Nitric oxide does not modulate the increases in blood flow, O2 consumption, or contractility during CaCl2 administration in canine hearts (original) (raw)
Related papers
Naunyn-Schmiedeberg’s Archives of Pharmacology, 1994
We investigated the relative contribution of basal and agonist stimulated EDRF/NO release to the adjustment of coronary tone and myocardial perfusion in conscious dogs by inhibiting coronary endothelial NO formation with NG-nitro-L-arginine methyl ester (L-NAME). Chronically instrumented conscious dogs (n = 9) were prepared for measurement of mean arterial blood pressure (MAP), heart rate (HR), coronary blood flow (CF) and diameter of the left circumflex (CDLc) and left anterior descending (CDLAD) coronary artery, respectively. Intracoronary infusions of L-NAME (30.3 mM; 0.25 ml x min-1) caused significant increases in MAP and decreases in HR. CDLc decreased by 3.8°70 from 3.01_+0.04 to 2.90+0.04 mm and CF decreases by 30% from 12.9_+0.2 to 9.1 +0.2 (aU). Peak reactive hyperemia (CFmax) evoked by 20-s-lasting occlusions of the left circumflex coronary artery decreased from 29.9+0.8 to 25.8_+ 1.0 aU and maximal flow-dependent coronary dilation were reduced from 2.04_+0.08 to 0.91 _+0.12% after inhibition of NO-synthesis. Intracoronary infusions of acetylcholine (ACh), adenosine (Ado), bradykinin (Bk), and papaverine (Pap) caused dose-dependent increases in CDLc and CE Infusion of L-NAME nearly abolished the dilator effect of Ado on CDLc and reduced those to ACh, Bk and Pap. Increases in CF to ACh, Ado and Bk but not to Pap were reduced by L-NAME. Subsequent intracoronary infusions of L-arginine (303 mM; 0.25 ml x min-1) reduced L-NAME-induced CF-changes partly, but did not reverse coronary constriction. These results suggest that inhibition of the continuous release of nitric oxide markedly reduces myocardial perfusion in vivo. Endogenous dilator mechanisms are likewise impaired. Thus, in the heart, nitric oxide deficiency probably cannot be fully compensated for by counterregulating mechanisms.
The nitroxyl anion (HNO) is a potent dilator of rat coronary vasculature
Cardiovascular Research, 2007
Objective: The nitroxyl anion (HNO) is the one-electron reduction product of NO U . This redox variant has been shown to be endogenously produced and to have effects that are pharmacologically distinct from NO U . This study investigates the vasodilator and chronotropic effects of HNO in the rat isolated coronary vasculature. Methods: Sprague-Dawley rat hearts were retrogradely perfused with Krebs' solution (8 ml/min) using the Langendorff technique. Perfusion pressure was raised using a combination of infusion of phenylephrine and bolus additions of the thromboxane mimetic U46619 to attain a baseline perfusion pressure of 100-120 mm Hg. The vasodilator effects of a nitroxyl anion donor, Angeli's salt, were examined in the absence and presence of HNO and NO U scavengers, K + channel inhibition, and soluble guanylate cyclase (sGC) inhibition. In addition, the inotropic and chronotropic effects of Angeli's salt were examined in hearts at resting perfusion pressure (50-60 mm Hg) and compared to responses evoked by acetylcholine and isoprenaline.
Experimental and clinical cardiology
Coronary blood flow in one (circumflex) branch of the left coronary artery increases when an adjacent (left anterior descending [LAD]) branch is occluded for periods of between 1 min and 25 min. To examine the possible role of the myocardial release of vasoactive substances in such 'compensatory blood flow' increase by the classical pharmacological approach of inhibition of synthesis, or blockade at the receptor level, of the most likely mediators. In pentobarbitone anesthetized, thoracotomized dogs, coronary blood flow changes were measured in both the LAD (using a Doppler flow probe) and the left circumflex (using an electromagnetic flow probe) coronary arteries. The flow increase during 5 min occlusions of the LAD coronary artery was unaffected by blockade of adenosine receptors by 8-sulfophenyltheophylline, inhibition of prostanoid synthesis by sodium meclofenamate or celecoxib, blockade of bradykinin B(1) receptors by icatibant, inhibition of nitric oxide synthesis by N...
