UMLS:C0406810 - FACTA Search

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Query: UMLS:C0406810 (NAME)
13,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The present study was performed to evaluate the role of nitric oxide (NO) in coronary vasodilation during hypercapnic acidosis (HC). The left anterior descending coronary arteries of 17 anesthetized, open-chest dogs were perfused with normal arterial blood or with arterial blood equilibrated in an extracorporeal circuit with 90% O2-10% CO2 [arterial carbon dioxide tension (PaCO2) 72 +/- 3 mmHg, arterial pH 7.16 +/- 0.02]. Coronary perfusion pressure (CPP) was initially set at 100 mmHg. Coronary blood flow (CBF) was measured with a Doppler transducer. Studies were conducted under constant-pressure (variable CBF; n = 13) and constant-flow (variable CPP) conditions (n = 4). Steady-state changes in CBF (or CPP) during HC and during intracoronary infusions of acetylcholine (ACh, 20 micrograms/min), an endothelium-dependent vasodilator, and sodium nitroprusside (SNP, 80 micrograms/min), an endothelium-independent vasodilator, were compared before and after intracoronary infusion of a NO synthase inhibitor, either NG-nitro-L-arginine methyl ester (L-NAME, 4.5 mg) or NG-monomethyl-L-arginine (L-NMMA, 30 mg). Under constant pressure, L-NAME blunted increases in CBF by HC (274 +/- 32 vs. 113 +/- 24%) and ACh (400 +/- 43 vs. 68 +/- 17%), whereas increases in CBF by SNP were not significantly affected (207 +/- 34 vs. 186 +/- 18%). Results with L-NMMA were similar. Under constant flow, L-NAME attenuated decreases in CPP by HC and ACh, whereas it had no significant effect on decreases in CPP by SNP. In conclusion, HC elicits release of NO from coronary vascular endothelium via a direct effect rather than secondary to an increased flow rate.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Contribution of nitric oxide to coronary vasodilation during hypercapnic acidosis. 753 Sep 20

To test the hypothesis that release of endothelium-derived relaxing factor/nitric oxide is inhibited by Gram-negative lipopolysaccharide (LPS; endotoxin), we examined endothelium-independent and endothelium-dependent vasodilator agents in aortic vascular smooth muscle isolated from guinea pigs 4 h after injection of saline (controls) or induction of Escherichia coli endotoxemia. LPS significantly inhibited vasodilator responses to the endothelium-dependent agonists acetylcholine (ACh; 10(-10)-10(-5) M) and ADP (10(-8)-10(-5) M). However, LPS did not affect vasodilator responses to the endothelium-independent agonist nitroprusside (10(-10)-10(-4) M). The nitric oxide synthase (NOS) inhibitor N gamma-nitro-L-arginine methyl ester (L-NAME) inhibited the vasodilator response to ACh; whereas, the cyclooxygenase inhibitor indomethacin (INDO) did not reduce vasodilator effects of ACh. Neither L-NAME nor INDO affected the vasodilator effects of nitroprusside in LPS or control vessels. In contrast, L-NAME converted the vasodilator action of ADP to a vasoconstrictor response that was blocked individually by INDO and the thromboxane synthase inhibitor dazoxiben, suggesting that ADP releases NO and also the vasoconstrictor and platelet aggregating eicosanoid thromboxane A2. These findings suggest that acute (4 h) endotoxemia inhibits function of the constitutive isoform of NOS in vascular endothelial cells. Since L-NAME unmasked a vasoconstrictor action of the endogenous purinoceptor agonist ADP, pharmacologic agents that inhibit NOS may exacerbate LPS-induced inhibition of endothelial NOS; this series of events could lead to diminution of vasodilator reserves and perhaps to augmentation of platelet aggregation during Gram-negative sepsis.
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PMID:Inhibition of endothelium-dependent vasodilation by Escherichia coli endotoxemia. 753 38

