A review of the preclinical cardiovascular pharmacology of cilazapril, a new angiotensin converting enzyme inhibitor.

Abstract

1. Cilazapril is the monoethyl ester prodrug form of the di-acid cilazaprilat, a new angiotensin converting enzyme (ACE) inhibitor. Cilazaprilat has an IC50 of 1.9 nM as an inhibitor of rabbit lung ACE in vitro making it one of the most potent ACE inhibitors currently available. Studies on a wide range of other enzymes show that the inhibition is highly specific. 2. An oral dose of 0.1 mg kg-1 cilazapril evoked the same maximum degree of plasma ACE inhibition (approximately 76%) in the rat as 0.25 mg kg-1 enalapril. Cilazapril (0.25 mg kg-1 p.o.) inhibited plasma ACE by greater than 95%. The rate of recovery of ACE activity was slower with cilazapril (5-6% h-1) than with enalapril (10% h-1). 3. In anaesthetised rats cilazaprilat was equipotent with ramiprilat and slightly more potent (1.5x) than enalaprilat as an inhibitor of the angiotensin I pressor response. 4. Following oral administration to conscious rats and intravenous administration to anaesthetised dogs, cilazapril was 2-4.5x more potent than enalapril as an ACE inhibitor. 5. In cats cilazapril (0.1 and 0.3 mg kg-1 p.o.) dose dependently decreased plasma ACE activity and the angiotensin pressor response. Peak effects occurred at 2 h after dosing and plasma ACE inhibition was maintained at greater than or equal to 50% for up to 18 h. Mean arterial pressure was also decreased dose dependently with a peak effect at 3-4 h. 6. Daily oral dosing of cilazapril (30 mg kg-1 p.o.) to spontaneously hypertensive rats evoked a progressive and prolonged (24 h) antihypertensive response with a maximum decrease in systolic blood pressure of 110 mm Hg. 7. Cilazapril (10 mg kg-1 p.o. twice daily for 3.5 days) progressively decreased blood pressure in volume depleted renal hypertensive dogs. The maximum fall in systolic pressure was 39 +/- 6 mm Hg. 8. Haemodynamic studies in open chest anaesthetised dogs showed that the hypotensive response to intravenous cilazapril was accompanied by a reduction in total peripheral resistance. Small decreases in cardiac output and myocardial contractile force were seen at high doses. 9. Cilazapril had no adverse effect on cardiovascular reflexes. There was no impairment of the baroreflex in rats. Exercise-induced tachycardia and pressor responses in conscious cats were unchanged. 10. Cilazapril is exceptionally well absorbed by the oral route (98% in rats).