Blood Pressure Lowering and Renal Hemodynamic Effects of Fosinopril in Conscious Animal Models

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Abstract
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 .mu.mol/kg) bolus plus 0.1 mg/kg/min (0.22 .mu.mol/kg/min)], the active moiety of the prodrug fosinopril, increased PAH clearance and GFR by 25 and 16%, respectively (p < 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 .mu.mol/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 < 0.05, each). When given orally to SHR at 10 and 30 mg/kg (5.9 and 17.6 .mu.mol/kg), fosinopril lowered AP by 23 (183 .+-. 4 to 160 .+-. 5 mmHg) and 20 mm Hg (176 .+-. 4 to 156 .+-. 4 mm Hg), respectively. The combination of fosinopril [10 mg/kg (5.9 .mu.mol/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 .mu.mol/kg), and from 205 .+-. 7 to 145 .+-. 7 mm Hg after 30 mg/kg (17.6 .mu.mol/kg). In DOCA/Salt hypertensive rats, AP fell by only 11 mm Hg after 30 mg/kg (17.6 .mu.mol/kg), a fall that was not statistically different from vehicle-treated DOCA/Salt rats (-9 mm Hg.). Finally, in a high renin model of primate hypertension (bilateral perinephritis), fosinopril [15 .mu.mol/kg (8.8 mg/kg) p.o.] lowered AP from 148 .+-. 3 to 117 .+-. 5 mm Hg (p < 0.05). It is concluded that fosinopril is an effective blood pressure lowering agent in hypertensive and sodium-depleted monkeys and several experimental murine models of hypertension. Fosinopril also increased renal hemodynamic function in normotensive, conscious, sodium-replete dogs.