1. Membrane potential and tension were measured simultaneously in ring segments of main coronary artery of guinea-pigs. The synthetic thromboxane A2 analogue U46619 depolarized the tissues from -58 +/- 2 to -40 +/- 1 mV and increased tension by 12 +/- 1 mN mm-1. Nitric oxide (NO) and Iloprost, the stable analogue of prostacyclin, evoked hyperpolarization and relaxation. 2. The concentration of NO required to evoke half-maximal hyperpolarization (EC50 of 2 x 10(-5) M) was 40-fold higher than that which was required to induce relaxation (EC50 of 5 x 10(-7) M). The EC50 for Iloprost-induced hyperpolarization (3 x 10(-8) M) was similar to that for relaxation (4 x 10(-8) M). 3. Glibenclamide (10(-6) M) abolished the hyperpolarization in response to both NO and Iloprost but was without effect on the amplitudes of the relaxations over the complete concentration-response curves. 4. Acetylcholine evoked concentration-dependent hyperpolarization and relaxation in the presence of N omega-nitro-L-arginine methyl ester (NAME; 10(-5) M) and indomethacin (10(-6) M), and these responses were attributed to endothelium-derived hyperpolarizing factor (EDHF). The hyperpolarization produced by EDHF always preceded relaxation, and relaxation never occurred at concentrations of acetylcholine that were insufficient to evoke hyperpolarization. 5. The concentration-hyperpolarization and concentration-relaxation curves in response to acetylcholine were not affected by glibenclamide or barium (1-3 mM) but were shifted to the right 4- and 5-fold, respectively, by 1 mM tetraethylammonium. The hyperpolarization and relaxation evoked by acetylcholine were also reduced in a parallel manner when the potassium concentration in the superfusate was increased. 6. Hyperpolarizing current steps, applied to spiral strips of coronary artery denuded of endothelium and depolarized and constricted with U46619, caused relaxation. The relationship between hyperpolarization and relaxation evoked electronically was similar to that which was due to EDHF in intact tissues stimulated with acetylcholine. 7. It is concluded that the ability of NO or Iloprost to relax guinea-pig coronary artery does not depend upon hyperpolarization of the smooth muscle. In contrast, hyperpolarization is likely to play a major, if not the only, role in the relaxation in response to EDHF in this tissue.
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PMID:Role of membrane potential in endothelium-dependent relaxation of guinea-pig coronary arterial smooth muscle. 754 69

Analogues of L-arginine with modifications at the terminal guanidino nitrogen and/or the carboxyl terminus of the molecule have been widely used for their ability to inhibit the production of nitric oxide and are thought to be competitive antagonists of nitric oxide synthase. The present studies were designed to test the possibility that these agents are also muscarinic receptor antagonists. Acetylcholine produced concentration-dependent contraction of endothelium-denuded rabbit coronary artery as well as isolated strips of canine colonic smooth muscle. The arginine analogue NG-nitro L-arginine methyl ester (L-NAME, 100 microM) but not NG-monomethyl L-arginine (L-NMMA, 100 microM) significantly shifted these contractile relations to the right, an effect that was not reversed by addition of 1 mM L-arginine. In radioligand binding studies using the muscarinic radioligand [3H]quinuclidinyl benzilate and tissues known to contain differing contributions of M1, M2, and M3 muscarinic receptors, addition of increasing concentrations of L-NAME resulted in a monophasic competition of binding with affinities (Ki) ranging from 68 microM in endothelium to 317 microM in whole aorta. Addition of the hydrolysis-resistant guanosine 5'-triphosphate analogue GTP gamma S (100 microM) had no effect on L-NAME competition of [3H]quinuclidinyl benzilate binding. Addition of L-NAME in radioligand binding competition studies using the agonist carbachol did not result in an alteration of the receptor's affinity for agonist, confirming the competitive nature of the interaction of L-NAME with the muscarinic receptor.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:NG-nitro L-arginine methyl ester and other alkyl esters of arginine are muscarinic receptor antagonists. 767 6

