Characterization of endothelin-1-induced vascular effects in the rat heart by using endothelin receptor antagonists

The coronary vasoconstrictor effect of endothelin-1 was characterized in the isolated rat heart by using the endothelin ETA receptor antagonist D-Asp-L-Pro-D-Val-L-Leu-D-Trp (BQ-123) and the endothelin ETB receptor antagonist [Cys11-Cys15]endothelin-1-(11-21) (IRL 1038). In addition, the involvement of nitric oxide and cyclooxygenase products was investigated. Endothelin-1 (0.012-0.4 nmol) dose dependently reduced coronary flow, which reached a maximum reduction of 83% at 0.4 nmol. BQ-123 (1 microM) attenuated the responses to all doses of endothelin-1, whereas a lower concentration of BQ-123 (0.1 microM) only reduced the vasoconstriction due to the lower doses of endothelin-1 (0.012-0.12 nmol). In contrast, IRL 1038, which markedly antagonized the vasodilator response to the endothelin ETB receptor agonist Suc-[Glu9,Ala11,15]endothelin-1-(8-21) (IRL 1620), significantly enhanced the endothelin-1-evoked coronary vasoconstriction. Endothelin-1 (0.04 nmol) reduced coronary flow by 61% in the presence of IRL 1038 as compared to 30% in the absence of the endothelin ETB receptor antagonist. The endothelin-1-evoked reduction in coronary flow was also significantly enhanced by the nitric oxide synthesis inhibitor NG-nitro-L-arginine but was unaffected by the cyclooxygenase inhibitor diclofenac. IRL 1038 did not affect the response to endothelin-1 after blockade of nitric oxide synthesis. These results demonstrate that the coronary vasoconstriction induced by endothelin-1 in the isolated rat heart is a net effect of the stimulation of both endothelin ETA and endothelin ETB receptors.(ABSTRACT TRUNCATED AT 250 WORDS)