes mellitus (T1DM) modulates these responses. Adults with ( n = 11, 25 ± 5 yr) and without ( n = 12, 24 ± 4 yr) T1DM performed two bouts of 30-min cycling at a fixed rate of heat production of 400 W in the heat (35°C); each followed by a 20- and 40-min recovery period, respectively. Sweat rate and cutaneous vascular conductance (CVC) were measured at four intradermal microdialysis sites treated with either 1) lactated Ringer (vehicle control site), 2) 10 mM ketorolac (nonselective COX inhibitor), 3) 10 mM NG-nitro-l-arginine methyl ester (nonselective NOS inhibitor), or 4) a combination of both inhibitors. In nondiabetic adults, separate and combined inhibition of COX and NOS reduced exercise sweat rate ( P ≤ 0.05), and the magnitude of reductions were similar across sites. In individuals with T1DM, inhibition of COX resulted in an increase in sweat rate of 0.10 ± 0.09 and 0.09 ± 0.08 mg·min−1·cm−2 for the first and second exercise bouts, respectively, relative to vehicle control site ( P ≤ 0.05), whereas NOS inhibition had no effect on sweating. In both groups, NOS inhibition reduced CVC during exercise ( P ≤ 0.05), although the magnitude of reduction did not differ between the nondiabetic and T1DM groups ( exercise 1: −28 ± 10 vs. −23 ± 8% max, P = 0.51; exercise 2: −31 ± 12 vs. −24 ± 10% max, P = 0.38). We show that in individuals with T1DM performing moderate intensity exercise in the heat, NOS-dependent sweating but not cutaneous vasodilation is attenuated, whereas COX inhibition increases sweating.
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Wadley, G. D., and G. K. McConell. "Effect of nitric oxide synthase inhibition on mitochondrial biogenesis in rat skeletal muscle." Journal of Applied Physiology 102, no. 1 (January 2007): 314–20. http://dx.doi.org/10.1152/japplphysiol.00549.2006.
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The purpose of this study was to determine whether nitric oxide synthase (NOS) inhibition decreased basal and exercise-induced skeletal muscle mitochondrial biogenesis. Male Sprague-Dawley rats were assigned to one of four treatment groups: NOS inhibitor NG-nitro-l-arginine methyl ester (l-NAME, ingested for 2 days in drinking water, 1 mg/ml) followed by acute exercise, no l-NAME ingestion and acute exercise, rest plus l-NAME, and rest without l-NAME. The exercised rats ran on a treadmill for 53 ± 2 min and were then killed 4 h later. NOS inhibition significantly ( P < 0.05; main effect) decreased basal peroxisome proliferator-activated receptor-γ coactivator 1β (PGC-1β) mRNA levels and tended ( P = 0.08) to decrease mtTFA mRNA levels in the soleus, but not the extensor digitorum longus (EDL) muscle. This coincided with significantly reduced basal levels of cytochrome c oxidase (COX) I and COX IV mRNA, COX IV protein and COX enzyme activity following NOS inhibition in the soleus, but not the EDL muscle. NOS inhibition had no effect on citrate synthase or β-hydroxyacyl CoA dehydrogenase activity, or cytochrome c protein abundance in the soleus or EDL. NOS inhibition did not reduce the exercise-induced increase in peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) mRNA in the soleus or EDL. In conclusion, inhibition of NOS appears to decrease some aspects of the mitochondrial respiratory chain in the soleus under basal conditions, but does not attenuate exercise-induced mitochondrial biogenesis in the soleus or in the EDL.
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Beierwaltes, William H. "Cyclooxygenase-2 products compensate for inhibition of nitric oxide regulation of renal perfusion." American Journal of Physiology-Renal Physiology 283, no. 1 (July 1, 2002): F68—F72. http://dx.doi.org/10.1152/ajprenal.00364.2001.
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Cyclooxygenase (COX)-2 is in the macula densa, cosegregating with neuronal nitric oxide synthase (nNOS). It is hypothesized that in response to acute inhibition of NOS, the influence of COX-2-derived prostanoids is exaggerated, compensating for renal vasoconstriction. Blood pressure (BP) and renal blood flow (RBF) were measured after selective COX-2 inhibition with NS-398 followed by NOS inhibition with l-nitro arginine methyl ester (l-NAME) or after l-NAME followed by NS-398. BP was 106 ± 4 mmHg and was unaffected by NS-398.l-NAME after NS-398 increased BP by 27 ± 2 mmHg, decreased RBF by one-half, and doubled renal vascular resistance (RVR; P < 0.001). Initial l-NAME increased BP by 26 ± 3 mmHg ( P < 0.001) and decreased RBF by 44% ( P < 0.001), doubling RVR. Afterl-NAME, NS-398 induced a further 7 ± 3-mmHg rise in BP ( P < 0.05), decreased RBF by 20% ( P < 0.025), and increased RVR by 23% ( P < 0.01). The constrictor response to COX-2 inhibition after l-NAME could not be duplicated by either selective nNOS inhibition or NOS-independent renal vasoconstriction. Acute NOS inhibition unmasked renal vasoconstriction with COX-2 inhibition, suggesting that the influence of COX-2-derived vasodilator eicosanoids is exaggerated to maintain renal perfusion, compensating for the acute loss of NO.
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Lekontseva, Olga, Yanyan Jiang, Caitlyn Schleppe, and Sandra T. Davidge. "Altered Neuronal Nitric Oxide Synthase in the Aging Vascular System: Implications for Estrogens Therapy." Endocrinology 153, no. 8 (June 14, 2012): 3940–48. http://dx.doi.org/10.1210/en.2012-1071.
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Ovarian dysfunction at any age is associated with increased cardiovascular risk in women; however, therapeutic effects of exogenous estrogens are age dependent. Estradiol (E2) activates neuronal nitric oxide synthase (nNOS) in vascular cells. Because nNOS is prone to uncoupling under unfavorable biochemical conditions (as seen in aging), E2 stimulation of nNOS may lack vascular benefits in aging. Small mesenteric arteries were isolated from female Sprague Dawley rats, 3 or 12 months old, who were ovariectomized (Ovx) and treated with placebo or E2 for 4 wk. Vascular relaxation to exogenous E2 (0.001–100 μmol/liter) ± selective nNOS inhibitor (N-propyl-l-arginine, 2 μmol/liter) or pan-NOS inhibitor [Nω-nitro-l-arginine methyl ester (l-NAME), 100 μmol/liter] was examined on wire myograph. NOS expression was measured by Western blotting in thoracic aortas, in which superoxide generation was detected as dihydroethidium (DHE) fluorescence. E2 relaxations were impaired in Ovx conditions. E2 treatment (4 wk) normalized vascular function in young rats only. Both l-N-propyl-l-arginine and l-NAME blunted E2 relaxation in young controls, but only l-NAME did so in aging controls. NOS inhibition had no effect on acute E2 relaxation in Ovx rats, regardless of age or treatment. nNOS expression was similar in all animal groups. However, nNOS inhibition increased DHE fluorescence in young controls, whereas it reduced it in aging or Ovx animals. In E2-treated animals of either age, superoxide production was NOS independent. In conclusion, nNOS contributed to vascular relaxation in young, but not aging rats, where its enzymatic function shifted toward superoxide production. Thus, nNOS dysfunction may explain a mechanism of impaired E2 signaling in aging conditions.
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Irikura, Katsumi, Kenneth I. Maynard, and Michael A. Moskowitz. "Importance of Nitric Oxide Synthase Inhibition to the Attenuated Vascular Responses Induced by Topical L-Nitroarginine during Vibrissal Stimulation." Journal of Cerebral Blood Flow & Metabolism 14, no. 1 (January 1994): 45–48. http://dx.doi.org/10.1038/jcbfm.1994.7.
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We assessed the regional cerebral blood flow (rCBF) response to vibrissal stimulation before and after nitric oxide synthase (NOS) inhibitors were topically applied through a closed cranial window placed over the cortical barrel fields in anesthetized Sprague–Dawley rats. In the presence of L-nitroarginine (1 m M), both the maximum and total responses became reduced, but only in those animals demonstrating >50% inhibition of NOS activity as determined by the conversion of [3H]arginine to [3H]citrulline within homogenates taken from cortical gray matter under the cranial window. The degree of enzyme inhibition depended in part, upon duration after topical application of NOS inhibitor. When >50%, enzyme inhibition correlated with the decrease in maximum and total rCBF response (p < 0.01). These findings emphasize the merits of assessing enzyme activity after administering NOS inhibitors, and suggest that NO generated from parenchymal NOS activity plays an important role in the cerebrovascular response to physiologic somatosensory stimulation under the stated conditions.
