Dilation Of Coronary Resistance Vessels Research Articles

Phosphodiesterase 5 inhibition-induced coronary vasodilation is reduced after myocardial infarction

The balance between the production and removal of cGMP in coronary vascular smooth muscle is of critical importance in determining coronary vasomotor tone and thus in the regulation of coronary blood flow. cGMP production by soluble guanylyl cyclase is activated by nitric oxide (NO), whereas cGMP breakdown occurs through phosphodiesterase 5 (PDE5). We hypothesized that myocardial infarction (MI) alters the balance between the production and removal of cGMP in the coronary vasculature and thereby alters the control of coronary vasomotor tone. Chronically instrumented swine with and without a 2-wk-old MI were exercised on a treadmill in the absence and presence of the PDE5 inhibitor EMD-360527 (300 μg·kg(-1)·min(-1) iv). Inhibition of PDE5 produced coronary resistance vessel dilation, which was more pronounced at rest than during exercise in normal swine. PDE5 gene expression was markedly reduced in coronary resistance vessels isolated from the remote myocardium of MI swine, which was accompanied by a similarly marked attenuation of coronary vasodilation by PDE5 inhibition in MI swine. The coronary vasoconstriction produced by inhibition of NO synthesis with N(ω)-nitro-L-arginine (20 mg/kg iv) was only slightly smaller in swine with MI. Interestingly, inhibition of NO synthesis reduced the vasodilator response to subsequent PDE5 inhibition in normal swine but not in MI swine. Conversely, PDE5 inhibition enhanced the coronary vasoconstriction produced by NO synthesis inhibition in normal swine but not in MI swine, suggesting that downregulation of PDE5 mitigated the loss of NO vasodilator influence. In conclusion, the expression and vasoconstrictor influence of PDE5 are markedly attenuated in coronary resistance vessels in the remote myocardium after MI, which appears to serve as a compensatory mechanism to mitigate the loss of NO vasodilator influence.

The muscle metaboreflex: reining in the heart?

the muscle metaboreflex, also known as the muscle chemoreflex, is one of the principal mediators of the cardiovascular exercise response. This reflex is thought to be triggered by metabolic by-products of ischemia that stimulate afferent nerve endings in skeletal muscle and leads to an increase in

Both β1- and β2-adrenoceptors contribute to feedforward coronary resistance vessel dilation during exercise

During exercise, beta-feedforward coronary vasodilation has been shown to contribute to the matching of myocardial oxygen supply with the demand of the myocardium. Since both beta(1)- and beta(2)-adrenoceptors are present in the coronary microvasculature, we investigated the relative contribution of these subtypes to beta-feedforward coronary vasodilation during exercise as well as to infusion of the beta(1)-agonist norepinephrine and the beta(1)- and beta(2)-agonist isoproterenol. Chronically instrumented swine were studied at rest and during graded treadmill exercise (1-5 km/h) under control conditions and after beta(1)-blockade with metoprolol (0.5 mg/kg iv) and beta(1)/beta(2)-blockade with propranolol (0.5 mg/kg iv). The selectivity and degree of beta-blockade of metoprolol and propranolol were confirmed using isoproterenol infusion (0.05-0.4 microg. kg(-1).min(-1)) under resting conditions. Isoproterenol-induced coronary vasodilation was mediated through the beta(2)-adrenoceptor, whereas norepinephrine-induced coronary vasodilation was principally mediated through the beta(1)-adrenoceptor. Exercise resulted in a significant increase in left ventricular norepinephrine release and epinephrine uptake. beta(1)-Adrenoceptor blockade with metoprolol had very little effect under resting conditions. However, during exercise, metoprolol attenuated the increase in myocardial oxygen supply in excess of the reduction in myocardial oxygen demand, as evidenced by a progressive decrease in coronary venous Po(2). Consequently, metoprolol caused a clockwise rotation of the relationship between myocardial oxygen consumption and coronary venous Po(2). Additional beta(2)-adrenoceptor blockade with propranolol further inhibited myocardial oxygen supply during exercise, resulting in a further clockwise rotation of the relationship between myocardial oxygen consumption and coronary venous Po(2). In conclusion, both beta(1)- and beta(2)-adrenoceptors contribute to the beta-feedforward coronary resistance vessel dilation during exercise.

Pathophysiological plasma ET-1 levels antagonize beta-adrenergic dilation of coronary resistance vessels in conscious dogs.

