NO and prostanoids blunt endothelin-mediated coronary vasoconstrictor influence in exercising swine

Abstract

Withdrawal of the endothelin (ET)-mediated vasoconstrictor influence contributes to metabolic coronary vasodilation during exercise. Because production of nitric oxide (NO) and prostanoids increases with increasing shear stress and because NO and prostanoids are able to modify the release of ET, we hypothesized that the withdrawal of ET-mediated coronary vasoconstriction during exercise is mediated through NO and/or prostanoids. To test this hypothesis, 19 chronically instrumented swine were studied at rest and while running on a treadmill up to 85-90% of maximal heart rate. Blockade of ET(A)/ET(B) receptors with tezosentan resulted in an increase in coronary venous O(2) levels (i.e., in coronary vasodilation) at rest, which waned at increasing levels of exercise intensity. Inhibition of either NO synthase [N(omega)-nitro-l-arginine (l-NNA)] or cyclooxygenase (indomethacin) did not affect the response to tezosentan under resting conditions but unmasked a vasodilator response to tezosentan during exercise. The vasodilator response to tezosentan during exercise increased progressively after combined administration of l-NNA and indomethacin. These findings suggest that NO and prostanoids act synergistically to inhibit the vasoconstrictor influence of ET on the coronary circulation during exercise, thereby facilitating the exercise-induced vasodilation of coronary resistance vessels.

Prostanoids suppress the coronary vasoconstrictor influence of endothelin after myocardial infarction

“…The withdrawal of ET-mediated coronary vasoconstriction after MI was not due to a loss of ET receptors, as coronary arterioles isolated from remote myocardium after MI displayed a more pronounced (34). The withdrawal of ET-mediated vasoconstriction during exercise in the normal heart was shown to be mediated by NO and prostanoids (37); these data indicate that recruitment of coronary flow reserve during exercise depends critically on a healthy well-functioning endothelium. Since endothelial dysfunction has been shown to be present after MI (4,47,49), we investigated in the present study if the contributions of the three main endothelial vasoactive systems (NO, prostanoids, and ET) to control of coronary resistance vessel tone in remodeled myocardium were altered at rest and/or during exercise.…”

“…Since statistical analyses revealed no differences between male and female swine, data from both sexes were pooled. Data on part of the normal swine have been previously reported (37).…”

“…Coronary vasomotor tone is tightly regulated by a multitude of vasodilator and vasoconstrictor influences, which, in addition to any direct effects on the vascular smooth muscle, can also impact each others expression, secretion, and receptor activation (7,9,37). After MI, endothelial and neurohumoral control of coronary vasomotor tone is altered (12).…”

“…Ninety minutes after 11 MI and 10 normal swine had undergone a control exercise trial (as described above), animals received the COX inhibitor indomethacin (Sigma) in a dose of 10 mg/kg iv infused over 10 min (36) and 5 min later underwent a second exercise trial. Another 90 min later, a subset of animals (7 MI; 8 N) animals received indomethacin in a dose of 5 mg/kg iv, which resulted in hemodynamic conditions that were identical to those following administration of 10 mg/kg before the second exercise trial (37). Subsequently, animals received tezosentan (3 mg/kg iv ϩ 6 mg·kg Ϫ1 ·h Ϫ1 iv) and underwent a third exercise trial.…”

Phosphodiesterase-5 activity exerts a coronary vasoconstrictor influence in awake swine that is mediated in part via an increase in endothelin production

“…NO not only induces coronary vasodilation through cGMPmediated activation of vascular smooth muscle K ϩ channels (26) but also produces vasodilation by inhibiting the coronary vasoconstrictor influence of ET during exercise (30). We recently observed that this inhibition of ET by NO, which is likely cGMP-mediated (5,14,25), occurs principally through a reduced production of ET from Big ET (7).…”