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.