Effects of chronic infusion of renin inhibitor A-64662 in sodium-depleted monkeys.
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.
Verburg
K M
KM
Cardiovascular Research Division, Abbott Laboratories, Abbott Park, Illinois 60064.
Kleinert
H D
HD
Kadam
J R
JR
Chekal
M A
MA
Mento
P F
PF
Wilkes
B M
BM
D000450:Aldosterone / Q000097:blood; D000804:Angiotensin II / Q000097:blood; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004039:Diet, Sodium-Restricted; D004151:Dipeptides / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects; D007022:Hypotension / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D007262:Infusions, Intravenous; D008252:Macaca fascicularis; D008297:Male; D012083:Renin / Q000097:blood; D012084:Renin-Angiotensin System / Q000187:drug effects; D012964:Sodium / Q000032:analysis / Q000172:deficiency*; D013997:Time Factors; D000092502:Renin Inhibitors
D000450:Aldosterone; D000804:Angiotensin II; D004151:Dipeptides; D012083:Renin; D012964:Sodium; D000092502:Renin Inhibitors; C056622:enalkiren