Selective Antagonism of Endothelin ET_A or ET_B Receptor in Renal Hemodynamics and Function of Deoxycorticosterone Acetate-Salt-Induced Hypertensive Rats

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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 decrease 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 (C-<cr>), urinary excretion of protein (U_<protein>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 C_<cr>, and increase in U_<protein>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.
公益社団法人日本薬学会の論文
1999-08-15

Selective Antagonism of Endothelin ET_A or ET_B Receptor in Renal Hemodynamics and Function of Deoxycorticosterone Acetate-Salt-Induced Hypertensive Rats

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