Selective blockade of endothelin receptor subtypes on systemic and renal vascular responses to endothelin-1 and IRL1620, a selective endothelin ET(B)-receptor agonist, in anesthetized rats

By using BQ-788 as a selective endothelin ET(B)-receptor antagonist and FR139317 as a selective endothelin ET(A)-receptor antagonist, we have characterized the receptor subtypes mediating the systemic and renal vascular effects of endothelin-l and IRL1620, a selective endothelin ET(B)-receptor agonist (succinyl-[Glu(9),Ala(11,5)]-endothelin-1(8-21)), in anesthetized rats. Bolus intravenous injection of endothelin-1 (0.5 nmol/kg) and IRL1620 (1.65 nmol/kg) produced a transient fall in systemic blood pressure followed by a sustained increase. The initial fall in blood pressure observed after endothelin-l and IRL1620 administration was completely blocked by BQ-788 (0.5 mu mol/kg, i.v.), whereas the presser response was blocked by FR139317 (0.8 mu mol/kg, i.v.). Renal blood flow was decreased and calculated renal vascular resistance was dramatically increased by endothelin-l and IRL1620. The reduction of renal blood flow by endothelin-l was significantly suppressed by FR139317 but potentiated by BQ-788. Both BQ-788 and FR139317 partially blocked the renal vasoconstriction by IRL1620. Pretreatment by BQ-788 itself decreased renal blood flow by 14.1%. These results indicate that the systemic depressor responses induced by endothelin-l and IRL1620 are mediated through the endothelin ET(B)-receptor, and the presser responses are mediated through the endothelin ET(A)-receptor. In the renal vasculature of anesthetized rats, it is suggested that vasoconstriction is mediated through both endothelin ET(A)- and ET(B)-receptors and that endothelin ET(B)-receptors may be also involved in vasodilating responses to endothelin peptides.