Nitroglycerin-induced Vasorelaxation Research Articles

Role of aldehyde dehydrogenase 2-catalyzed nitric oxide formation in nitroglycerin-induced vasorelaxation

Role of aldehyde dehydrogenase 2-catalyzed nitric oxide formation in nitroglycerin-induced vasorelaxation

Endothelial Dysfunction in Normal and Prediabetic Rats With Metabolic Syndrome Exposed by Oral Gavage to Carbon Black Nanoparticles

Exposure to nanosized particles may increase the risk of cardiovascular diseases by endothelial dysfunction, particularly in susceptible subjects with metabolic syndrome. We investigated vasomotor dysfunction in aorta from obese and lean Zucker rats after oral exposure to nanosized carbon black (CB). Rats were exposed to 1 or 10 weekly doses of 0, 0.064, 0.64 or 6.4 mg/kg bodyweight and sacrificed 24 h or 13 weeks later. The exposure to 10 doses of 0.064 or 0.64 mg/kg reduced the acetylcholine-induced vasorelaxation in the lean and obese rats. The half maximal effect concentration values increased by twofold (95% CI: 1.1-3.5-fold) and fourfold (95% CI: 2.3-6.9-fold) in the rats exposed to 0.064 and 0.64 mg/kg compared with the controls, respectively. The rats exposed to 10 doses of 0.64 mg/kg had also 20% (95% CI: 10-29%) lower maximal effect value compared with the controls. However, the nitroglycerin-induced vasorelaxation and phenylephrine-induced vasocontraction was not affected in rats exposed to CB. The endothelial dysfunction was not observed in rats sacrificed 13 weeks after the last CB exposure. There was unaltered expression of Chrm3, Nos3, Nos2, Ccl2, and Hmox1 in aorta tissue of CB-exposed rats. In conclusion, repeated oral exposure to CB was associated with endothelial dysfunction in rats, further aggravating the effect of metabolic syndrome.

Oxidation-Induced Activation of PKG 1alpha Contributes To Nitroglycerin-Induced Vasorelaxation

Oxidation-Induced Activation of PKG 1alpha Contributes To Nitroglycerin-Induced Vasorelaxation

Impairment by Hypoxia or Hypoxia/Reoxygenation of Nitric Oxide–Mediated Relaxation in Isolated Monkey Coronary Artery: the Role of Intracellular Superoxide

To investigate the effect of hypoxia or hypoxia/reoxygenation on vascular smooth muscle function, mechanical response of monkey coronary artery without endothelium was studied under normoxia, hypoxia, and hypoxia/reoxygenation. Hypoxia or hypoxia/reoxygenation impaired the relaxation by nitroglycerin or isosorbide dinitrate but not that by 8-bromoguanosine-3',5'-cyclic monophosphate or isoproterenol. Tempol restored the impaired relaxation by nitroglycerin or isosorbide dinitrate, but superoxide dismutase had no effect. Apocynin, an NADPH oxidase inhibitor, improved the nitroglycerin-induced relaxation under hypoxia, but not under reoxygenation. Under combined treatment of apocynin with oxypurinol (xanthine oxidase inhibitor), rotenone (mitochondria electron transport inhibitor), or both, hypoxic impairment of vasorelaxation was restored more effectively. Similarly, impairment of the nitroglycerin-induced vasorelaxation under hypoxia/reoxygenation was restored by combined treatment with three inhibitors, apocynin, oxypurinol, and rotenone. Increase in superoxide production under hypoxia tended to be inhibited by apocynin and that under hypoxia/reoxygenation was abolished by combined treatment with three inhibitors. These findings suggest that increased intracellular superoxide production under hypoxia or hypoxia/reoxygenation attenuates vasodilation mediated with a nitric oxide/soluble guanylyl cyclase, but not adenylyl cyclase, signaling pathway. The main source of superoxide production under hypoxia seems to be different from that under reoxygenation: superoxide is produced by NADPH oxidase during hypoxia, whereas it is produced by xanthine oxidase, mitochondria, or both during reoxygenation.[Supplementary Figure: available only at http://dx.doi.org/10.1254/jphs.11031FP].