New insights into nitric oxide and coronary circulation
Life Sciences, 1999
Since its discovery over 20 years ago as an intercellular messenger, nitric oxide (NO), has been extensively studied with regard to its involvement in the control of the circulation and, more recently, in the prevention of atherosclerosis. The importance of NO in coronary blood flow control has also been recognized. NO-independent vasodilation causes increased shear stress within the blood vessel which, in turn, stimulates endothelial NO synthase activation, NO release and prolongation of vasodilation. Reactive hyperemia, myogenic vasodilation and vasodilator effects of acetylcholine and bradykinin are all mediated by NO. Ischemic preconditioning, which protects the myocardium from cellular damage and arrhythmias, is itself linked with NO and both the first and second windows of protection may be. due to NO release. Exercise increases NO synthesis via increases in shear stress and pulse pressure and so it is likely that NO is an important blood flow regulatory mechanism in exercise. This phenomenon may account for the beneficial effects of exercise seen in atherosclerotic individuals. Whilst NO plays a protective role in preventing atherosclerosis via superoxide anion scavenging, risk factors such as hypercholesterolemia reduce NO release leading the way for endothelial dysfunction and atherosclerotic lesions. Exercise reverses this process by stimulating NO synthesis and release. Other factors impacting on the activity of NO include estrogens, endothelins, adrenomedullin and adenosine, the last appearing to be a compensatory pathway for coronary control in the presence of NO inhibition. These studies reinforce the pivotal role played by the substance in the control of coronary circulation.
British Journal of Pharmacology, 1991
1 The effect of N-nitro-L-arginine (L-NNA), an inhibitor of nitric oxide biosynthesis, on large coronary artery diameter and coronary blood flow was examined in anaesthetized greyhounds. The effects of L-NNA on the coronary vascular responses to acetylcholine (ACh), glyceryl trinitrate (GTN) and 5hydroxytryptamine (5-HT) were also assessed. 2 L-NNA (5 mg kg 1), infused into the left circumflex coronary artery, increased systemic mean arterial pressure and decreased the external diameter of the artery. Infusion of L-NNA decreased coronary blood flow in 5 of the 7 dogs tested and increased mean coronary resistance but neither of these effects was statistically significant. There was no change in heart rate.
British Journal of Pharmacology, 2014
The NO redox sibling nitroxyl (HNO) elicits soluble guanylyl cyclase (sGC)-dependent vasodilatation. HNO has high reactivity with thiols, which is attributed with HNO-enhanced left ventricular (LV) function. Here, we tested the hypothesis that the concomitant vasodilatation and inotropic actions induced by a HNO donor, Angeli's salt (sodium trioxodinitrate), were sGC-dependent and sGC-independent respectively. Haemodynamic responses to Angeli's salt (10 pmol-10 μmol), alone and in the presence of scavengers of HNO (L-cysteine, 4 mM) or of NO [hydroxocobalamin (HXC), 100 μM] or a selective inhibitor of sGC [1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), 10 μM], a CGRP receptor antagonist (CGRP8-37 , 0.1 μM) or a blocker of voltage-dependent potassium channels [4-aminopyridine (4-AP), 1 mM] were determined in isolated hearts from male rats. Angeli's salt elicited concomitant, dose-dependent increases in coronary flow and LV systolic and diastolic function. Both L-cysteine and ODQ shifted (but did not abolish) the dose-response curve of each of these effects to the right, implying contributions from HNO and sGC in both the vasodilator and inotropic actions. In contrast, neither HXC, CGRP8-37 nor 4-AP affected these actions. Both vasodilator and inotropic actions of the HNO donor Angeli's salt were mediated in part by sGC-dependent mechanisms, representing the first evidence that sGC contributes to the inotropic and lusitropic action of HNO in the intact heart. Thus, HNO acutely enhances LV contraction and relaxation, while concomitantly unloading the heart, potentially beneficial actions in failing hearts.