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West, S. D., K. S. Helmer, L. K. Chang, and D. W. Mercer. "INFLUENCE OF NOS INHIBITION ON GUT PEPTIDES DURING ENDOTOXEMIA." Shock 19, Supplement (June 2003): 42–43. http://dx.doi.org/10.1097/00024382-200306001-00125.
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Sandt, A., R. Windler, A. Gödecke, J. Ohlig, S. Becher, T. Rassaf, J. Schrader, M. Kelm, and M. Merx. "Neuronal NOS-inhibition in the setting of septic cardiomyopathy." Critical Care 14, Suppl 1 (2010): P20. http://dx.doi.org/10.1186/cc8252.
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Joubert, Jacques, Sandra van Dyk, and Sarel F. Malan. "Fluorescent polycyclic ligands for nitric oxide synthase (NOS) inhibition." Bioorganic & Medicinal Chemistry 16, no. 19 (October 2008): 8952–58. http://dx.doi.org/10.1016/j.bmc.2008.08.049.
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Filipczak, Piotr T., Albert P. Senft, JeanClare Seagrave, Waylon Weber, Philip J. Kuehl, Laura E. Fredenburgh, Jacob D. McDonald, and Rebecca M. Baron. "NOS-2 Inhibition in Phosgene-Induced Acute Lung Injury." Toxicological Sciences 146, no. 1 (April 13, 2015): 89–100. http://dx.doi.org/10.1093/toxsci/kfv072.
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Fretland, Donald J., Barnett S. Pitzele, Jane R. Connor, Mark G. Currie, and Pamela T. Manning. "Inhibition of Nitric Oxide Synthase and Prospects For Therapy in Inflammatory Diseases." Current Pharmaceutical Design 3, no. 5 (1997): 447–62. http://dx.doi.org/10.2174/138161280305221010094339.
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Abstract: Nitric oxide is synthesized enzymatically from arginine in numerous tissues and cell types by three_distinct isoforms of the enzyme nitric oxide synthase (NOS). Two of these isoforms are expressed in a constitutive manner (cNOS) predominantly in the vascular endothelium (eNOS, type III NOS) and in the nervous system (nNOS, type I NOS) and function in the maintenance of normal homeostasis. Under normal physiological conditions, these constitutive isoforms of NOS generate low levels of nitric oxide in response to increases in intracellular calcium concentrations. The expression of the third form (iNOS, type II NOS) is induced by endotoxin and/or inflammatory cytokines and generates high levels of nitric oxide over long periods of time. The excessive production of nitric oxide, generated either by iNOS or by the sustained activation of nNOS, elicits cellular cytotoxicity and tissue damage and is thought to contribute to the pathophysiology of human disease states. The development of selective inhibitors of iNOS and/or nNOS offers the potential of blocking the synthesis of a major injurious agent, nitric oxide, and ultimately reducing tissue damage during states of chronic inflammation or prolonged elevations in cytosolic calcium. In this review, the selective inhibition of the various isoforms of NOS is examined by structure activity relationships as unique targets for drug research and therapeutic intervention in a variety of disease states.
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Carlström, Mattias, Christopher S. Wilcox, and William J. Welch. "Adenosine A2A receptor activation attenuates tubuloglomerular feedback responses by stimulation of endothelial nitric oxide synthase." American Journal of Physiology-Renal Physiology 300, no. 2 (February 2011): F457—F464. http://dx.doi.org/10.1152/ajprenal.00567.2010.
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Adenosine A2 receptors have been suggested to modulate tubuloglomerular feedback (TGF) responses by counteracting adenosine A1 receptor-mediated vasoconstriction, but the mechanisms are unclear. We tested the hypothesis that A2A receptor activation blunts TGF by release of nitric oxide in the juxtaglomerular apparatus (JGA). Maximal TGF responses were measured in male Sprague-Dawley rats as changes in proximal stop-flow pressure (ΔPSF) in response to increased perfusion of the loop of Henle (0 to 40 nl/min) with artificial tubular fluid (ATF). The maximal TGF response was studied after 5 min intratubular perfusion (10 nl/min) with ATF or ATF + A2A receptor agonist (CGS-21680; 10−7 mol/l). The interaction with nitric oxide synthase (NOS) isoforms was tested by perfusion with a nonselective NOS inhibitor [ Nω-nitro-l-arginine methyl ester hydrochloride (l-NAME); 10−3 mol/l] or a selective neuronal NOS (nNOS) inhibitor [ Nω-propyl-l-arginine (l-NPA); 10−6 mol/l] alone, and with the A2A agonist. Blood pressure, urine flow, and PSF at 0 nl/min were similar among the groups. The maximal TGF response (ΔPSF) with ATF alone (12.3 ± 0.6 mmHg) was attenuated by selective A2A stimulation (9.5 ± 0.4 mmHg). l-NAME enhanced maximal TGF responses (18.9 ± 0.4 mmHg) significantly more than l-NPA (15.2 ± 0.7 mmHg). Stimulation of A2A receptors did not influence maximal TGF response during nonselective NOS inhibition (19.0 ± 0.4) but attenuated responses during nNOS inhibition (10.3 ± 0.4 mmHg). In conclusion, adenosine A2A receptor activation attenuated TGF responses by stimulation of endothelial NOS (eNOS), presumably in the afferent arteriole. Moreover, NO derived from both eNOS and nNOS in the JGA may blunt TGF responses.
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Andersen, Jens Lundbæk, Niels C. F. Sandgaard, and Peter Bie. "Volume expansion during acute angiotensin II receptor (AT1) blockade and NOS inhibition in conscious dogs." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 282, no. 4 (April 1, 2002): R1140—R1148. http://dx.doi.org/10.1152/ajpregu.00665.2000.
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The responses to AT1-receptor blockade (candesartan 1 mg/kg) and to concomitant volume expansion (saline 35 ml/kg for 90 min) with and without nitric oxide synthase (NOS) inhibition ( N G-nitro-l-arginine methyl ester 30 μg · kg−1 · min−1) were investigated in separate experiments in normal dogs. AT1 blockade decreased arterial pressure (106 ± 4 to 96 ± 5 mmHg) and increased glomerular filtration rate (GFR) by 17% and sodium excretion threefold. NOS inhibition increased arterial pressure (103 ± 3 to 116 ± 3 mmHg) and decreased GFR by 21% and reduced sodium excretion by some 80%. Volume expansion increased arterial pressure significantly in all series involving this procedure, most pronounced during combined AT1 blockade and NOS inhibition (21 ± 4 mmHg). Volume expansion during AT1 blockade elicited marked natriuresis (26 ± 11 to 274 ± 55 μmol/min) that was severely reduced by concomitant NOS inhibition (10 ± 3 to 45 ± 11 μmol/min), but still much larger than that seen with volume expansion during NOS inhibition alone (2 ± 1 to 23 ± 7 μmol/min). Volume expansion during AT1 blockade increased GFR (+30%), less so during combined AT1 blockade and NOS inhibition (+13%), but it did not increase GFR significantly ( P = 0.07) during NOS inhibition alone. Plasma ANG II increased greater than sevenfold with AT1 blockade and doubled with NOS inhibition (paired t-test, P < 0.05), whereas it decreased by 50–80% during volume expansion irrespective of pretreatment, i.e., during NOS inhibition, volume expansion did not generate subnormal plasma ANG II concentrations. In conclusion, 1) acute AT1 blockade leads to hyperfiltration, natriuresis, and hyperresponsiveness to volume expansion, 2) these responses are >85% inhibitable by unspecific NOS inhibition, and 3) NOS inhibition alone is followed by increases in plasma ANG II, hypofiltration, and severe antinatriuresis that may be counterbalanced but not overwhelmed by volume expansion. Thus NOS inhibition virtually abolishes the volume expansion natriuresis, at least in part, due to the lack of appropriate inhibition of the renin-angiotensin-aldosterone system.
