Abstract

CI-996, a novel potent angiotensin II (Ang II) type 1 (AT1) receptor antagonist was characterized in a number of in vitro and in vivo assays. In addition, CI-996 was compared with several reported AT1 receptor antagonists including losartan, SK&F 108566 and L-158,809. In rat liver membranes CI-996 displaced specifically bound [125I]Ang II with an IC50 of 0.8 +/- 0.1 nM. In isolated rabbit aorta CI-996 produced a concentration-dependent inhibition of Ang II-induced contraction and decreased the maximal contractile response to Ang II. CI-996 had no effect on the contractile responses to KCl, norepinephrine or endothelin. In anesthetized, ganglionic-blocked rats CI-996 produced dose-dependent inhibition of the Ang II pressor dose-response curve with an IC50 of 6.2 micrograms/kg/min i.v. Orally administered CI-996 dose dependently lowered mean arterial blood pressure in conscious renal hypertensive rats, conscious sodium-depleted dogs, conscious sodium-depleted monkeys and conscious renal hypertensive monkeys. The duration of antihypertensive activity of CI-996 in rats was > 24 hr after a single oral dose. The blood pressure lowering potency of CI-996 in dogs was less than that observed in either rats or monkeys. There was no tachyphylaxis to the antihypertensive effects of CI-996 after repeated administration in renal hypertensive monkeys. These data demonstrate that CI-996 is a potent, selective Ang II antagonist. Furthermore, CI-996 has demonstrated blood pressure-lowering activity after oral administration in rats, dogs and monkeys.