Constitutive nitric oxide synthase activation is a significant route for nitroglycerin-mediated vasodilation

The physiological effects of nitroglycerin as a potent vasodilator have long been documented. However, the molecular mechanisms by which nitroglycerin exerts its biological functions are still a matter of intense debate. Enzymatic pathways converting nitroglycerin to vasoactive compounds have been identified, but none of them seems to fully account for the reported clinical observations. Here, we demonstrate that nitroglycerin triggers constitutive nitric oxide synthase (NOS) activation, which is a major source of NO responsible for low-dose (1-10 nM) nitroglycerin-induced vasorelaxation. Our studies in cell cultures, isolated vessels, and whole animals identified endothelial NOS activation as a fundamental requirement for nitroglycerin action at pharmacologically relevant concentrations in WT animals.

AT1 receptor antagonism improves endothelial dysfunction in postmenopausal women

The menopause is associated with an increased incidence of atherosclerotic disease. Estrogen deficiency causes AT1 receptor overexpression which is involved in the development of vascular dysfunction. The effect of a 6 week-treatment with the AT1 receptor antagonist candesartan (16 mg/d) on endothelium-dependent vasorelaxation was compared to the treatment with placebo or the calcium channel antagonist felodipine (5 mg/d) in 29 postmenopausal women in the absence or presence of hormone replacement therapy (HRT) in a prospective, double-blind, randomized cross-over study. Endothelial function was assessed by measurement of forearm blood flow (FBF) by venous occlusion plethysmography. FBF during reactive hyperemia was significantly improved by candesartan in patients without HRT (hyperemic peak flow and area under the FBF curve), whereas felodipine and placebo exerted no effect. In patients with HRT, no treatment regimen showed a significant effect on endothelial function. Nitroglycerin-induced vasorelaxation and basal FBF were not significantly altered in all groups. AT1 receptor antagonism improves vascular function in postmenopausal women without HRT. Thus, AT1 receptor blockade may resemble an efficient approach for the prevention of vascular dysfunction in estrogen-deficient women.

Effects of large conductance Ca 2+-activated K + channels on nitroglycerin-mediated vasorelaxation in humans

Nitric oxide (NO)-induced vasorelaxation and the regulation of endothelial superoxide anion levels is partly mediated by vascular large conductance Ca 2+-activated K + (BK Ca) channels. Nitroglycerin acts through the release of NO and its effect is modulated by changes in endothelial superoxide levels. This study examines the effect of BK Ca channel blockade on nitroglycerin-induced vasorelaxation in human arterial and venous vascular segments and whether responses to BK Ca channel blockade are influenced by the development of venous nitroglycerin tolerance. Dose–relaxation curves to nitroglycerin (10 −10–10 −4 M) were obtained in segments of the saphenous vein and the left mammary artery. Studies were performed with and without pre-incubation with the BK Ca channel blocker iberiotoxin (10 −7 M) and venous tolerance to nitroglycerin were induced by a 24-h i.v. infusion (0.5 μg/kg/min). Iberiotoxin reduced the vasorelaxant effect of nitroglycerin ( E max) by 60% in endothelium-intact arteries and 13% in endothelium-denuded arteries ( P<0.05). Development of nitroglycerin tolerance did not affect the response to iberiotoxin in the venous vascular segments ( P>0.05) and (compared to arterial segments) veins were less sensitive to BK Ca channel blockade (30% reduction in E max) or endothelial removal. The results suggest that primarily arterial effects of nitroglycerin are significantly inhibited by changes in the activity of the endothelial BK Ca channels. Although endothelial BK Ca are likely regulators of mechanisms underlying arterial tolerance development to nitroglycerin, they do not appear to play a role in human venous nitroglycerin tolerance development.

Halothane Attenuates Nitroglycerin-Induced Vasodilation and a Decrease in Intracellular Ca2+ in the Rat Thoracic Aorta