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Hong, Yet Hoi, Andrew C. Betik, Dino Premilovac, Renee M. Dwyer, Michelle A. Keske, Stephen Rattigan, and Glenn K. McConell. "No effect of NOS inhibition on skeletal muscle glucose uptake during in situ hindlimb contraction in healthy and diabetic Sprague-Dawley rats." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 308, no. 10 (May 15, 2015): R862—R871. http://dx.doi.org/10.1152/ajpregu.00412.2014.
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Nitric oxide (NO) has been shown to be involved in skeletal muscle glucose uptake during contraction/exercise, especially in individuals with Type 2 diabetes (T2D). To examine the potential mechanisms, we examined the effect of local NO synthase (NOS) inhibition on muscle glucose uptake and muscle capillary blood flow during contraction in healthy and T2D rats. T2D was induced in Sprague-Dawley rats using a combined high-fat diet (23% fat wt/wt for 4 wk) and low-dose streptozotocin injections (35 mg/kg). Anesthetized animals had one hindlimb stimulated to contract in situ for 30 min (2 Hz, 0.1 ms, 35 V) with the contralateral hindlimb rested. After 10 min, the NOS inhibitor, NG-nitro-l-arginine methyl ester (l-NAME; 5 μM) or saline was continuously infused into the femoral artery of the contracting hindlimb until the end of contraction. Surprisingly, there was no increase in skeletal muscle NOS activity during contraction in either group. Local NOS inhibition had no effect on systemic blood pressure or muscle contraction force, but it did cause a significant attenuation of the increase in femoral artery blood flow in control and T2D rats. However, NOS inhibition did not attenuate the increase in muscle capillary recruitment during contraction in these rats. Muscle glucose uptake during contraction was significantly higher in T2D rats compared with controls but, unlike our previous findings in hooded Wistar rats, NOS inhibition had no effect on glucose uptake during contraction. In conclusion, NOS inhibition did not affect muscle glucose uptake during contraction in control or T2D Sprague-Dawley rats, and this may have been because there was no increase in NOS activity during contraction.
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Hesslinger, Christian, Andreas Strub, Rainer Boer, Wolf-Rüdiger Ulrich, Martin D. Lehner, and Clemens Braun. "Inhibition of inducible nitric oxide synthase in respiratory diseases." Biochemical Society Transactions 37, no. 4 (July 22, 2009): 886–91. http://dx.doi.org/10.1042/bst0370886.
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Nitric oxide (NO) is a key physiological mediator and disturbed regulation of NO release is associated with the pathophysiology of almost all inflammatory diseases. A multitude of inhibitors of NOSs (nitric oxide synthases) have been developed, initially with low or even no selectivity against the constitutively expressed NOS isoforms, eNOS (endothelial NOS) and nNOS (neuronal NOS). In the meanwhile these efforts yielded potent and highly selective iNOS (inducible NOS) inhibitors. Moreover, iNOS inhibitors have been shown to exert beneficial anti-inflammatory effects in a wide variety of acute and chronic animal models of inflammation. In the present mini-review, we summarize some of our current knowledge of inhibitors of the iNOS isoenzyme, their biochemical properties and efficacy in animal models of pulmonary diseases and in human disease itself. Moreover, the potential benefit of iNOS inhibition in animal models of COPD (chronic obstructive pulmonary disease), such as cigarette smoke-induced pulmonary inflammation, has not been explicitly studied so far. In this context, we demonstrated recently that both a semi-selective iNOS inhibitor {L-NIL [N6-(1-iminoethyl)-L-lysine hydrochloride]} and highly selective iNOS inhibitors (GW274150 and BYK402750) potently diminished inflammation in a cigarette smoke mouse model mimicking certain aspects of human COPD. Therefore, despite the disappointing results from recent asthma trials, iNOS inhibition could still be of therapeutic utility in COPD, a concept which needs to be challenged and validated in human disease.
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Tam, Siu Lin, and Susan Kaufman. "NOS inhibition restores renal responses to atrial distension during pregnancy." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 282, no. 5 (May 1, 2002): R1364—R1367. http://dx.doi.org/10.1152/ajpregu.00705.2001.
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Nitric oxide (NO) biosynthesis increases during pregnancy and has been shown to suppress baroreceptor activity. The renal response to a simulated increase in circulating blood volume (atrial distension) is also attenuated at this time. We hypothesized that blocking NO biosynthesis during pregnancy would restore the renal response. Female rats were implanted with indwelling intracardiac balloons and central venous cannulas. After recovery, they were mated, and on day 14 of pregnancy, osmotic minipumps containing the NO synthase inhibitor N G-nitro-l-arginine methyl ester (l-NAME) or its inactive enantiomer N G-nitro-d-arginine methyl ester (d-NAME) (120 mg/2 ml at 10 μg/min) were implanted. In response to atrial distension (1 h), urine output increased in the d- and l-NAME-treated virgin rats. During pregnancy ( day 20), this response was attenuated in the d-NAME-treated, but not thel-NAME-treated, animals, i.e., after a simulated increase in circulating blood volume, inhibition of NO biosynthesis restored the renal response of pregnant rats to that seen in virgin animals. We conclude that, during normal pregnancy, increased NO biosynthesis blunts the reflex renal response to atrial distension.
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Ichinose, Fumito, Wei-dong Mi, Miyuki Miyazaki, Tsuneko Onouchi, Takahisa Goto, and Shigeho Morita. "Lack of Correlation between the Reduction of Sevoflurane MAC and the Cerebellar Cyclic GMP Concentrations in Mice Treated with 7-Nitroindazole." Anesthesiology 89, no. 1 (July 1, 1998): 143–48. http://dx.doi.org/10.1097/00000542-199807000-00021.
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Background Although inhibition of nitric oxide synthase (NOS) has been reported to be antinociceptive and to reduce the threshold of general anesthesia, the mechanism of action is largely unknown. Specifically, the relation between the minimum alveolar concentration (MAC)-reducing effects of NOS inhibition and cyclic guanosine monophosphate (cGMP) concentrations in the brain has not been defined. To further characterize the effects of NOS inhibition, the authors studied the relation between the MAC of sevoflurane and the cGMP concentration of the brain after acute and chronic treatment with a neuronally selective NOS inhibitor, 7-nitroindazole (7-NI). Methods Sevoflurane MAC and cerebellar cGMP concentrations were determined in mice after acute intraperitoneal administration or after 1, 2, 3, and 4 days of gavage feeding of 7-NI. After acute or chronic treatment with 7-NI, the mice were separated into two groups. Sevoflurane MAC was measured by a tail-clamp method in the first group, and cerebellar cGMP concentrations were measured by enzyme-linked immunosorbent assay in the second group of the mice. Results In mice, acute intraperitoneal administration of 7-NI dose dependently decreased sevoflurane MAC and cerebellar cGMP; and 4-day-long gavage feeding with 7-NI (500 mg/ kg, every 8 h) time dependently decreased cerebellar cGMP, but sevoflurane MAC was reduced only for the first 2 days and returned to its baseline after 3 days of 7-NI feeding. Conclusions Although an acute selective inhibition of neuronal NOS decreases sevoflurane MAC and cerebellar cGMP concentrations in mice, there was a dissociation between the two parameters during long-term neuronal NOS inhibition. There may be cGMP-independent compensatory mechanisms that mediate nociception when NOS is chronically inhibited.
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DiMagno, Matthew J., John A. Williams, Yibai Hao, Stephen A. Ernst, and Chung Owyang. "Endothelial nitric oxide synthase is protective in the initiation of caerulein-induced acute pancreatitis in mice." American Journal of Physiology-Gastrointestinal and Liver Physiology 287, no. 1 (July 2004): G80—G87. http://dx.doi.org/10.1152/ajpgi.00525.2003.
