Renal actions of endothelin-1 under endothelin receptor blockade by BE-18257B

Purpose: Endothelin-1 (ET-1), a peptide produced by the vascular endothelium, causes profound renal vasoconstriction by binding to ET-A receptors. The present study examined the renal actions of ET-1 after ET-A receptors were blocked by BE-18257B to unmask the functions of ET-B receptors. Materials and Methods: Renal hemodynamics and clearance measurements were obtained in anesthetized dogs after intrarenal infusion of BE-18257B at 100 ng./kg./min. (Group 1), after intrarenal infusion of ET-1 at 2 ng./kg./min. (Group 2), or after intrarenal infusion of ET-1 superimposed on BE-18257B (Group 3). Results: In Group 1, BE-18257B infusion did not alter arterial pressure, renal blood flow (RBF), GFR or tubular function. In Group 2, ET-1 infusion led to a significant decrease in RBF and GFR (37 and 40%, respectively) without altering arterial pressure. Urinary volume and sodium excretion were not changed but osmolality decreased significantly. In Group 3, BE-18257B infusion significantly attenuated the decrease in RBF caused by ET-1 and increased GFR by 40% without altering arterial pressure, associated with significant diuresis and natriuresis. Conclusion: Renal vasoconstriction caused by ET-1 is attenuated by ET-A receptor blockade with BE-18257B, which unmasks the hemodynamic and tubular actions of ET-B receptors. As a result, it limits the ET-1 induced decrease in RBF and raises GFR, and leads to a diuresis and natriuresis.