NO and prostanoids blunt endothelin-mediated coronary vasoconstrictor influence in exercising swine.
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.
Merkus
Daphne
D
Experimental Cardiology, Thoraxcenter, Erasmus MC, Univ. Medical Center Rotterdam, Box 1738, 3000DR Rotterdam, The Netherlands. d.merkus@erasmusmc.nl
Sorop
Oana
O
Houweling
Birgit
B
Boomsma
Frans
F
van den Meiracker
Anton H
AH
Duncker
Dirk J
DJ
D000818:Animals; D002302:Cardiac Output / Q000187:drug effects / Q000502:physiology; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D004347:Drug Interactions; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000097:blood / Q000494:pharmacology*; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D007213:Indomethacin / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D009569:Nitric Oxide / Q000494:pharmacology*; D019335:Nitroarginine / Q000008:administration & dosage / Q000494:pharmacology; D010101:Oxygen Consumption / Q000187:drug effects; D010805:Physical Conditioning, Animal; D005082:Physical Exertion / Q000502:physiology*; D011453:Prostaglandins / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D034421:Sus scrofa; D013777:Tetrazoles / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects* / Q000502:physiology; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology
D016861:Cyclooxygenase Inhibitors; D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D011453:Prostaglandins; D011725:Pyridines; D013777:Tetrazoles; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D019335:Nitroarginine; D009569:Nitric Oxide; C120582:tezosentan; D007213:Indomethacin