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The effect of inhibiting nitric oxide (NO) synthase (NOS) or enhancing NO on the course of acute pancreatitis (AP) is controversial, in part because three NOS isoforms exist: neuronal (nNOS), endothelial (eNOS), and inducible (iNOS). We investigated whether inhibition or selective gene deletion of NOS isoforms modified the initiation phase of caerulein-induced AP in mice and explored whether this affected pancreatic microvascular blood flow (PMBF). We investigated the effects of nonspecific NOS inhibition with Nω-nitro-l-arginine (l-NNA; 10 mg/kg ip) or targeted deletion of eNOS, nNOS, or iNOS genes on the initiation phase of caerulein-induced AP in mice using in vivo and in vitro models. Western blot analysis was performed to assess eNOS phosphorylation status, an indicator of enzyme activity, and microsphere studies were used to measure PMBF. l-NNA and eNOS deletion, but not nNOS or iNOS deletion, increased pancreatic trypsin activity and serum lipase during the initiation phase of in vivo caerulein-induced AP. l-NNA and eNOS did not affect trypsin activity in caerulein-hyperstimulated isolated acini, suggesting that nonacinar events mediate the effect of NOS blockade in vivo. The initiation phase of AP in wild-type mice was associated with eNOS Thr495 residue dephosphorylation, which accompanies eNOS activation, and a 178% increase in PMBF; these effects were absent in eNOS-deleted mice. Thus eNOS is the main isoform influencing the initiation of caerulein-induced AP. eNOS-derived NO exerts a protective effect through actions on nonacinar cell types, most likely endothelial cells, to produce greater PMBF.
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Saito, Takayuki, Fu Hu, Lara Tayara, Linda Fahas, Hani Shennib, and Adel Giaid. "Inhibition of NOS II prevents cardiac dysfunction in myocardial infarction and congestive heart failure." American Journal of Physiology-Heart and Circulatory Physiology 283, no. 1 (July 1, 2002): H339—H345. http://dx.doi.org/10.1152/ajpheart.00596.2001.
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Strong expression of the inducible form of nitric oxide synthase (NOS II) has been shown in the myocardium of patients with myocardial infarction (MI). We hypothesized that NOS II plays an important role in the development of MI and subsequent heart failure and that inhibition of NOS II may beneficially alter the course of the disease. Long-term administration (2 mo) of the selective NOS II inhibitor S-methylisothiourea (SMT) to rats with MI significantly improved cardiac function. A significant drop in mortality, lung water content, infarct size, and cardiomyocyte hypertrophy was also associated with the use of SMT. Plasma concentration of nitrite and nitrate was also reduced by SMT. Short-term administration of SMT (first 2 wk only) significantly reduced infarct size; however, it did not improve cardiac dysfunction measured 2 mo after MI. These findings demonstrate that induction of NOS II during MI exerts negative effects on cardiac function and structure. Long-term administration of a selective NOS II inhibitor may prove to be beneficial in the treatment of MI and congestive heart failure.
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Yi, G. B., D. Mc Clendon, D. Desaiah, J. Goddard, A. Lister, J. Moffitt, R. K. Vander Meer, R. de Shazo, K. S. Lee, and R. W. Rockhold. "Fire Ant Venom Alkaloid, Isosolenopsin A, a Potent and Selective Inhibitor of Neuronal Nitric Oxide Synthase." International Journal of Toxicology 22, no. 2 (March 2003): 81–86. http://dx.doi.org/10.1080/10915810305090.
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Massive, multiple fire ant, Solenopsis invicta, stings are often treated aggressively, particularly in the elderly, despite limited evidence of systemic toxicity due to the venom. Over 95% of the S. invicta venom is composed of piperidine alkaloid components, whose toxicity, if any, is unknown. To assess a possible pharmacological basis for systemic toxicity, an alkaloid-rich, protein-free methanol extract of the venom from whole ants was assayed for inhibitory activity on the following nitric oxide synthase (NOS) isoforms, rat cerebellar neuronal (n NOS), bovine recombinant endothelial (e NOS), and murine recombinant immunologic (i NOS). Cytosolic NOS activity was determined by measuring the conversion of [3H]arginine to [3H]citrulline in vitro. Rat n NOS activity was inhibited significantly and in a concentration-dependent manner by the alkaloid-rich venom extract. For n NOS, enzyme activity was inhibited by approximately 50% with 0.33 ± 0.06 μgg of this venom extract, and over 95% inhibition of the three isoforms, n NOS, e NOS, and i NOS, was found with doses of 60 μg in 60-μl reaction mixture. These results indicate that the alkaloid components of S. invicta venom can produce potent inhibition of all three major NOS isoforms. Isosolenopsin A ( cis-2-methyl-6-undecylpiperidine), a naturally occurring fire ant piperidine alkaloid, was synthesized and tested for inhibitory activity against the three NOS isoforms. Enzyme activities for n NOS and e NOS were over 95% inhibited with 1000 μM of isosolenopsin A, whereas the activity of i NOS was inhibited by only about 20% at the same concentration. The IC50 for each of three NOS isoforms was approximately 18 ± 3.9 μM for n NOS, 156 ± 10 μM for e NOS, and >1000 μM for i NOS, respectively. Kinetic studies showed isosolenopsin A inhibition to be noncompetitive with L-arginine ( Ki = 19 ± 2 μM). The potency of isosolenopsin A as an inhibitor of n NOS compares favorably with the inhibitory potency of widely used n NOS inhibitors. Inhibition of NOS isoforms by isosolenopsin A and structurally similar compounds may have toxicological significance with respect to adverse reactions to fire ant stings.
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Chmelíková, Eva, Michal Ješeta, Markéta Sedmíková, Jaroslav Petr, Lenka Tůmová, Tomáš Kott, Petra Lipovová, and František Jílek. "Nitric oxide synthase isoforms and the effect of their inhibition on meiotic maturation of porcine oocytes." Zygote 18, no. 3 (January 29, 2010): 235–44. http://dx.doi.org/10.1017/s0967199409990268.
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SummaryIn this paper we assessed: (i) the change in nitric oxide synthase (NOS) isoforms' expression and intracellular localization and in NOS mRNA in porcine oocytes during meiotic maturation; (ii) the effect of NOS inhibition by Nω-nitro-l-arginine methyl ester (l-NAME) and aminoguanidine (AG) on meiotic maturation of cumulus–oocyte complexes (COC) as well as denuded oocytes (DO); and (iii) nitric oxide (NO) formation in COC. All three NOS isoforms (eNOS, iNOS and nNOS) and NOS mRNA (eNOS mRNA, iNOS mRNA and nNOS mRNA) were found in both porcine oocytes and their cumulus cells except for nNOS mRNA, which was not detected in the cumulus cells. NOS isoforms differed in their intracellular localization in the oocyte: while iNOS protein was dispersed in the oocyte cytoplasm, nNOS was localized in the oocyte cytoplasm and in germinal vesicles (GV) and eNOS was present in dots in the cytoplasm, GV and was associated with meiotic spindles. l-NAME inhibitor significantly suppressed metaphase (M)I to MII transition (5.0 mM experimental group: 34.9% MI, control group: 9.5% MI) and at the highest concentration (10.0 mM) also affected GV breakdown (GVBD); in contrast also AG inhibited primarily GVBD. The majority of the oocytes (10.0 mM experimental group: 60.8%, control group: 1.2%) was not able to resume meiosis. AG significantly inhibited GVBD in DO, but l-NAME had no significant effect on the GVBD of these cells. During meiotic maturation, NO is formed in COC and the NO formed by cumulus cells is necessary for the process of GVBD.
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Kleinschnitz, Christoph, Stine Mencl, Pamela WM Kleikers, Michael K. Schuhmann, Manuela G López, Ana I. Casas, Bilge Sürün, Andreas Reif, and Harald HHW Schmidt. "NOS knockout or inhibition but not disrupting PSD-95-NOS interaction protect against ischemic brain damage." Journal of Cerebral Blood Flow & Metabolism 36, no. 9 (July 20, 2016): 1508–12. http://dx.doi.org/10.1177/0271678x16657094.
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Promising results have been reported in preclinical stroke target validation for pharmacological principles that disrupt the N-methyl-D-aspartate receptor–post-synaptic density protein-95–neuronal nitric oxide synthase complex. However, post-synaptic density protein-95 is also coupled to potentially neuroprotective mechanisms. As post-synaptic density protein-95 inhibitors may interfere with potentially neuroprotective mechanisms and sufficient validation has often been an issue in translating basic stroke research, we wanted to close that gap by comparing post-synaptic density protein-95 inhibitors with NOS1−/− mice and a NOS inhibitor. We confirm the deleterious role of NOS1 in stroke both in vivo and in vitro, but find three pharmacological post-synaptic density protein-95 inhibitors to be therapeutically ineffective.