1. The effects of acute inhibition of nitric oxide (NO) synthase on cardiovascular responses to vasodilator challenges have already been described. We now report the responses to vasodilators during and after chronic NO synthase inhibition. 2. In conscious Brattleboro rats, the regional haemodynamic effects of 3 min infusions of acetylcholine (4 micrograms min-1), sodium nitroprusside (15 micrograms min-1) or adrenaline (0.2 micrograms min-1) were assessed (from areas under or over curves (AUC, AOC)) under control conditions, 6 and 72 h after the addition of the NO synthase inhibitor, NG-monomethyl-L-arginine (L-NMMA) to the drinking water (1 mg ml-1), and 6, 24 and 48 h after the withdrawal of L-NMMA. In a separate group of Brattleboro rats, responses to acetylcholine, sodium nitroprusside and adrenaline were assessed before and 6 h after the onset of oral ingestion of the more potent nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME; 0.05 mg ml-1). 3. Acetylcholine caused renal vasodilation (87 +/- 11 units) and mesenteric vasoconstriction (-31 +/- 5 units), sodium nitroprusside caused vasodilatation in renal (96 +/- 12 units), mesenteric (222 +/- 13 units) and hindquarters (49 +/- 15 units) vascular beds, whereas adrenaline caused hindquarters vasodilatation (92 +/- 8 units). Seventy two h after the onset of oral ingestion of L-NMMA, acetylcholine had a decreased renal vasodilator (59 +/- 9 units) effect, sodium nitroprusside had an increased renal vasodilator (142 +/- 23 units) action, while adrenaline had a decreased hindquarters vasodilator (55 +/- 6 units) influence. Twenty four h after withdrawal of L-NMMA, the renal vasodilator effect of acetylcholine was greater than the control response (106 +/- 14 units), but the regional haemodynamic effects of sodium nitroprusside and adrenaline were not different from those under control conditions. Hence, the increased renal vasodilator response to acetylcholine was probably due to changes in muscarinic receptor-mediated mechanisms rather than to any increase in guanylyl cyclase or its sensitivity to NO.
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PMID:Effects of chronic treatment with nitric oxide synthase inhibitors on regional haemodynamic responses to vasodilators in conscious Brattleboro rats. 768 4

1. The effects of NG-nitro-L-arginine methyl ester (L-NAME) and NG-monomethyl-L-arginine (L-NMMA), their D-isomers, and dexamethasone on noradrenaline (NA)-induced contractions and antagonism by alpha-adrenoceptor antagonists, have been investigated in rat isolated thoracic aortic rings with/without endothelium. 2. NA produced concentration-dependent contractions of isolated aortic rings with EC50 values of 2.41 +/- 0.54 (n = 21) and 28.00 +/- 8.50 (n = 25) nM for endothelium-denuded and -intact preparations respectively. Acetylcholine (ACh) relaxed NA-precontracted rings with intact, but not those denuded of endothelium. 3. Treatment with L-NAME (1-30 microM), or L-NMMA (10-500 microM), but not their D-isomers, resulted in an endothelium-dependent enhancement of NA-induced contractions. Pre-treatment, in vitro, with 0.5 microM dexamethasone neither directly potentiated, nor influenced L-NAME-induced potentiation of NA-mediated contractions in endothelium-intact rings; however, dexamethasone pretreatment reduced EC50 values for NA, and also prevented L-NAME-induced potentiation, in denuded rings equilibrated for 5 h under resting tension. 4. In both intact and denuded rings, phentolamine, prazosin and WB 4101 shifted NA concentration-response curves to the right; L-NAME, and also L-NMMA, but not their D-isomers, reversed the blockade as indicated by significant decreases in NA dose-ratios. In denuded rings, reversal by L-NAME or L-NMMA was prevented following pretreatment with dexamethasone. 5. Following treatment with 5 or 50 nM phenoxybenzamine (PBZ), NA concentration-response (C-R)curves were shifted to the right with marked depression of maximal responses; 100 microM L-NAME reversed the antagonism in both endothelium intact and denuded rings. However, 500 nM PBZ treatment resulted in complete abolition of the responses to NA, and contractions were not restored by either L-NAME or L-NMMA.6. 5-Hydroxytryptamine (5-HT)-induced contractions of aortic rings were potentiated by endothelium denudation and also by L-, but not D-, NAME. 5-HT-induced contractions were non-competitively antagonized by 10nM ritanserin, and 100 microM L-NAME partially reversed the antagonism in intact but not denuded rings.7. It is concluded that the inhibition of constitutive endothelial NO synthase and inducible smooth muscle NO synthase accounts for the ability of L-NAME, and L-NMMA, to potentiate the effects of agonists and reduce alpha-adrenoceptor antagonism in endothelium-intact and denuded rings. Furthermore,endothelial cell removal/damage triggers the induction of a smooth muscle NO synthase.
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PMID:Interactions of nitric oxide synthase inhibitors and dexamethasone with alpha-adrenoceptor-mediated responses in rat aorta. 768 95

