Selective antagonism of endothelin ET(A) or ET(B) receptor in renal hemodynamics and function of deoxycorticosterone acetate-salt-induced hypertensive rats.

Abstract

Effects of acute and chronic blockade of endothelin ET(A) or ET(B) receptors on renal hemodynamics and function were investigated using deoxycorticosterone acetate (DOCA)-salt-induced hypertensive rats. At 4 weeks after initiating DOCA-salt treatment, intravenous bolus injection of ABT-627 (1 mg/kg), a selective ET(A) receptor antagonist, produced a sustained and significant hypotension, which was accompanied by potent renal vasodilation. When the selective ET(B) receptor antagonist A-192621 (3 mg/kg) was intravenously administered, there were marked decreases in renal blood flow and glomerular filtration rate, and increases in renal vascular resistance. A slight hypertensive effect was observed after the injection of A-192621. Next, we examined the effects of chronic treatment with ABT-627 (10 mg/kg/d, p.o., b.i.d.) or A-192621 (30 mg/kg/d, p.o., b.i.d.) for 2 weeks on renal function of animals at 2 weeks after initiating DOCA-salt treatment. In the 2-week-treated DOCA-salt animals, the levels of creatinine clearance (Ccr), urinary excretion of protein (Uprotein V) and blood urea nitrogen (BUN) were not significantly different compared with those of sham-operated control animals. These parameters did show statistically significant differences over the 3 to 4 weeks treatment period, between the DOCA-salt and the control animals (decrease in Ccr, and increase in Uprotein V and BUN in DOCA-salt rats), thereby indicating the gradual establishment of renal dysfunction in this hypertensive model. The DOCA-salt-induced changes in renal functional parameters were markedly attenuated by daily administration of ABT-627. In contrast, treatment with A-192621 augmented the above renal dysfunction. Our findings clearly indicate that selective blockade of the ET(B) receptor is detrimental to renal hemodynamics and the function of the hypertensive condition, and support the view that a selective ET(A) receptor antagonist is useful for treatment of subjects with mineralocorticoid-dependent hypertension.