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-cilazapril evoked the same maximum degree of plasma ACE inhibition (-76%) in the rat as 0.25 mg kg-1 enalapril. Cilazapril (0.25 mg kg-' p.o.) inhibited plasma ACE by > 95%. The rate of recovery of ACE activity was slower with cilazapril (5-6% h-1) than with enalapril (10% h'-). 3 In anaesthetised rats cilazaprilat was equipotent with ramiprilat and slightly more potent (1.5 x) 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 2-4.5 x more potent than enalapril as an ACE inhibitor. 5 In cats cilazapril (0.1 and 0.3 mg kg-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 : 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).

Lipopolysaccharides decrease angiotensin converting enzyme activity expressed by cultured human endothelial cells

“…However, ACE inhibitors substantially decrease blood pressure and total peripheral vascular resistance in normal subjects who are Na+ depleted andlor hypovolemic because their renin-angiotensin system is activated (Atlas et al, 1983). Inhibition of ACE activity by ACE inhibitors dose-dependently suppresses angiotensin I-induced increases in blood pressure in normal subjects, and the extent of the suppression is highly correlated with suppression of plasma ACE activity; in normal subjects a concentration of ACE inhibitor that decreased plasma ACE activity by 75% decreased the blood pressure response to angiotensin I infusion by =60%, thus demonstrating equivalent suppressive effects of ACE inhibitors on plasma and vascular ACE activities (Essig et al, 1989;Massarella et al, 1989;Waterfall, 1989). Since septic shock with endotoxemia decreases renal perfusion pressure and elevates renin and angiotensin I production, inhibition by LPS of vascular ACE activity by 75% should decrease angiotensin I1 production by a similar amount and thus could contribute to the hypotension associated with sepsis.…”

Characterisation of cancer stem cells and the renin-angiotensin system in colon adenocarcinoma

“…When administered as cilazapril, the bioavailability of the resulting cilazaprilat is approximately 57% (Waterfall, 1989). It is more potent than captopril and has better absorption following oral administration (Waterfall, 1989). Cilazaprilat remains active in the plasma for up to 8 h, where it binds ACE with high specificity (Fasanella d'Amore et al, 1987).…”

Therapeutic Peptides as Emerging Options to Restore Misguided Host Defence and Homeostasis: From Teaching to Concept to Clinic

“…2). [12] The communication of the results to the next class of students allows for an iterative improvement of the design strategy.…”