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Frasch, H. Frederick, Carol Marshall, and Bryan E. Marshall. "Endothelin-1 is elevated in monocrotaline pulmonary hypertension." American Journal of Physiology-Lung Cellular and Molecular Physiology 276, no. 2 (February 1, 1999): L304—L310. http://dx.doi.org/10.1152/ajplung.1999.276.2.l304.
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These studies document striking pulmonary vasoconstrictor response to nitric oxide synthase (NOS) inhibition in monocrotaline (MCT) pulmonary hypertension in rats. This constriction is caused by elevated endothelin (ET)-1 production acting on ETA receptors. Isolated, red blood cell plus buffer-perfused lungs from rats were studied 3 wk after MCT (60 mg/kg) or saline injection. MCT-injected rats developed pulmonary hypertension, right ventricular hypertrophy, and heightened pulmonary vasoconstriction to ANG II and the NOS inhibitor N G-monomethyl-l-arginine (l-NMMA). In MCT-injected lungs, the magnitude of the pulmonary pressor response to NOS inhibition correlated strongly with the extent of pulmonary hypertension. Pretreatment of isolated MCT-injected lungs with combined ETA (BQ-123) plus ETB (BQ-788) antagonists or ETA antagonist alone prevented thel-NMMA-induced constriction. Addition of ETA antagonist reversed establishedl-NMMA-induced constriction; ETB antagonist did not. ET-1 concentrations were elevated in MCT-injected lung perfusate compared with sham-injected lung perfusate, but ET-1 levels did not differ before and after NOS inhibition. NOS inhibition enhanced hypoxic pulmonary vasoconstriction in both sham- and MCT-injected lungs, but the enhancement was greater in MCT-injected lungs. Results suggest that in MCT pulmonary hypertension, elevated endogenous ET-1 production acting through ETA receptors causes pulmonary vasoconstriction that is normally masked by endogenous NO production.
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D'Souza, K. M., L. A. Biwer, L. Madhavpeddi, P. Ramaiah, W. Shahid, and T. M. Hale. "Persistent change in cardiac fibroblast physiology after transient ACE inhibition." American Journal of Physiology-Heart and Circulatory Physiology 309, no. 8 (October 2015): H1346—H1353. http://dx.doi.org/10.1152/ajpheart.00615.2015.
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Transient angiotensin-converting enzyme (ACE) inhibition induces persistent changes that protect against future nitric oxide synthase (NOS) inhibitor-induced cardiac fibrosis and inflammation. Given the role of fibroblasts in mediating these effects, the present study investigates whether prior ACE inhibition produced persistent changes in cardiac fibroblast physiology. Adult male spontaneously hypertensive rats (SHRs) were treated with vehicle (C+L) or the ACE inhibitor, enalapril (E+L) for 2 wk followed by a 2-wk washout period and a subsequent 7-day challenge with the NOS inhibitor Nω-nitro-l-arginine methyl ester. A third set of untreated SHRs served as controls. At the end of the study period, cardiac fibroblasts were isolated from control, C+L, and E+L left ventricles to assess proliferation rate, collagen expression, and chemokine release in vitro. After 7 days of NOS inhibition, there were areas of myocardial injury but no significant change in collagen deposition in E+L and C+L hearts in vivo. In vitro, cardiac fibroblasts isolated from C+L but not E+L hearts were hyperproliferative, demonstrated increased collagen type I gene expression, and an elevated secretion of the macrophage-recruiting chemokines monocyte chemoattractant protein-1 and granulocyte macrophage-colony stimulating factor. These findings demonstrate that in vivo Nω-nitro-l-arginine methyl ester treatment produces phenotypic changes in fibroblasts that persist in vitro. Moreover, this is the first demonstration that transient ACE inhibition can produce a persistent modification of the cardiac fibroblast phenotype to one that is less inflammatory and fibrogenic. It may be that the cardioprotective effects of ACE inhibition are related in part to beneficial changes in cardiac fibroblast physiology.
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Blokland, Arjan, Jos Prickaerts, Wiel Honig, and Jan de Vente. "State-dependent impairment in object recognition after hippocampal NOS inhibition." NeuroReport 9, no. 18 (December 1998): 4205–8. http://dx.doi.org/10.1097/00001756-199812210-00037.
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Bratz, Ian N., Ricardo Falcon, L. Donald Partridge, and Nancy L. Kanagy. "Vascular smooth muscle cell membrane depolarization after NOS inhibition hypertension." American Journal of Physiology-Heart and Circulatory Physiology 282, no. 5 (May 1, 2002): H1648—H1655. http://dx.doi.org/10.1152/ajpheart.00824.2001.
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Nitric oxide (NO) synthase (NOS) inhibition with N ω-nitro-l-arginine (l-NNA) produces l-NNA hypertensive rats (LHR), which exhibit increased sensitivity to voltage-dependent Ca2+ channel-mediated vasoconstriction. We hypothesized that enhanced contractile responsiveness after NOS inhibition is mediated by depolarization of membrane potential ( E m) through attenuated K+ channel conductance. E m measurements demonstrated that LHR vascular smooth muscle cells (VSMCs) are depolarized in open, nonpressurized (−44.5 ± 1.0 mV in control vs. −36.8 ± 0.8 mV in LHR) and pressurized mesenteric artery segments (−41.8 ± 1.0 mV in control vs. −32.6 ± 1.4 mV in LHR). Endothelium removal or exogenous l-NNA depolarized control VSMCs but not LHR VSMCs. Superfused l-arginine hyperpolarized VSMCs from both the control and LHR groups and reversedl-NNA-induced depolarization (−44.5 ± 1.0 vs. −45.8 ± 2.1 mV). A Ca2+-activated K+channel agonist, NS-1619 (10 μM), hyperpolarized both groups of arteries to a similar extent (from −50.8 ± 1.0 to −62.5 ± 1.2 mV in control and from −43.7 ± 1.1 to −55.6 ± 1.2 mV in LHR), although E m was still different in the presence of NS-1619. In addition, superfused iberiotoxin (50 nM) depolarized both groups similarly. Increasing the extracellular K+ concentration from 1.2 to 45 mM depolarized E m, as predicted by the Goldman-Hodgkin-Katz equation. These data support the hypothesis that loss of NO activation of K+ channels contributes to VSMC depolarization inl-NNA-induced hypertension without a change in the number of functional large conductance Ca2+-activated K+ channels.
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Lyon, Melvin. "NEUROLEPTIC POTENTIAL OF NITRIC OXIDE SYNTHASE (NOS) INHIBITION IN SCHIZOPHRENIA." Behavioural Pharmacology 10, SUPPLEMENT 1 (August 1999): S59. http://dx.doi.org/10.1097/00008877-199908001-00148.
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Demchenko, Ivan T., Alexander N. Moskvin, Alexander I. Krivchenko, Claude A. Piantadosi, and Barry W. Allen. "Nitric oxide-mediated central sympathetic excitation promotes CNS and pulmonary O2 toxicity." Journal of Applied Physiology 112, no. 11 (June 1, 2012): 1814–23. http://dx.doi.org/10.1152/japplphysiol.00902.2011.
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In hyperbaric oxygen (HBO2) at or above 3 atmospheres absolute (ATA), autonomic pathways link central nervous system (CNS) oxygen toxicity to pulmonary damage, possibly through a paradoxical and poorly characterized relationship between central nitric oxide production and sympathetic outflow. To investigate this possibility, we assessed sympathetic discharges, catecholamine release, cardiopulmonary hemodynamics, and lung damage in rats exposed to oxygen at 5 or 6 ATA. Before HBO2 exposure, either a selective inhibitor of neuronal nitric oxide synthase (NOS) or a nonselective NOS inhibitor was injected directly into the cerebral ventricles to minimize effects on the lung, heart, and peripheral circulation. Experiments were performed on both anesthetized and conscious rats to differentiate responses to HBO2 from the effects of anesthesia. EEG spikes, markers of CNS toxicity in anesthetized animals, were approximately four times as likely to develop in control rats than in animals with central NOS inhibition. In inhibitor-treated animals, autonomic discharges, cardiovascular pressures, catecholamine release, and cerebral blood flow all remained below baseline throughout exposure to HBO2. In control animals, however, initial declines in these parameters were followed by significant increases above their baselines. In awake animals, central NOS inhibition significantly decreased the incidence of clonic-tonic convulsions or delayed their onset, compared with controls. The novel findings of this study are that NO produced by nNOS in the periventricular regions of the brain plays a critical role in the events leading to both CNS toxicity in HBO2 and to the associated sympathetic hyperactivation involved in pulmonary injury.
