Physiologic Role of ETA Receptors in the Regulation of Renal Hemodynamics in Normal and Salt-Depleted Rats

Abstract

Exogenous endothelin (ET) promotes powerful vasoconstriction in systemic and renal microcirculation. However, the physiologic role of endogenous ET on the moment-to-moment regulation of the circulation remains unclear. We investigated the effects of acute administration of FR139317, a nonpeptide inhibitor specific for the ETA receptor shown in preliminary experiments to reverse the established vasoconstrictor effects of exogenous ET. Renal and glomerular functional parameters were determined in eight anesthetized adult male Munich-Wistar rats receiving a standard diet (0.5% Na) before and after bolus injection of FR139317, 10 mg/kg. To assess the physiologic role of ET in sodium depletion, eight rats received a low-salt (0.06% Na) diet for 2 weeks before acute FR139317 treatment. Eight additional salt-restricted rats received a bolus injection of the angiotensin II inhibitor losartan, 10 mg/kg i.v., as a positive control. FR139317 exerted no detectable microcirculatory effect in rats receiving standard diet. In sodium-depleted rats, losartan lowered blood pressure by 12 mm Hg, raised heart rate by 20 beats/min, and decreased renal vascular resistance by 33%. By contrast, FR139317 had only slight hemodynamic effects, although it increased heart rate by 15 beats/min. These results suggest that ET does not participate, at least via ETA receptors, in the regulation of renal and systemic microcirculation in the rat. However, it may be involved in the circulatory adaptations to chronic sodium depletion. A regulatory role for ET via ETB receptors is also possible.