Although halothane inhibits endothelium-mediated vasorelaxation, the sites of inhibition remain controversial. Because the cytosolic concentration of Ca2+ ([Ca2+]i) has crucial roles for tension development, we examined the effects of halothane on nitroglycerin-induced vasorelaxation from the standpoint of [Ca2+]i. Isolated spiral strips of rat thoracic aorta without endothelium were suspended for isometric tension recordings in a physiologic salt solution. Muscle contraction was evoked with 10-8 M norepinephrine, followed by endothelium-independent vasorelaxation with nitroglycerin 10-7 and 10-6 M. The effects of halothane 1.5% and 3% on nitroglycerin-induced vasorelaxation were evaluated along with the concomitant measurement of [Ca2+]i using fura-2-Ca2+ fluorescence. In other muscle strips, incremental doses of norepinephrine were administered during halothane exposure to induce contractions comparable to those without halothane. Nitroglycerin dose-dependently reduced norepinephrine-induced muscle contractions, but the decrease in [Ca2+]i reached a plateau at 10-7 M, which indicates that nitroglycerin induced [Ca2+]i-dependent and [Ca2+]i-independent vasorelaxation. Both concentrations of halothane inhibited nitroglycerin-induced decreases in muscle tension and [Ca2+]i, not only when the same dose of norepinephrine was used for contraction during halothane exposure, but also at incremental doses of norepinephrine. In conclusion, halothane inhibits nitroglycerin-induced vasorelaxation partly by suppressing Ca2+ changes in the smooth muscle. Implications: We examined nitroglycerin-induced vasorelaxation in the rat thoracic aorta, along with the concomitant measurement of the cytosolic concentrations of Ca2+, and found that halothane attenuated endothelium-independent vasorelaxation by suppressing Ca2+ dynamics in the smooth muscle. (Anesth Analg 1999;89:49-54)

Halothane Attenuates Nitroglycerin-Induced Vasodilation and a Decrease in Intracellular Ca2+ in the Rat Thoracic Aorta

Although halothane inhibits endothelium-mediated vasorelaxation, the sites of inhibition remain controversial. Because the cytosolic concentration of Ca2+ ([Ca2+]i) has crucial roles for tension development, we examined the effects of halothane on nitroglycerin-induced vasorelaxation from the standpoint of [Ca2+]i. Isolated spiral strips of rat thoracic aorta without endothelium were suspended for isometric tension recordings in a physiologic salt solution. Muscle contraction was evoked with 10(-8) M norepinephrine, followed by endothelium-independent vasorelaxation with nitroglycerin 10(-7) and 10(-6) M. The effects of halothane 1.5% and 3% on nitroglycerin-induced vasorelaxation were evaluated along with the concomitant measurement of [Ca2+]i using fura-2-Ca2+ fluorescence. In other muscle strips, incremental doses of norepinephrine were administered during halothane exposure to induce contractions comparable to those without halothane. Nitroglycerin dose-dependently reduced norepinephrine-induced muscle contractions, but the decrease in [Ca2+]i reached a plateau at 10(-7) M, which indicates that nitroglycerin induced [Ca2+]i-dependent and [Ca2+]i-independent vasorelaxation. Both concentrations of halothane inhibited nitroglycerin-induced decreases in muscle tension and [Ca2+]i, not only when the same dose of norepinephrine was used for contraction during halothane exposure, but also at incremental doses of norepinephrine. In conclusion, halothane inhibits nitroglycerin-induced vasorelaxation partly by suppressing Ca2+ changes in the smooth muscle. We examined nitroglycerin-induced vasorelaxation in the rat thoracic aorta, along with the concomitant measurement of the cytosolic concentrations of Ca2+, and found that halothane attenuated endothelium-independent vasorelaxation by suppressing Ca2+ dynamics in the smooth muscle.

Effects of l -Arginine on Atherogenesis and Endothelial Dysfunction due to Secondhand Smoke

Secondhand smoke (SHS) and hypercholesterolemia increase cardiovascular risk. We hypothesized that L-arginine, the precursor of nitric oxide (NO), might protect against atherogenesis and endothelial dysfunction caused by SHS. The effects of L-arginine supplementation (2.25% solution ad libitum) and SHS (smoking chambers for 10 weeks) were examined in 32 hypercholesterolemic rabbits. Eight normal rabbits served as controls. Acetylcholine- and nitroglycerin-induced vasorelaxation was assessed in aortic rings precontracted with norepinephrine. Hypercholesterolemia increased intimal lesion area (P=0.012), reduced endothelium-dependent relaxation (P=0.009), and reduced basal (P=0.005) and stimulated (P<0.0005) production of NOs. SHS increased intimal lesion area (P=0. 01) norepinephrine-induced contraction (P=0.001) and reduced endothelium-dependent relaxation (P=0.02). SHS-induced increase in norepinephrine contraction was abolished by the inhibition of NO synthase and removal of endothelium. L-Arginine improved endothelium-dependent relaxation (P=0.001) and attenuated SHS-induced endothelial dysfunction (P=0.007) and atherogenesis (P=0. 001). Basal production of nitrogen oxides correlated inversely with intimal lesion area (r=-0.66; P<0.0005) and stimulated production of NOs correlated with endothelium-dependent relaxation (r=-0.66; P<0. 001). SHS causes endothelial dysfunction and increased adrenergic responsiveness and atherogenesis in hypercholesterolemic rabbits. Chronic dietary supplementation with the NO precursor L-arginine mitigates these effects. The adverse vascular consequences of SHS appear to be mediated via deleterious effects on endothelial function.

