Renal hemodynamic and excretory responses to renin inhibition induced by A-64662.
Experiments were conducted in sodium-depleted anesthetized monkeys to determine the effects of the primate-selective renin inhibitor A-64662 on renal function. Five groups of monkeys were examined with each group receiving an i.v. infusion of vehicle or A-64662 at doses (bolus plus continuous infusion) of 0.1 + 0.01, 1.0 + 0.1, 10 + 1.0 or 100 micrograms/kg + 10 micrograms/kg/min (n = 6/dose). Plasma renin activity was inhibited (P less than .05) at all infusion doses ranging from 33 +/- 8% at the lowest dose to 95 +/- 3% at the highest dose. Inhibition of plasma renin activity was accompanied by renal vasodilation as renal blood flow (RBF) increased (P less than .05) in a dose-dependent manner beginning at the dose of 1.0 microgram/kg + 0.1 micrograms/kg/min. RBF increased 36 +/- 7% at the highest dose of A-64662 examined. Associated with the increments in RBF, renal vascular resistance progressively decreased (P less than .05) by 12 +/- 3, 31 +/- 3 and 40 +/- 6%, respectively, with increasing doses of A-64662. Glomerular filtration rate was unchanged at all doses of A-64662. As a result, a significant (P less than .05) fall in the filtration fraction was observed as the dose of A-64662 increased. Mean arterial pressure was unaffected by the two lowest doses of A-64662, but decreased (P less than 0.05) by 13 +/- 1 and 18 +/- 4 mm Hg, respectively, at the two highest doses of A-64662 infusion.(ABSTRACT TRUNCATED AT 250 WORDS)
Verburg
K M
KM
Cardiovascular Research Division, Abbott Laboratories, Abbott Park, Illinois.
Kleinert
H D
HD
Chekal
M A
MA
Kadam
J R
JR
Young
G A
GA
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004151:Dipeptides / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005919:Glomerular Filtration Rate / Q000187:drug effects; D007668:Kidney / Q000187:drug effects* / Q000502:physiology; D008252:Macaca fascicularis; D008297:Male; D012079:Renal Circulation / Q000187:drug effects; D012083:Renin / Q000097:blood; D012964:Sodium / Q000378:metabolism; D014655:Vascular Resistance / Q000187:drug effects; D000092502:Renin Inhibitors
D004151:Dipeptides; D012083:Renin; D012964:Sodium; D000092502:Renin Inhibitors; C056622:enalkiren