Different endothelial mechanisms involved in coronary responses to known vasodilators.
The role of the endothelium in mediating flow responses to acetylcholine (ACh), bradykinin (BK), adenosine (Ado), and the poorly hydrolyzable ATP-derivative beta,gamma-methylene-ATP (MeATP) was evaluated in the intact coronary system of the isolated perfused guinea pig heart. In the presence of superoxide anions, known to inactivate the endothelium-derived relaxing factor nitric oxide (NO), only steady-state dilatation induced by ACh (1 microM) was fully inhibited and that of BK (0.1 nM) attenuated. Similar effects were obtained with methylene blue and N omega-nitro-L-arginine; however, the latter also reduced the actions of Ado (0.1 microM) and MeATP (0.5 microM). Conversely, perfusion with the NO precursor L-arginine (10 microM) resulted in a potentiated relaxation by ACh, whereas steady-state responses to BK and Ado remained unchanged. Pretreatment of hearts with hydroxyl radicals (.OH) elevated vascular permeability. Under this condition, flow increases induced by ACh, BK, and Ado were enhanced by 130, 89, and 47%, respectively, whereas the effect of MeATP (0.5 microM) was reduced by 45%. Preexposure of hearts to the oxidant hypochlorous acid (HOCl) prevented dilatations by ACh, BK, MeATP and Ado (0.1 microM), and the response to Ado (5 microM) was reduced by 68%; postischemic hyperemia was attenuated. Glyburide, an inhibitor of ATP-sensitive K+ channels, halved the flow response to infused Ado (0.1 and 5 microM), inhibited MeATP, and abolished reactive hyperemia. We conclude that in the guinea pig coronary system ACh, BK, MeATP, and Ado (0.1 microM) induce endothelium-dependent vasodilatation, some step(s) of the signal transmission being vulnerable to oxidative attack by HOCl.(ABSTRACT TRUNCATED AT 250 WORDS)
Leipert
B
B
Department of Physiology, University of Munich, Federal Republic of Germany.
Becker
B F
BF
Gerlach
E
E
D000818:Animals; D001120:Arginine / Q000494:pharmacology; D001241:Aspirin / Q000494:pharmacology; D003331:Coronary Vessels / Q000187:drug effects*; D004730:Endothelium, Vascular / Q000502:physiology*; D016166:Free Radical Scavengers; D005905:Glyburide / Q000494:pharmacology; D006168:Guinea Pigs; D008297:Male; D009569:Nitric Oxide / Q000037:antagonists & inhibitors; D016877:Oxidants / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology*
D016166:Free Radical Scavengers; D016877:Oxidants; D014665:Vasodilator Agents; D009569:Nitric Oxide; D001120:Arginine; D001241:Aspirin; D005905:Glyburide