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Kamii, Hideyuki, Shigeki Mikawa, Kensuke Murakami, Hiroyuki Kinouchi, Takashi Yoshimoto, Liza Reola, Elaine Carlson, Charles J. Epstein, and Pak H. Chan. "Effects of Nitric Oxide Synthase Inhibition on Brain Infarction in SOD-1-Transgenic Mice following Transient Focal Cerebral Ischemia." Journal of Cerebral Blood Flow & Metabolism 16, no. 6 (November 1996): 1153–57. http://dx.doi.org/10.1097/00004647-199611000-00009.
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To investigate the role of superoxide in the toxicity of nitric oxide (NO), we examined the effect of nitric oxide synthase (NOS) inhibition on brain infarction in transgenic mice overexpressing CuZn-superoxide dismutase (SOD-1). Male SOD-transgenic mice and nontransgenic littermates (30–35 g) were subjected to 60 min of middle cerebral artery occlusion followed by 24 h of reperfusion. Either N G-nitro-l-arginine methyl ester (l-NAME; 3 mg/kg), a mixed neuronal and endothelial NOS inhibitor, or 7-nitroindazole (7-NI; 25 mg/kg), a selective neuronal NOS inhibitor, was administered intraperitoneally 5 min after the onset of ischemia. At 24 h of reperfusion, the mice were decapitated and the infarct volume was evaluated in each group. In the nontransgenic mice, l-NAME significantly increased the infarct volume as compared with the vehicle, while 7-NI significantly decreased it. In the SOD-transgenic mice, l-NAME-treated animals showed a significantly larger infarct volume than vehicle-treated ones, whereas there were no significant differences between 7-NI- and vehicle-treated mice. Our findings suggest that selective inhibition of neuronal NOS ameliorates ischemic brain injury and that both neuronal and endothelial NOS inhibition may result in the deterioration of ischemic injury due to vasoconstriction of the brain. Since l-NAME increased infarct volume even in SOD-transgenic mice, the protective effect of SOD could result from the vasodilation by increased endothelial NO as well as the reduction of neuronal injury due to less production of peroxynitrite compared to wild-type mice. Moreover, the neurotoxic role of NO might not be dependent on NO itself, but the reaction with superoxide to form peroxynitrite, because of no additive effects of SOD and a neuronal NOS inhibitor.
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DiMagno, Matthew J., Yibai Hao, Yasuhiro Tsunoda, John A. Williams, and Chung Owyang. "Secretagogue-stimulated pancreatic secretion is differentially regulated by constitutive NOS isoforms in mice." American Journal of Physiology-Gastrointestinal and Liver Physiology 286, no. 3 (March 2004): G428—G436. http://dx.doi.org/10.1152/ajpgi.00368.2003.
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Nitric oxide (NO) and NO synthase (NOS) play controversial roles in pancreatic secretion. NOS inhibition reduces CCK-stimulated in vivo pancreatic secretion, but it is unclear which NOS isoform is responsible, because NOS inhibitors lack specificity and three NOS isoforms exist: neuronal (nNOS), endothelial (eNOS), and inducible (iNOS). Mice having individual NOS gene deletions were used to clarify the NOS species and cellular interactions influencing pancreatic secretion. In vivo secretion was performed in anesthetized mice by collecting extraduodenal pancreatic duct juice and measuring protein output. Nonselective NOS blockade was induced with Nω-nitro-l-arginine (l-NNA; 10 mg/kg). In vivo pancreatic secretion was maximal at 160 pmol·kg-1·h-1 CCK octapeptide (CCK-8) and was reduced by NOS blockade (45%) and eNOS deletion (44%). Secretion was unaffected by iNOS deletion but was increased by nNOS deletion (91%). To determine whether the influence of NOS on secretion involved nonacinar events, in vitro CCK-8-stimulated secretion of amylase from isolated acini was studied and found to be unaltered by NOS blockade and eNOS deletion. Influence of NOS on in vivo secretion was further examined with carbachol. Protein secretion, which was maximal at 100 nmol·kg-1·h-1 carbachol, was reduced by NOS blockade and eNOS deletion but unaffected by nNOS deletion. NOS blockade by l-NNA had no effect on carbachol-stimulated amylase secretion in vitro. Thus constitutive NOS isoforms can exert opposite effects on in vivo pancreatic secretion. eNOS likely plays a dominant role, because eNOS deletion mimics NOS blockade by inhibiting CCK-8 and carbachol-stimulated secretion, whereas nNOS deletion augments CCK-8 but not carbachol-stimulated secretion.
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West, Sonlee D., Kenneth S. Helmer, Lily K. Chang, Yan Cui, George H. Greeley, and David W. Mercer. "Cholecystokinin secretagogue-induced gastroprotection: role of nitric oxide and blood flow." American Journal of Physiology-Gastrointestinal and Liver Physiology 284, no. 3 (March 1, 2003): G399—G410. http://dx.doi.org/10.1152/ajpgi.00130.2002.
Full textAbstract:
This study was done to examine the role of CCK in gastric mucosal defense and to assess the gastroprotective roles of nitric oxide and blood flow. In rats, the CCK secretagogues oleate and soybean trypsin inhibitor augmented gastric mucosal blood flow and prevented gastric injury from luminal irritants. Type A CCK receptor blockade negated CCK secretagogue-induced gastroprotection and exacerbated gastric injury from bile and ethanol but did not block adaptive cytoprotection. CCK secretagogue-induced gastroprotection and hyperemia were negated by nonselective nitric oxide synthase (NOS) inhibition ( N G-nitro-l-arginine methyl ester) but not by selective inducible NOS inhibition (aminoguanidine). Gastric mucosal calcium-dependent NOS activity, but not calcium-independent NOS activity, was increased following CCK and CCK secretagogues. The release of endogenous CCK plays a role in the intrinsic gastric mucosal defense system against injury from luminal irritants. The protective mechanism appears to involve increased production of nitric oxide from primarily the constitutive isoforms of NOS and a resultant increase in blood flow.
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GORREN, Antonius C. F., Astrid SCHRAMMEL, Christoph RIETHMÜLLER, Kurt SCHMIDT, Doris KOESLING, Ernst R. WERNER, and Bernd MAYER. "Nitric oxide-induced autoinhibition of neuronal nitric oxide synthase in the presence of the autoxidation-resistant pteridine 5-methyltetrahydrobiopterin." Biochemical Journal 347, no. 2 (April 10, 2000): 475–84. http://dx.doi.org/10.1042/bj3470475.
Full textAbstract:
Nitric oxide synthase (NOS) catalysis results in formation of NO or superoxide (O2-−) depending on the presence or absence of the cofactor tetrahydrobiopterin (BH4). In the absence of O2-− scavengers, net NO formation cannot be detected even at saturating BH4 concentrations, which is thought to be due to O2-− production by BH4 autoxidation. Because the N-5-methylated analogue of BH4 (5-Me-BH4) sustains NOS catalysis and is autoxidation-resistant, net NO formation by the neuronal isoform of NOS (nNOS) can be observed at saturating 5-Me-BH4 concentrations. Here we compare the effects of 5-Me-BH4 on L-citrulline formation, NADPH oxidation, H2O2 production and soluble guanylate cyclase (sGC) stimulation. All activities were stimulated biphasically (EC50 approx. 0.2 μM and more than 1 mM), with an intermediate inhibitory phase at the same pterin concentration as that required for net NO generation and sGC stimulation (4 μM). Concomitantly with inhibition, the NADP+/L-citrulline stoichiometry decreased from 2.0 to 1.6. Inhibition occurred only at high enzyme concentrations (IC50 approx. 10 nM nNOS) and was antagonized by oxyhaemoglobin and by BH4. We ascribe the first stimulatory phase to high-affinity binding of 5-Me-BH4. The inhibitory phase is due to low-affinity binding, resulting in fully coupled catalysis, complete inhibition of O2-− production and net NO formation. At high enzyme concentrations and thus high NO levels, this causes autoinhibition. NO scavenging by 5-Me-BH4 at concentrations above 1 mM, resulting in the antagonization of inhibition of NOS, explains the second stimulatory phase. In agreement with these assignments 5-Me-BH4 was found to stimulate formation of a haem-NO complex during NOS catalysis. The observation of inhibition with 5-Me-BH4 but not with BH4 implies that, unless O2-− scavengers are present, a physiological role for NO-induced autoinhibition is unlikely.
