The potent and primate-selective
renin inhibitor A-64662 (n = 8) or vehicle (n = 6) was administered intravenously for 7 days to
sodium-depleted cynomolgus monkeys to investigate the chronic effects on arterial pressure,
sodium excretion, and the renin-angiotensin-aldosterone system. A 0.1-mg/kg i.v. bolus followed by a continuous 0.01-mg/kg/min infusion of
A-64662 lowered mean arterial pressure from 89 +/- 3 (average of 4 control days) to 75 +/- 4 mm Hg (p less than 0.05) after 1 day of administration. This decrement was associated with marked inhibition of plasma
renin activity (PRA) from 57.7 +/- 11.1 to 1.3 +/- 0.6 ng
angiotensin I (Ang I)/ml/hr (p less than 0.05). Similar hypotensive levels (range 73 +/- 4 to 77 +/- 4 mm Hg) were observed on days 2-7 of
A-64662 infusion and PRA remained suppressed, ranging from 0.6 +/- 0.4 to 1.9 +/- 1.0 ng Ang I/ml/hr. Plasma
angiotensin II (Ang II) levels were reduced (p less than 0.05) from the control value of 66.7 +/- 20.2 to 12.4 +/- 3.3 and 26.4 +/- 6.5 pg/ml on the second and seventh days, respectively, of
A-64662 infusion. In contrast, infusion of vehicle alone had no discernible effect on mean arterial pressure, PRA, or plasma Ang II concentrations. Plasma
aldosterone decreased (p less than 0.05) from control on the second and third days of
A-64662 infusion, although differences between the treatment groups were not detected throughout the study. Urinary
sodium excretion remained at control levels throughout the infusion of
A-64662. Cessation of
A-64662 administration resulted in a recovery of mean arterial pressure to preinfusion levels within 1 day. This study indicates that continuous infusion of
A-64662 results in a sustained
hypotension in
sodium-depleted monkeys. This effect appears to be related, at least partially, to inhibition of PRA and lower plasma Ang II levels.