The effect of chronic inhibition of nitric oxide (NO) synthesis by NG-nitro-L-arginine methyl ester (L-NAME) on cutaneous ear blood flow (EBF) in the rabbit was examined in vivo with use of laser Doppler flowmetry. Additionally, the efficacy of inhibition of NO by L-NAME was studied ex vivo in isolated preparations of aortic rings from these rabbits. Before surgical implantation of osmotic pumps loaded with L-NAME, resting EBF was not significantly different in rabbits selected for control or L-NAME treatment. Although chronic L-NAME treatment had no significant effect on resting core temperature, resting EBF was reduced significantly in L-NAME-treated rabbits as compared with EBF in control rabbits. Short-term body warming for 10-20 min caused a significant increase in EBF, but not in body temperature, to levels that were not significantly different between groups at 0, 1 and 2 weeks. Prolonged body warming for a further 30-40 min produced a rise in body temperature and a further increase in EBF of 22% to levels that were not significantly different in control and L-NAME-treated groups. Acetylcholine-induced relaxations of aortic rings and levels of cyclic GMP were significantly reduced in L-NAME-treated rabbits as compared with control rabbits, whereas relaxations to sodium nitroprusside were enhanced significantly. These findings demonstrate that the synthesis of NO can be inhibited chronically in the rabbit and are consistent with the concept that NO participates in the control of skin blood flow by counteracting vasoconstrictor tone but not in the vasodilation induced by body warming.
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PMID:Chronic inhibition of nitric oxide production augments skin vasoconstriction in the rabbit ear. 769 70

1. The vascular effects of the soluble guanylyl cyclase inhibitor, methylene blue as well as the nitric oxide (NO) synthase inhibitors, NG-nitro-L-arginine (L-NOARG) and diphenyleneiodonium (DPI) were studied in rat isolated aortic rings and conscious, unrestrained rats. 2. Acetylcholine (ACh) and sodium nitroprusside (SNP) caused concentration-dependent relaxation of preconstricted aortic rings. Both methylene blue (1 x 10(-5) M) and L-NOARG (3 x 10(-5) M) abolished ACh-induced relaxation; however, methylene blue but not L-NOARG shifted the concentration-response curve of SNP to the right. 3. In conscious rats, i.v. infusion of methylene blue (1.1 x 10(-5) mol kg-1 min-1), at a concentration which reduced the aortic tissue level of cyclic GMP by 50%, did not significantly alter mean arterial pressure (MAP) and heart rate (HR). In contrast, i.v. bolus injection of L-NOARG (1.5 x 10(-4) mol kg-1) markedly increased MAP and decreased HR. 4. Both ACh and SNP dose-dependently decreased MAP in conscious rats. Methylene blue did not alter the magnitude or duration of ACh- or SNP-induced depressor responses. L-NOARG, on the other hand, significantly though incompletely, reduced the magnitude and duration of the depressor response to ACh but not SNP. The depressor response to ACh or SNP was not altered by pretreatment with indomethacin (1.4 x 10(-5) mol kg-1) or capsaicin (3.3 x 10(-4) mol kg-1). 5. NG-nitro-L-arginine methyl ester (L-NAME) also caused dose-dependent increases in MAP in conscious rats. Both methylene blue and DPI (1 x 10-5 mol kg-1) selectively shifted the dose-pressor response curve of L-NAME to the right.6. These results suggest that: (1) the inhibition of endogenous NO biosynthesis does not necessarily lead to pressor response in vivo, (2) L-NOARG may not produce pressor response solely via the inhibition of endogenous endothelial NO biosynthesis, and (3) the depressor responses to ACh and SNP may not involve the release of NO or prostanoids or afferent nerve transmitters.
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PMID:Vascular pharmacology of methylene blue in vitro and in vivo: a comparison with NG-nitro-L-arginine and diphenyleneiodonium. 771 18

