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 ET(A) receptor antag onist D-Asp-L-Pro-D-Val-L-Leu-D-Trp (BQ-123) and the endothelin ET(B) receptor antagonist [Cys(11)-Cys(15)]endothelin-1-(11-21) (IRL 1038). In addition, the involvement of nitric oxide and cyclooxygenase produc ts was investigated. Endothelin-1 (0.012-0.4 nmol) dose dependently re duced coronary flow, which reached a maximum reduction of 83% at 0.4 n mol. BQ-123 (1 mu M) attenuated the responses to all doses of endothel in-1, whereas a lower concentration of BQ-123 (0.1 mu M) only reduced the vasoconstriction due to the lower doses of endothelin-1 (0.012-0.1 2 nmol). In contrast, IRL 1038, which markedly antagonized the vasodil ator response to the endothelin ET(B) receptor agonist Suc-[Glu(9),Ala (11,15)]endothelin-1-(8-21) (IRL 1620), significantly enhanced the end othelin-1-evoked coronary vasoconstriction. Endothelin-1 (0.04 nmol) r educed coronary flow by 61% in the presence of IRL 1038 as compared to 30% in the absence of the endothelin ET(B) receptor antagonist. The e ndothelin-1-evoked reduction in coronary flow was also significantly e nhanced by the nitric oxide synthesis inhibitor N-G-nitro-L-arginine b ut 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 vasoconst riction induced by endothelin-1 in the isolated rat heart is a net eff ect of the stimulation of both endothelin ET(A) and endothelin ET(B) r eceptors. Thus, the endothelin ET(A) receptor mediates endothelin-1-ev oked vasoconstriction whereas the endothelin ET(B) receptor stimulatio n counteracts the vasoconstriction by a mechanism depending on the rel ease of nitric oxide.