Effects of A-192621.1, a Specific Endothelin-B Antagonist, on Intrarenal Hemodynamic Responses to Endothelin-1

Abstract

The present study examined the effects of A-192621.1, a highly selective endothelin-B- (ETB) receptor antagonist, on the renal hemodynamic and systemic actions of endothelin-1 (ET-1). Intravenous injection of ET-1 (1.0 nmol/kg) into anesthetized rats produced a sustained decrease in renal blood flow (assessed by ultrasonic flowmeter) and a significant increase in renal vascular resistance, as well as an increase in mean arterial pressure. These changes were significantly augmented by pretreatment with A-192621.1 (3.0 mg/kg/h). Analysis of intrarenal blood flow by laser-Doppler flowmeter revealed that ET-1 caused a marked and sustained decrease in cortical blood flow, associated with a transient increase in medullary blood flow. The reduction in cortical blood flow in response to ET-1 was further enhanced by pretreatment with A-192621.1, whereas the ET-1-induced medullary vasodilatation was completely abolished and reversed into a vasoconstrictor response. These findings suggest that the ETB-receptors mediate the systemic and renal vasodilatory actions of ET-1 in the rat, and that their activation may serve as a physiological counterbalance that modulates ET-1-induced vasoconstriction.