To assess the effect of endothelium-derived relaxing factor (EDRF) on the diaphragmatic microcirculation under basal conditions and after vasodilator stimulation, prepared diaphragms from anesthetized rats were studied. With bicarbonate-buffered Ringer's solution suffusing the diaphragm, the microcirculatory blood flow was recorded by laser-Doppler flowmetry (QLDF). Drugs were applied to the surface of the diaphragm. Five series of experiments were performed. In Series 1, the effects of acetylcholine (ACh, 10(-4) M) and sodium nitroprusside (SNP, 3 x 10(-6) M) were measured before and after 15 minutes suffusion of N omega-nitro-L-arginine methyl ester (L-NAME, 10(-4) M). Trend analyses revealed that the vasodilator effect of SNP was not affected, while that of ACh was abolished by L-NAME. In Series 2, both ACh and SNP elicited a concentration-dependent increase in QLDF. In Series 3, following 15 minutes suffusion with L-NAME (10(-4) M), there was no change in baseline QLDF and the ACh-induced QLDF change was abolished, while the effect of SNP was maintained. In Series 4, five minutes of pretreatment with L-arginine (L-arg, 10(-2) M), followed by co-administration of L-arg (10(-2) M) and L-NAME (10(-4) M) for another 15 minutes, did not prevent the inhibitory effect on ACh-induced QLDF change by L-NAME. In Series 5, 20 minutes application of L-arg (10(-2) M) alone did not affect baseline QLDF. Also, L-arg did not influence the ACh-induced vasodilating response, whereas it slightly increased the SNP-induced vasodilating response.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Differential effects of nitric oxide synthesis inhibitor on rat diaphragmatic microcirculation under basal conditions and after vasodilator stimulation. 773 9

The involvement of L-arginine/nitric oxide (NO) pathway in the vascular reactivity following hypovolemic hemorrhagic shock was studied in male anesthetized Wistar rats. Aortic rings from shocked rats showed a marked hyporeactivity (p < .01) to phenylephrine (PE, 1 nM to 10 microM), whereas the responsiveness to acetylcholine (ACh, 10 nM to 10 microM) remained unaffected. The response of these rings was restored to control values by N gamma-nitro-L-arginine methyl ester (L-NAME, 10 microM). D-NAME was without effect. L-Arginine (300 microM), but not D-arginine, significantly increased the vascular hyporeactivity of aortic rings from hemorrhagic shocked rats (p < .01), while it had no effect in rings from sham shocked rats. Dexamethasone (.1, 1, or 2 mg/kg), given intravenously 2 h before bleeding, significantly (p < .01) increased survival rate and reduced the severe hypotension due to hemorrhagic shock (p < .01). Additionally, aortic rings of hemorrhagic shocked rats pretreated with dexamethasone exhibited a greater contractile response to PE when compared to aortic rings from vehicle-pretreated shocked rats (p < .01). These results suggest that dexamethasone exerts beneficial effects in hemorrhagic shock by inhibiting NO synthesis.
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PMID:Dexamethasone prevents vascular failure mediated by nitric oxide in hemorrhagic shock. 774 52

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