Role of endothelin ET_B receptors in the renal hemodynamic and excretory responses to big endothelin-1

We determined the role of endothelin ET_B receptor in the renal hemodynamic and excretory responses to big endothelin-1, using A-192621, a selective endothelin ET_B receptor antagonist and the spotting-lethal (sl) rat, which carries a naturally occurring deletion in the endothelin ET_B receptor gene. An intravenous injection of big endothelin-1 produced a hypertensive effect, which is greater in wild-type (+/+) rats pretreated with A-192621 and in homozygous (sl/sl) rats. Big endothelin-1 markedly increased urine flow, urinary excretion of sodium and fractional excretion of sodium in wild-type rats treated with the vehicle. These excretory responses to big endothelin-1 were markedly reduced by pharmacological endothelin ET_B receptor blockade. On the other hand, big endothelin-1 injection to the endothelin ET_B receptor-deficient homozygous animals resulted in a small diuretic effect. When renal perfusion pressure was protected from big endothelin-1-induced hypertension by an aortic clamp, the excretory responses in vehicle-treated wild-type rats were markedly attenuated. In homozygous or A-192621-treated wild-type rats, there was a small but significant decreasing effect in urine flow. In addition, big endothelin-1 significantly elevated nitric oxide (NO) metabolite production in the kidney of wild-type rats but not in the homozygous rats. We suggest that the diuretic and natriuretic responses to big endothelin-1 consist of pressure-dependent and pressure-independent effects and that the increased NO production via the activation of endothelin ET_B receptors in the kidney is closely related to the big endothelin-1-induced excretory responses.