1994
Coronary vascular responses to bilateral carotid occlusion (BCO) and the intravenous infusion of tyramine (Tyr, 20fLg kg-' min-) and noradrenaline (NA, 0.5 Lg kg-min-') were examined after bilateral vagotomy and antagonism of P-adrenoceptors. BCO, Tyr and NA decreased large coronary artery diameter and increased mean coronary resistance and systemic arterial pressure without affecting heart rate. 2 Inhibition of nitric oxide (NO) synthase with NG-nitro-L-arginine (L-NNA, 5 and 15 mg kg-') significantly increased mean arterial pressure and decreased heart rate and large coronary artery diameter. Mean coronary resistance was unaffected by either dose of L-NNA. L-NNA significantly reduced depressor and coronary vasodilator responses to the endothelium-dependent vasodilator acetylcholine (ACh, 0 tg kg-', i.v.). Systemic and coronary vasodilator responses to sodium nitroprusside (SNP, 5 ftg kg-') were unaffected by L-NNA with the exception that the dilatation of the large coronary artery was significantly enhanced by the higher dose. 3 L-NNA significantly enhanced constriction of the large coronary arteries caused by BCO, Tyr and NA but did not affect the increases in mean coronary resistance or systemic arterial pressure. 4 Inhibition of NO synthesis enhances adrenergic constriction of large coronary arteries caused by both neuronally released and exogenous noradrenaline. In contrast, L-NNA did not affect adrenergic constriction of coronary or systemic resistance vessels. Endothelium-derived NO may play an important role in the modulation of noradrenergic vasoconstriction in coronary conductance arteries.
European Journal of Pharmacology, 2000
The present study examined the role of nitric oxide in coronary vascular tone and in the coronary vasodilatation in response to β-adrenoceptor stimulation and adenosine. In anesthetized goats, the effects of intracoronary and i.v. administration of the inhibitor of nitric oxide synthesis, Nw-nitro-l-arginine methyl ester (l-NAME), and those of isoproterenol, adenosine and acetylcholine on coronary blood flow, measured electromagnetically in the left circumflex coronary artery, were recorded. Intracoronary infusion of l-NAME (30–40 μg kg−1 min−1, four goats) reduced resting coronary blood flow by 14±3% (P<0.05) without changing arterial pressure and heart rate. l-NAME (40 mg kg−1, eight goats) i.v. reduced resting coronary blood flow by 19±4% (P<0.05), increased mean systemic arterial pressure by 22±3% (P<0.01) and decreased heart rate by 10±2% (P<0.05). These effects of l-NAME were partially, but significantly reversed by l-arginine (six goats). Isoproterenol (10–100 ng, eight goats), adenosine (0.3–10 μg, seven goats) and acetylcholine (3–100 ng, five goats), injected intracoronarily, increased coronary conductance in a dose-dependent way and, under control conditions, these increases for isoproterenol, ranged from 32±5% to 82±12%; for adenosine, 6±2% to 174±22%; and for acetylcholine, 39±5% to 145±15%. During i.v. l-NAME the increases in coronary conductance induced by isoproterenol and acetylcholine were significantly reduced by about 50 and 60% (P<0.05), respectively, whereas those induced by adenosine were significantly increased further (about 30–100%, P<0.05). During l-NAME plus l-arginine, the effects of isoproterenol, acetylcholine and adenosine on coronary conductance were not significantly different from those under control conditions. Therefore, it is suggested that in the coronary circulation: (a) nitric oxide may produce a basal vasodilator tone under normal conditions; (b) nitric oxide may be an intermediate in the vasodilatation due to β-adrenoceptor stimulation and acetylcholine, and (c) the vasodilatation due to adenosine is potentiated during reduction of nitric oxide production.