On the basis of in vitro experiments showing that endothelin (ET)-1 interferes with smooth muscle ATP-sensitive K(+) (K(ATP)) channel opening, which is pivotal in beta-adrenergic coronary dilation, we hypothesized that pathophysiological plasma ET-1 levels impair beta-adrenergic dilation of resistance coronary vessels. In conscious instrumented dogs, graded intravenous doses of dobutamine caused the expected inotropic responses. As myocardial O(2) consumption (MVo(2)) increased, the disproportionate rise in coronary sinus (CS) Po(2) indicates that increases in coronary blood flow (CBF) exceeded metabolic requirements, consistent with beta-adrenergic dilation. ET-1 intravenous infusions, to reach pathophysiological plasma levels, reduced slopes of the Po(2)-MVo(2) and CBF-MVo(2) relations. In contrast, the first derivative of left ventricular pressure over time responses to dobutamine were not impaired during ET-1 delivery. Clazosentan, an ET(A) receptor blocker, prevented reduction of the slope of Po(2)-MVo(2) and CBF-MVo(2) relations. After ganglionic blockade to exclude reflex influences, ET-1 still reduced slopes of Po(2)-MVo(2) and CBF-MVo(2) relations. To assess effects of ET-1 on endothelium-dependent and -independent coronary vascular responses, intracoronary ACh and nitroglycerin were given to directly target coronary vessels. CBF responses to ACh and nitroglycerin were maintained during ET-1 delivery. In contrast, responses to intracoronary K(ATP) channel-dependent dilators adenosine and lemakalim were impaired by ET-1. In conclusion, pathophysiological levels of ET-1 impaired beta-adrenergic dilation of resistance coronary vessels through an ET(A) receptor-dependent process. In contrast, left ventricular inotropic responses to dobutamine were not impaired during ET-1 delivery. Our data suggest that ET-1 may interfere with smooth muscle K(ATP) channels to impair beta-adrenergic coronary dilation.

Effect of sildenafil on coronary active and reactive hyperemia

Sildenafil, a selective inhibitor of phosphodiesterase type 5, produces relaxation of isolated epicardial coronary artery segments by causing accumulation of cGMP. Because shear-induced nitric oxide-dependent vasodilation is mediated by cGMP, this study was performed to determine whether sildenafil would augment the coronary resistance vessel dilation that occurs during the high-flow states of exercise or reactive hyperemia. In chronically instrumented dogs, sildenafil (2 mg/kg per os) augmented the vasodilator response to acetylcholine, with a leftward shift of the dose-response curve relating coronary flow to acetylcholine dose. Sildenafil caused a 6. 7 +/- 2.1 mmHg decrease of mean aortic pressure, which was similar at rest and during treadmill exercise (P < 0.05), with no change of heart rate, left ventricular (LV) systolic pressure, or LV maximal first time derivative of LV pressure. Sildenafil tended to increase myocardial blood flow at rest and during exercise (mean increase = 14 +/- 3%; P < 0.05 by ANOVA), but this was associated with a significant decrease in hemoglobin, so that the relationship between myocardial oxygen consumption and oxygen delivery to the myocardium (myocardial blood flow x arterial O(2) content) was unchanged. Furthermore, sildenafil did not alter coronary venous PO(2), indicating that the coupling between myocardial blood flow and myocardial oxygen demands was not altered. In addition, sildenafil did not alter the peak coronary flow rate, debt repayment, or duration of reactive hyperemia that followed a 10-s coronary occlusion. The findings suggest that cGMP-mediated resistance vessel dilation contributes little to the increase in myocardial flow that occurs during exercise or reactive hyperemia.

Coronary nitric oxide production in response to exercise and endothelium-dependent agonists.

Endothelium-derived nitric oxide (NO) contributes to epicardial coronary artery vasodilation during exercise. However, blockade of NO production does not impair the increase in coronary blood flow (CBF) during exercise, suggesting that NO is not obligatory for exercise-induced coronary resistance vessel dilation. In contrast, the increases in CBF produced by endothelium-dependent agonists are decreased after NO blockade. Consequently, this study was performed to determine whether the increase in coronary NO production in response to agonists is greater than that which occurs during exercise. We measured the oxidation products of NO (nitrate+nitrite=NO(x)) in aortic and coronary sinus plasma using chemiluminescence to assess NO(x) production across the coronary circulation in chronically instrumented dogs during a 3-stage treadmill exercise protocol and in response to intracoronary administration of the endothelium-dependent agonists acetylcholine (37.5 microg/min) and bradykinin (3.0 microg/min). No coronary NO(x) production could be detected at rest or during the first 2 stages of exercise; only at the highest level of exercise was a small increase in coronary NO(x) production measured. In contrast, coronary production of NO(x) was significantly increased in response to endothelium-dependent agonists. Coronary NO production in response to endothelium-dependent agonists is greater than in response to the increase in shear stress associated with exercise. These findings support previous studies suggesting that NO is not required for the coronary vasodilation that occurs in the normal heart during exercise.