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Jendzjowsky, Nicholas G., and Darren S. DeLorey. "Role of neuronal nitric oxide in the inhibition of sympathetic vasoconstriction in resting and contracting skeletal muscle of healthy rats." Journal of Applied Physiology 115, no. 1 (July 1, 2013): 97–106. http://dx.doi.org/10.1152/japplphysiol.00250.2013.
Full textAbstract:
Isoform-specific nitric oxide (NO) synthase (NOS) contributions to NO-mediated inhibition of sympathetic vasoconstriction in resting and contracting skeletal muscle are incompletely understood. The purpose of the present study was to investigate the role of neuronal NOS (nNOS) in the inhibition of sympathetic vasoconstriction in resting and contracting skeletal muscle of healthy rats. We hypothesized that acute pharmacological inhibition of nNOS would augment sympathetic vasoconstriction in resting and contracting skeletal muscle, demonstrating that nNOS is primarily responsible for NO-mediated inhibition of sympathetic vasoconstriction. Sprague-Dawley rats ( n = 13) were anesthetized and instrumented with an indwelling brachial artery catheter, femoral artery flow probe, and lumbar sympathetic chain stimulating electrodes. Triceps surae muscles were stimulated to contract rhythmically at 60% of maximal contractile force. In series 1 ( n = 9), the percent change in femoral vascular conductance (%FVC) in response to sympathetic stimulations delivered at 2 and 5 Hz was determined at rest and during muscle contraction before and after selective nNOS blockade with S-methyl-l-thiocitrulline (SMTC, 0.6 mg/kg iv) and subsequent nonselective NOS blockade with Nω-nitro-l-arginine methyl ester (l-NAME, 5 mg/kg iv). In series 2 ( n = 4), l-NAME was injected first, and then SMTC was injected to determine if the effect of l-NAME on constrictor responses was influenced by selective nNOS inhibition. Sympathetic stimulation decreased FVC at rest (−25 ± 7 and −44 ± 8%FVC at 2 and 5 Hz, respectively) and during contraction (−7 ± 3 and −19 ± 5%FVC at 2 and 5 Hz, respectively). The decrease in FVC in response to sympathetic stimulation was greater in the presence of SMTC at rest (−32 ± 6 and −49 ± 8%FVC at 2 and 5 Hz, respectively) and during contraction (−21 ± 4 and −28 ± 4%FVC at 2 and 5 Hz, respectively). l-NAME further increased ( P < 0.05) the sympathetic vasoconstrictor response at rest (−47 ± 4 and −60 ± 6%FVC at 2 and 5 Hz, respectively) and during muscle contraction (−33 ± 3 and −40 ± 6%FVC at 2 and 5 Hz, respectively). The effect of l-NAME was not altered by the order of nNOS inhibition. These data demonstrate that NO derived from nNOS and endothelial NOS contribute to the inhibition of sympathetic vasoconstriction in resting and contracting skeletal muscle.
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ALDERTON, Wendy K., Chris E. COOPER, and Richard G. KNOWLES. "Nitric oxide synthases: structure, function and inhibition." Biochemical Journal 357, no. 3 (July 25, 2001): 593–615. http://dx.doi.org/10.1042/bj3570593.
Full textAbstract:
This review concentrates on advances in nitric oxide synthase (NOS) structure, function and inhibition made in the last seven years, during which time substantial advances have been made in our understanding of this enzyme family. There is now information on the enzyme structure at all levels from primary (amino acid sequence) to quaternary (dimerization, association with other proteins) structure. The crystal structures of the oxygenase domains of inducible NOS (iNOS) and vascular endothelial NOS (eNOS) allow us to interpret other information in the context of this important part of the enzyme, with its binding sites for iron protoporphyrin IX (haem), biopterin, l-arginine, and the many inhibitors which interact with them. The exact nature of the NOS reaction, its mechanism and its products continue to be sources of controversy. The role of the biopterin cofactor is now becoming clearer, with emerging data implicating one-electron redox cycling as well as the multiple allosteric effects on enzyme activity. Regulation of the NOSs has been described at all levels from gene transcription to covalent modification and allosteric regulation of the enzyme itself. A wide range of NOS inhibitors have been discussed, interacting with the enzyme in diverse ways in terms of site and mechanism of inhibition, time-dependence and selectivity for individual isoforms, although there are many pitfalls and misunderstandings of these aspects. Highly selective inhibitors of iNOS versus eNOS and neuronal NOS have been identified and some of these have potential in the treatment of a range of inflammatory and other conditions in which iNOS has been implicated.
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Tian, Qiu-Ying, Dong-Hua Sun, Min-Gui Zhao, and Wen-Hao Zhang. "Inhibition of nitric oxide synthase (NOS) underlies aluminum-induced inhibition of root elongation in Hibiscus moscheutos." New Phytologist 174, no. 2 (April 2007): 322–31. http://dx.doi.org/10.1111/j.1469-8137.2007.02005.x.
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Ilkka, Heinonen, Saltin Bengt, Kemppainen Jukka, Hannu T. Sipilä, Oikonen Vesa, Nuutila Pirjo, Knuuti Juhani, Kalliokoski Kari, and Hellsten Ylva. "Skeletal muscle blood flow and oxygen uptake at rest and during exercise in humans: a pet study with nitric oxide and cyclooxygenase inhibition." American Journal of Physiology-Heart and Circulatory Physiology 300, no. 4 (April 2011): H1510—H1517. http://dx.doi.org/10.1152/ajpheart.00996.2010.
Full textAbstract:
The aim of the present study was to determine the effect of nitric oxide and prostanoids on microcirculation and oxygen uptake, specifically in the active skeletal muscle by use of positron emission tomography (PET). Healthy males performed three 5-min bouts of light knee-extensor exercise. Skeletal muscle blood flow and oxygen uptake were measured at rest and during the exercise using PET with H2O15 and 15O2 during: 1) control conditions; 2) nitric oxide synthase (NOS) inhibition by arterial infusion of NG-monomethyl-l-arginine (l-NMMA), and 3) combined NOS and cyclooxygenase (COX) inhibition by arterial infusion of l-NMMA and indomethacin. At rest, inhibition of NOS alone and in combination with indomethacin reduced ( P < 0.05) muscle blood flow. NOS inhibition increased ( P < 0.05) limb oxygen extraction fraction (OEF) more than the reduction in muscle blood flow, resulting in an ∼20% increase ( P < 0.05) in resting muscle oxygen consumption. During exercise, muscle blood flow and oxygen uptake were not altered with NOS inhibition, whereas muscle OEF was increased ( P < 0.05). NOS and COX inhibition reduced ( P < 0.05) blood flow in working quadriceps femoris muscle by 13%, whereas muscle OEF and oxygen uptake were enhanced by 51 and 30%, respectively. In conclusion, by specifically measuring blood flow and oxygen uptake by the use of PET instead of whole limb measurements, the present study shows for the first time in humans that inhibition of NO formation enhances resting muscle oxygen uptake and that combined inhibition of NOS and COX during exercise increases muscle oxygen uptake.
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Tracey, W. Ross, Masaki Nakane, Fatima Basha, and George Carter. "In vivo pharmacological evaluation off two novel type II (inducible) nitric oxide synthase inhibitors." Canadian Journal of Physiology and Pharmacology 73, no. 5 (May 1, 1995): 665–69. http://dx.doi.org/10.1139/y95-085.
