Blood pressure lowering and renal hemodynamic effects of fosinopril in conscious animal models.

The blood pressure lowering and renal hemodynamic effects of fosinopril, the chemically novel inhibitor of angiotensin I converting enzyme (ACE), was assessed in conscious animal models. In conscious dogs, intravenous infusion of SQ 27,519 [0.5 mg/kg (1.1 mumol/kg) bolus plus 0.1 mg/kg/min (0.22 mumol/kg/min)], the active moiety of the prodrug fosinopril, increased PAH clearance and GFR by 25 and 16%, respectively (p less than 0.05, each) without changing arterial pressure (AP). Urine volume, sodium excretion, and potassium excretion were elevated, although not significantly increased. In sodium-depleted cynomolgus monkeys, 1.5 and 5.0 mumol/kg (0.88 and 2.9 mg/kg) p.o. of fosinopril lowered arterial pressure from 115 +/- 5 to 99 +/- 5 mm Hg and from 116 +/- 3 to 87 +/- 4 mmHg, respectively (p less than 0.05, each). When given orally to SHR at 10 and 30 mg/kg (5.9 and 17.6 mumol/kg), fosinopril lowered AP by 23 (183 +/- 4 to 160 +/- 5 mm Hg) and 20 mm Hg (176 +/- 4 to 156 +/- 4 mm Hg), respectively. The combination of fosinopril [10 mg/kg (5.9 mumol/kg)] plus hydrochlorothiazide (10 mg/kg) reduced AP from 206 +/- 4 to 167 +/- 2 mm Hg when given orally to SHR. Fosinopril was more effective in two-kidney, one-clip hypertensive rats relative to SHR; AP fell from 201 +/- 9 to 160 +/- 7 mm Hg after 10 mg/kg (5.9 mumol/kg), and from 205 +/- 7 to 145 +/- 7 mm Hg after 30 mg/kg (17.6 mumol/kg).(ABSTRACT TRUNCATED AT 250 WORDS)

Fosinopril, a phosphinic acid inhibitor of angiotensin I converting enzyme: in vitro and preclinical in vivo pharmacology.

Fosinopril is the first member of a new chemical class of angiotensin I (AI) converting enzyme (ACE) inhibitors, the phosphinic acids. In vitro, SQ 27,519, the active moiety of the prodrug fosinopril, was a more potent inhibitor of purified rabbit lung ACE- (IC50 = 11 vs. 23 nM) and bradykinin-induced contractions of guinea pig ileum than captopril. In vivo, SQ 27,519 was equipotent to captopril as an inhibitor of an AI pressor response after intravenous (i.v.) administration to conscious rats and monkeys but appeared to be less potent in conscious dogs. After oral administration, fosinopril again was equipotent to captopril as an inhibitor of an AI pressor response in rats and monkeys and slightly less potent in dogs. However, both SQ 27,519 (i.v. studies) and fosinopril (oral studies) had a longer effect than captopril in all three species. When fosinopril was administered orally for 5 days, its effects on an AI pressor response were the same on days 1 and 5, suggesting lack of tolerance to the compound. The ACE inhibitory effect of captopril, but not fosinopril, was prolonged in conscious rats with glycerol-induced acute renal failure, suggesting that fosinopril is excreted by an extrarenal route. Finally, fosinopril had no effect on the pressor or chronotropic effects of norepinephrine (NE) or 1,1-dimethyl-4-phenylpiperinium (DMPP) or electrical stimulation of the sympathetic ganglia of pithed rats. Fosinopril attenuated the pressor, but not the chronotropic effects of tyramine. We conclude that fosinopril is a potent and long-lasting inhibitor of ACE in conscious animal models that does not impair adrenergic function or reflexes.(ABSTRACT TRUNCATED AT 250 WORDS)