Acute and chronic effects of renin inhibitor GR70982 in the conscious marmoset.
The effects on plasma renin activity (PRA), mean arterial blood pressure (MABP) and heart rate (HR) of GR70982, a low molecular weight inhibitor of human renin, were studied in conscious marmosets. In vitro, GR70982 is a potent and selective inhibitor of human plasma renin (concentration producing 50% inhibition (IC50): human renin = 6.9 x 10(-9) M; porcine pepsin and bovine cathepin D = greater than 10(-3) M). In normotensive marmosets, i.v. GR70982 (0.001-0.1 mg kg-1) produced a dose-related inhibition of PRA. Larger oral doses (0.2, 1 and 5 mg kg-1) were required to achieve similar effects. In renin-dependent hypertensive marmosets, i.v. GR70982 (0.01 and 0.5 mg kg-1) produced dose-related decreases in MABP (-12 and -18 mm Hg) and PRA (-93 and -100%), with only minimal effects on HR. A 7-day continuous i.v. infusion of GR70982 (0.36 mg kg-1 day-1) in sodium-deplete marmosets produced a gradual decrease in MABP (-17 mm Hg at day 7, cf. control), accompanied by an inhibition of PRA (approximately 75%) and minimal HR effects.
Gardner
C J
CJ
Glaxo Group Research Ltd., Greenford, Middlesex, U.K.
Twissell
D J
DJ
Charlton
P A
PA
Cherry
P C
PC
D000284:Administration, Oral; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D002143:Callitrichinae; D003250:Constriction; D004151:Dipeptides / Q000494:pharmacology*; D005260:Female; D006339:Heart Rate / Q000187:drug effects*; D066298:In Vitro Techniques; D007262:Infusions, Intravenous; D008297:Male; D015394:Molecular Structure; D008970:Molecular Weight; D011480:Protease Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D012964:Sodium / Q000502:physiology; D013997:Time Factors; D000092502:Renin Inhibitors
D004151:Dipeptides; D011480:Protease Inhibitors; D011725:Pyridines; D012964:Sodium; D000092502:Renin Inhibitors; C069475:GR 70982