The role of nitric oxide in bradykinin-induced dilation of coronary resistance vessels in patients with hypercholesterolemia.

In hypercholesterolemic patients, acetylcholine- and substance P-mediated endothelium-dependent dilation of the coronary resistance vessels is impaired due to decreased nitric oxide production. However, it is not clear if bradykinin-induced coronary vasodilation is impaired in these patients. We investigated whether the endothelium-dependent dilation of coronary resistance vessels mediated by bradykinin is impaired in patients with hypercholesterolemia and, if so, whether this impairment is caused by a decreased production of nitric oxide. We examined the coronary vascular responses to acetylcholine and bradykinin. The vascular responses to bradykinin were also assessed after N(G)-monomethyl-L-arginine was infused to inhibit nitric oxide production. Drugs were infused into the left coronary ostium and coronary blood flow (CBF) and coronary vascular resistance were evaluated by quantitative angiography and Doppler flow velocity measurements. Twelve hypercholesterolemic patients and 11 control patients with angiographically normal coronary arteries were studied. The vasodilator responses to acetylcholine and bradykinin were reduced in hypercholesterolemic patients compared with control patients (p<0.005 and p<0.04, respectively, by two-way analysis of variance (ANOVA)). The CBF responses to acetylcholine and bradykinin were significantly correlated (r=0.56; p<0.01). Bradykinin-induced dilation was similar in hypercholesterolemic patients and control patients after inhibition of nitric oxide. These results suggest that the bradykinin-mediated endothelium-dependent dilation of coronary resistance vessels may be impaired due to depressed nitric oxide production in patients with hypercholesterolemia.

Bradykinin-induced Dilation of Coronary Resistance Vessels in Patients With Hypercholesterolemia: A Role of Nitric Oxide

Bradykinin-induced Dilation of Coronary Resistance Vessels in Patients With Hypercholesterolemia: A Role of Nitric Oxide

Bradykinin-induced dilation of coronary resistance vessels in patients with hypercholesterolemia: a role of nitric oxide

Bradykinin-induced dilation of coronary resistance vessels in patients with hypercholesterolemia: a role of nitric oxide

Relation of pacing-induced coronary resistance vessel dilation to total serum cholesterol and heart rate-blood pressure product

Coronary risk factors adversely affect coronary resistance vessel dilation to acetylcholine, but little is known about the effect of risk factors on coronary blood flow (CBF) responses to physiologic stimuli. CBF was derived from Doppler flow velocity (0.018-inch Doppler wire) and coronary diameter (quantitative angiography) in response to rapid atrial pacing in 50 patients (mean age 52 ± 12 years). Patients were prospectively divided into 3 groups based on their angiograms: group 1 (n = 17), normal coronary arteries; group 2 (n = 18), 1-vessel coronary artery disease (CAD) with a smooth study artery; group 3 (n = 15), 1-vessel CAD and an irregular study artery (<20% stenosis). Pacing produced a significant increase in CBF compared with baseline in groups 1 and 2 (34 ± 40%, 42 ± 35%, p < 0.0001), respectively, but not in group 3 (21 ± 33%), but there was no difference in the pacing response among the 3 groups. The increase in CBF to pacing was inversely related to serum cholesterol (p = 0.01) and triglycerides (p = 0.06) and directly related to the increase in heart rate-blood pressure product (p = 0.007). By multivariate analysis, total cholesterol and the increase in double product were the only factors related to the increase in CBF. Increases in CBF to atrial pacing are inversely related to serum total cholesterol and are not related to the angiographic presence of atherosclerosis in patients with mild CAD.

Effects of Various Doses of Intracoronary Verapamil on Coronary Resistance Vessels in Humans

