The pharmacokinetics and cardiovascular effects of YM-21095 ((2RS), (3S)-3-[N alpha-[1,4-dioxo-4-morpholino-2-(1-naphthylmethyl)- butyl]-L-histidylamino]-4-cyclohexyl-1-[(1-methyl-5-tetrazolyl)thi o]-2-butanol), a potent renin inhibitor, have been studied in beagle dogs and squirrel monkeys. Plasma levels of YM-21095 after 3 mg kg-1 intravenous dosing to dogs declined biphasically and fitted a two-compartment model. Kinetics were as follows: t1/2 alpha = 4.9 +/- 0.2 min, t1/2 beta = 2.76 +/- 0.79 h, Vdss = 3.86 +/- 1.04 L kg-1, plasma clearance = 2.22 +/- 0.39 L kg-1, and AUC = 1445 +/- 266 ng h mL-1. After 30 mg kg-1 oral dose, maximum plasma concentration, tmax and AUC of YM-21095 were 28.8 +/- 9.6 ng mL-1, 0.25 h and 23.6 +/- 7.7 ng h mL-1, respectively. Systemic bioavailability as determined on the basis of the ratio of AUC after intravenous and oral dose was 0.16 +/- 0.04%. In conscious, sodium-depleted monkeys, YM-21095 at an oral dose of 30 mg kg-1 lowered systolic blood pressure and inhibited plasma renin activity without affecting heart rate and plasma aldosterone concentration. Maximum plasma concentration of YM-21095 after 30 mg kg-1 oral dose to monkeys was 71.8 +/- 41.5 ng mL-1, which was reached 0.5 h after the dose. At equihypotensive doses, captopril and nicardipine increased plasma renin activity markedly and slightly, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)