Jpn. J. Pharmacol. 71 (3), 213-222 (1996)

Selective Blockade of Endothelin Receptor Subtypes on Systemic and Renal Vascular Responses to Endothelin-1 and IRL1620, a Selective Endothelin ETB-Receptor Agonist, in Anesthetized Rats

Takeshi Matsuura, Tokihito Yukimura, Shokei Kim, Katsuyuki Miura and Hiroshi Iwao

Department of Pharmacology, Osaka City University Medical School, 1-4-54 Asahimachi, Abeno-ku, Osaka 545, Japan

Abstract: By using BQ-788 as a selective endothelin ETB-receptor antagonist and FR139317 as a selective endothelin ETA-receptor antagonist, we have characterized the receptor subtypes mediating the systemic and renal vascular effects of endothelin-1 and IRL1620, a selective endothelin ETB-receptor agonist (succinyl-[Glu9,Ala11,5]-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-1 and IRL1620 administration was completely blocked by BQ-788 (0.5 micromol/kg, i.v.), whereas the pressor response was blocked by FR139317 (0.8 micromol/kg, i.v.). Renal blood flow was decreased and calculated renal vascular resistance was dramatically increased by endothelin-1 and IRL1620. The reduction of renal blood flow by endothelin-1 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-1 and IRL1620 are mediated through the endothelin ETB-receptor, and the pressor responses are mediated through the endothelin ETA-receptor. In the renal vasculature of anesthetized rats, it is suggested that vasoconstriction is mediated through both endothelin ETA- and ETB-receptors and that endothelin ETB-receptors may be also involved in vasodilating responses to endothelin peptides.

Keywords: Endothelin-1, Systemic blood pressure, Renal blood flow, BQ-788, FR139317

Copyright© The Japanese Pharmacological Society 1996

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