To investigate the vasodilatory effect of various doses of intracoronary verapamil on coronary resistance vessels, we studied 13 patients with normal angiograms. A coronary Doppler guide wire was inserted into the left anterior descending coronary artery, and coronary blood flow velocity (CBFV) was measured. Verapamil was injected into the left coronary artery at doses of 0.1 mg, 0.5 mg, 1.0 mg, and 2.0 mg at 10-min intervals. Nitroglycerin was also injected into the same artery to avoid changes in cross-sectional area. As a measure of coronary vascular resistance, coronary vascular resistance index (CVRI) was calculated as the quotient of mean aortic pressure/CBFV. An injection of verapamil produced a dose-dependent increase in CBFV: 79 +/- 38% with 0.1 mg, 131 +/- 56% with 0.5 mg, 143 +/- 46% with 1.0 mg, and 128 +/- 47% with 2.0 mg of verapamil. The percent peak decreases in CVRI were dose dependent: -42 +/- 13% with 0.1 mg, -50 +/- 17% with 0.5 mg, -62 +/- 14% with 1.0 mg, and -60 +/- 9% with 2.0 mg of verapamil. Thus, intracoronary verapamil produces a dose-dependent dilation of coronary resistance vessels, and the optimal effect is produced with an injection of verapamil at a dose of 1.0 mg into the left coronary artery. At this dose, verapamil did not affect atrioventricular conduction.

Effect of alpha-adrenergic blockade with prazosin on large coronary diameter during exercise.

Exercise-induced dilation of coronary resistance vessels is limited by alpha-adrenergic mechanisms. However, the effect of alpha-adrenergic mechanisms on large coronary arteries during exercise is not known. In the present study, sonomicrometry was used to measure circumflex coronary arterial diameter during treadmill exercise before and after alpha 1-adrenergic blockade with prazosin in eight instrumented dogs. Before infusion of prazosin, exercise caused a fall in coronary vascular resistance (2.1 +/- 0.4 to 1.6 +/- 0.2 units, p less than 0.05) and dilation of the circumflex coronary artery (4.66 +/- 0.37 to 4.79 +/- 0.34 mm, p less than 0.05). Intracoronary infusion of prazosin during exercise caused a further decrease in coronary vascular resistance (1.6 +/- 0.2 to 1.4 +/- 0.2 units, p less than 0.05) and a further increase in circumflex coronary arterial diameter (4.79 +/- 0.34 to 4.83 +/- 0.34 mm, p less than 0.05). Intracoronary infusion of vehicle without prazosin during exercise did not cause a further decrease in coronary vascular resistance or increase in coronary diameter. Prazosin caused no significant increase in heart rate, aortic pressure, or coronary blood flow. Therefore, both small coronary resistance vessels and large epicardial coronary arteries dilated during exercise and dilated further after alpha-adrenergic blockade. This finding indicates that alpha 1-adrenergic activity during exercise limits dilation of both large and small coronary arteries.

Reversal of acetycholine-induced coronary resistance vessel dilation by hemoglobin

In large arteries, acetylcholine-induced dilation is mediated by endothelium-derived relaxing factor (EDRF) and can be blocked by hemoglobin (Hb). However, the role of EDRF in the microcirculation is uncertain. Therefore, the effect of Hb on acetylcholine-induced dilation of resistance vessels was studied in isolated, constant-flow perfused rabbit hearts. Hb reversibly blocked the acetylcholine-induced lowering of perfusion pressure (control −27 ± 3%; during Hb 0 ± 4%) without inhibiting responses to other dilators, strongly suggesting that acetylcholine action in the microcirculation is mediated by EDRF.

Nonischemic myocardial hypoxia: coronary dilation without increased tissue adenosine.

Experiments were performed in 23 open-chest, anesthetized dogs to evaluate 1) the extent of coronary vasodilation during nonischemic hypoxia and 2) whether this dilation is associated with changes in cardiac concentrations of adenosine, inosine, and hypoxanthine. Three minutes of nonischemic myocardial hypoxia caused by selective perfusion of the left anterior descending coronary artery (LAD) with hypoxic blood (PO2 = 11.7 Torr) increased coronary flow 623%, an increase that was not significantly different from that at the peak hyperemic response following 3 min of ischemic hypoxia secondary to LAD occlusion (+534%). Concentrations for adenosine and inosine (nmol/g) in myocardium sampled during nonischemic hypoxia [0.8 +/- 0.2 (SE) and 0.8 +/- 0.2, respectively] were significantly less than values during control conditions (1.7 +/- 0.3 and 1.4 +/- 0.2). Hypoxanthine concentrations did not differ for nonischemic hypoxia and control conditions. During ischemic hypoxia concentrations for adenosine (31.2 +/- 4.9), inosine (91.0 +/- 13.6), and hypoxanthine (44.0 +/- 15.3) were considerably greater than values during nonischemic hypoxia and during control conditions. The results indicate that nonischemic hypoxia induced pronounced coronary vasodilation similar to that during ischemic hypoxia, with reduced rather than with increased tissue concentrations of adenosine and inosine. These findings suggest that reduced myocardial oxygen tension may cause dilation of coronary resistance vessels by a direct relaxant effect on arteriolar vascular smooth muscle.