Effects of a novel orally effective V₁-receptor antagonist, OPC-21268, on AVP-induced sympathoinhibition

Arginine vasopressin (AVP) plays an important role in control of circulation and may be involved in pathophysiology of cardiovascular diseases. Recently a novel oral V₁-receptor antagonist, OPC-21268, has been produced for possible human therapeutic use (Y. Yamamure et al. Science Wash. DC 252: 572-574, 1991). OPC-21268 is a nonpeptide antagonist and inhibits AVP-induced vasoconstriction in rats and humans. In this study, we examined the influence of OPC-21268 on the sympathoinhibitory and bradycardic effects of AVP in conscious rabbits. Before OPC-21268, AVP at doses of 1, 3, 10, and 30 mU/kg decreased renal sympathetic nerve activity (RSNA) by 24 ± 5, 40 ± 5, 65 ± 6 and 86 ± 5%, respectively, and decreased heart rate from 243 ± 10 beats/min at control to 232 ± 11, 221 ± 10, 197 ± 9, and 166 ± 6 beats/min, respectively (n = 12). Oral OPC-21268 at 30 mg/kg (n = 12) and 90 mg/kg (n = 5) did not alter the baseline values of arterial pressure, heart rate, and RSNA. After oral OPC-21268 the decreases in RSNA and heart rate evoked with AVP at graded doses were partially but significantly attenuated (P < 0.01). The attenuation of the AVP-induced decreases in RSNA and heart rate was similar between the two doses of OPC-21268. In another group of rabbits (n = 6), intravenous OPC-21268 at 30 mg/kg almost completely abolished AVP-induced decreases in heart rate and RSNA. The effects of intravenous OPC-21268 at 30 mg/kg was similar to those of the Manning compound (a specific V₁-receptor antagonist) at 10 mg/kg. OPC-21268 did not affect the phenylephrine-induced increases in blood pressure and reflex decreases in heart rate and RSNA. These results may suggest that OPC-21268 is a potent V₁-receptor antagonist and that oral OPC-21268 is partially effective to antagonize the V₁-receptor-mediated decreases in heart rate and RSNA.