Contribution of endothelin to the coronary vasoconstriction in the isolated rat heart induced by nitric oxide synthase inhibition.
The possible involvement of endothelin-1 (ET-1) and angiotensin II in the coronary vasoconstriction induced by nitric oxide synthase (NOS) inhibition was investigated in isolated Langendorff-perfused rat hearts. Fifteen minutes of perfusion with the NOS inhibitor NG-nitro-L-arginine (L-NNA, 0.1 mM) reduced coronary flow by 31%. Pre-treatment with the non-selective ETA/ETB receptor antagonist bosentan (1 and 10 microM) attenuated this reduction in coronary flow to 16% (P < 0.05) and 8% (P < 0.01), respectively. The selective ETA receptor antagonist BQ-123 (1 microM) induced a similar inhibitory action, whereas the selective ETB receptor antagonist BQ-788 and the angiotensin II type 1 receptor antagonist candesartan did not affect the vasoconstrictor response to L-NNA. In addition, bosentan administered after 15 min of L-NNA perfusion reversed the L-NNA-induced reduction in coronary flow in a dose-dependent manner. The high concentration of bosentan (10 microM) increased the basal coronary flow by 17%, while the lower concentration of bosentan, BQ-123, BQ-788 and candesartan did not affect basal coronary flow. Bosentan (10 microM) increased the level of ET-like immunoreactivity (-LI) in the coronary effluent twofold. L-NNA did not affect ET-LI level. These results indicate that ET-1 contributes to the coronary vasoconstrictor effect of L-NNA in the isolated rat heart, and that this action of ET-1 is mediated through ETA receptor activation. Angiotensin II does not seem to contribute to L-NNA-induced vasoconstriction under the present condition.
Wang
Q D
QD
Department of Cardiology, Karolinska Hospital, Stockholm, Sweden.
Gonon
A
A
Shimizu
M
M
Sjöquist
P O
PO
Pernow
J
J
D000818:Animals; D003326:Coronary Circulation / Q000187:drug effects; D003331:Coronary Vessels / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D016232:Endothelins / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006321:Heart / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052250:Nitric Oxide Synthase Type III; D019335:Nitroarginine / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014661:Vasoconstriction / Q000502:physiology*
D016232:Endothelins; D004791:Enzyme Inhibitors; D010456:Peptides, Cyclic; D019335:Nitroarginine; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; C072247:cyclo(Trp-Asp-Pro-Val-Leu)