Full textAbstract:
Selective type II (inducible) nitric oxide synthase (NOS) inhibitors have several potential therapeutic applications, including treatment of sepsis, diabetes, and autoimmune diseases. The ability of two novel, selective inhibitors of type II NOS, S-ethylisothiourea (EIT) and 2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine (AMT), to inhibit type II NOS function in vivo was studied in lipopolysaccharide (LPS) treated rats. Type II NOS activity was assessed by measuring changes in plasma nitrite and nitrate concentrations ([NOx]). Both EIT and AMT elicited a dose-dependent and >95% inhibition of the LPS-induced increase in plasma [NOx]. The ED50 values for EIT and AMT were 0.4 and 0.2 mg/kg, respectively. In addition, the administration of LPS and either NOS inhibitor resulted in a dose-dependent increase in animal mortality; neither compound was lethal when administered alone. Pretreatment with L-arginine (but not D-arginine) prevented the mortality, while not affecting the type II NOS-dependent NO production, suggesting the toxicity may be due to inhibition of one of the other NOS isoforms (endothelial or neuronal). Thus, although EIT and AMT are potent inhibitors of type II NOS function in vivo, type II NOS inhibitors of even greater selectivity may need to be developed for therapeutic applications.Key words: nitric oxide, nitrite, nitrate, sepsis, lipopolysaccharide.
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Levesque, Marc C., Dipak K. Ghosh, Bethany E. Beasley, Youwei Chen, Alicia D. Volkheimer, Charles W. O’Loughlin, Jon P. Gockerman, Joseph O. Moore, and J. Brice Weinberg. "Induction of Chronic Lymphocytic Leukemia (CLL) Apoptosis by Nitric Oxide Synthase (NOS) Inhibitors: Drug Efficacy Correlates with Lipid Solubility and NOS1 Dissociation Constant." Blood 106, no. 11 (November 16, 2005): 5044. http://dx.doi.org/10.1182/blood.v106.11.5044.5044.
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Abstract The viability of CLL cells may be dependent on the autocrine production of nitric oxide because nitric oxide synthase (NOS) inhibitors induce CLL cell apoptosis and CLL cells express inducible NOS (NOS2). Our previous study indicated that the non-specific NOS inhibitor NMMA induced CLL cell apoptosis but only at high concentrations (> 1 mM) (Levesque et al., Leukemia17:442, 2003). Therefore, we performed the current study to identify NOS inhibitors that induce CLL cell apoptosis at lower concentrations and to understand factors that promote NOS inhibitor-induced CLL cell toxicity. We isolated and enriched CLL cells from the blood of CLL patients and cultured the CLL cells in media containing various concentrations of 21 different NOS inhibitors. We determined CLL cell viability following culture with each NOS inhibitor. We found that NOS inhibitors with specificity for neuronal NOS (NOS1) induced CLL cell death at concentrations lower than non-specific NOS inhibitors and lower than inducible NOS (NOS2) specific inhibitors. There was a weak correlation (r2 = 0.29, p = 0.1608) of the NOS1 (but not NOS2) half-maximal inhibitory concentration (IC50) of each NOS inhibitor for purified recombinant NOS and its ability to induce CLL cell death. We confirmed the specificity of the NOS inhibitors by inhibition of purified recombinant NOS1 and NOS2 enzyme activity, and we confirmed that NOS1 specific inhibitors induced CLL cell death by apoptosis. Because there was only a weak correlation of the NOS1 IC50 with NOS inhibitor induced CLL cell death, we considered whether other factors such as the Kd and hydrophobicity of each compound correlated with CLL cell death. We found that there was a direct correlation between the NOS1 (but not NOS2) dissociation constant (Kd) of NOS inhibitors and CLL cell death (r2 = 0.77, p = 0.0041) and a direct correlation of the partitioning coefficient (a measure of hydrophobicity) of each NOS inhibitor and its ability to induce CLL cell death (r2 = 0.68, p < 0.0001). Therefore, NOS inhibitors that bound tightly to NOS1 and were hydrophobic induced CLL cell death at lower concentrations. There was variable expression of CLL cell NOS1 mRNA (6 of 28 samples positive) and we were unable to demonstrate CLL cell expression of NOS1 protein by immunoblotting. This suggests that if NOS1 is present in CLL cells, it exists at very low levels. Taken together, we believe that low level NO production promotes CLL cell viability and that inhibition of CLL NOS induces CLL cell apoptosis. Importantly, our studies provide direction for the rational design and selection of NOS inhibitors that may be useful as CLL therapeutics.
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Kellawan, J. Mikhail, Jacqueline K. Limberg, Zachariah M. Scruggs, Wayne T. Nicholson, William G. Schrage, Michael J. Joyner, and Timothy B. Curry. "Phosphodiesterase-5 inhibition preserves exercise-onset vasodilator kinetics when NOS activity is reduced." Journal of Applied Physiology 124, no. 2 (February 1, 2018): 276–82. http://dx.doi.org/10.1152/japplphysiol.00483.2017.
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Nitric oxide (NO)-mediated vasodilation contributes to the rapid rise in muscle blood flow at exercise onset. This occurs via increased cyclic guanosine monophosphate (cGMP), which is catabolized by phosphodiesterase-5 (PDE-5). Whether PDE-5 limits exercise vasodilation onset kinetics is unknown. We hypothesized the time course of exercise vasodilation would be 1) accelerated during PDE-5 inhibition (sildenafil citrate, SDF) and 2) decelerated during NO synthase inhibition ( NG-monomethyl-l-arginine, l-NMMA), and 3) the effect of SDF on vasodilation onset kinetics would be attenuated with concurrent l-NMMA. Data from 29 healthy adults were analyzed. Individuals completed 5 min of moderate-intensity forearm exercise under control conditions and during 1) oral SDF ( n = 8), 2) intra-arterial l-NMMA ( n = 15), or 3) combined SDF + l-NMMA ( n = 6). Forearm blood flow (FBF; Doppler ultrasound of the brachial artery) and mean brachial artery blood pressure (MAP) were measured continuously. Forearm vascular conductance (FVC, FBF ÷ MAP) was curve-fit with a monoexponential model, and vasodilation onset kinetics were assessed by mean response time (MRT, time to achieve 63% of steady state). SDF had no effect on MRT ( P = 0.90). NOS inhibition increased MRT ( P = 0.01). MRT during SDF+l-NMMA was not different from control exercise ( P = 0.76). PDE-5 inhibition alone has no effect on rapid-onset vasodilation. Whereas NOS inhibition decelerates vasodilator kinetics, when combined with SDF, vasodilator kinetics do not differ from control. These data suggest NO-independent activation of cGMP occurs at exercise onset; thus PDE-5 inhibition may improve vasodilation in pathologies where NO bioavailability is impaired. NEW & NOTEWORTHY We show that when NO bioavailability is reduced, PDE-5 inhibition can restore vasodilation onset kinetics of exercise-mediated vasodilation via NO-independent cGMP pathways. These data suggest PDE-5 inhibition may improve exercise vasodilation onset kinetics in pathologies where NO bioavailability is impaired.
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Albina, J. E., and B. Mastrofrancesco. "Modulation of glucose metabolism in macrophages by products of nitric oxide synthase." American Journal of Physiology-Cell Physiology 264, no. 6 (June 1, 1993): C1594—C1599. http://dx.doi.org/10.1152/ajpcell.1993.264.6.c1594.
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Nitric oxide (NO) is a product of L-arginine metabolism that suppresses cellular oxidative metabolism through the inhibition of tricarboxylic acid cycle and electron transport chain enzymes. The impact of NO synthase (NOS) activity on specific pathways of glucose metabolism in freshly harvested and overnight-cultured rat resident peritoneal macrophages, at rest and after stimulation with zymosan, was investigated using radiolabeled glucose. NOS activity was modulated through the L-arginine concentration in culture media and the use of its specific inhibitor, NG-monomethyl-L-arginine, and quantitated using radiolabeled L-arginine. Results demonstrated that NOS activity was associated with increased glucose disappearance, glycolysis, and hexose monophosphate shunt activity and, in line with the known inhibition of oxidative metabolism associated with the production of NO, with a decrease in the flux of glucose and butyrate carbon through the tricarboxylic acid cycle. In addition, the relative increase in glucose utilization that follows zymosan stimulation was enhanced by treatments that suppressed NOS activity. These results demonstrate that the characteristics of glucose metabolism by macrophages are, to a significant extent, determined by products of NOS.