Chronic Dietary l -Arginine Prevents Endothelial Dysfunction Secondary to Environmental Tobacco Smoke in Normocholesterolemic Rabbits

Our goal was to determine whether environmental tobacco smoke causes endothelial dysfunction in the absence of hypercholesterolemia and whether such an effect can be prevented by supplementation with L-arginine. Environmental tobacco smoke exposure is associated with an increase in coronary artery disease events and mortality. We have previously demonstrated that environmental tobacco smoke causes endothelial dysfunction and atherosclerosis in rabbits with diet-induced hypercholesterolemia and atherosclerosis and that chronic dietary L-arginine supplementation prevents this. The effects of L-arginine supplementation (2.25% solution ad libitum) and environmental tobacco smoke (smoking chambers for 10 weeks) were examined with a 2 x 2 design in 32 rabbits fed a normal diet. Acetylcholine, calcium ionophore A23187, and nitroglycerin-induced vasorelaxation were assessed in aortic rings precontracted with phenylephrine. Endothelial L-arginine levels were measured by chromatography. Chronic L-arginine supplementation increased serum (P < .001) and endothelial (P = .003) L-arginine levels. Environmental tobacco smoke reduced endothelium-dependent acetylcholine-induced relaxation, and L-arginine blocked this adverse effect (P = .04). Environmental tobacco smoke tended to increase phenylephrine-induced contraction (P = .06). Neither environmental tobacco smoke nor L-arginine influenced A23187-induced relaxation nor endothelium-independent nitroglycerin-induced relaxation. Endothelial dysfunction secondary to environmental tobacco smoke may occur in the absence of diet-induced hypercholesterolemia and atherosclerosis. Chronic dietary supplementation with a nitric oxide donor such as L-arginine offsets the endothelial dysfunction associated with environmental tobacco smoke in normocholesterolemic rabbits, possibly through substrate loading of the nitric oxide pathway.

B4 Ca2+-activated K+ channels are not involved in nitroglycerin-induced vasorelaxation in hypertensive rats

B4 Ca2+-activated K+ channels are not involved in nitroglycerin-induced vasorelaxation in hypertensive rats

Effect of selective inhibition of potassium channels on vasorelaxing response to cromakalim, nitroglycerin and nitric oxide of canine coronary arteries.

A comparative study was performed on the sensitivity of in-vitro vasorelaxation by nitroglycerin and cromakalim to block glibenclamide, a blocker of ATP-sensitive potassium channels, and iberiotoxin, a selective inhibitor of large-conductance calcium-activated potassium channels. In isolated canine coronary arteries preconstricted with 25 microM prostaglandin F2 alpha, nitroglycerin (0.005-1.8 microM) and cromakalim (0.15-9.6 microM) produced dose-dependent vasodilations. Glibenclamide (30 microM) had no significant effect on relaxation of the dose-response curve to nitroglycerin and almost completely abolished the relaxation by cromakalim, a known opener of ATP-sensitive potassium channels. Iberiotoxin (90 nM) decreased the maximal response to nitroglycerin and had no effect on the vasodilation induced by cromakalim. The effect of iberiotoxin on the vasorelaxing action of nitric oxide, the active metabolite of nitroglycerin, was also examined. In a low potassium chloride (14.4-20.4 mM) medium, as a contractile stimulus, iberiotoxin inhibited relaxations by exogenous nitric oxide (100-200 nM). Enhancement of potassium concentrations to 35.4-40.4 mM significantly decreased relaxation by nitric oxide and under these conditions the inhibitory action of iberiotoxin disappeared. The present study demonstrated that in canine coronary arteries, the functional role of two potassium channels can be separated by pharmacological means. Nitroglycerin-induced vasorelaxation may be mediated, at least in part, by its enzymatic breakdown product, nitric oxide that activates large-conductance calcium-activated potassium channels.