Comparisons in vitro, ex vivo, and in vivo of the actions of seven structurally diverse inhibitors of angiotensin converting enzyme (ACE).

Abstract

1. Seven drugs (captopril, zofenopril, enalapril, ramipril, lisinopril, fosinopril, and SQ 29,852) were compared in vitro in homogenates of aorta, brain, heart, lung, and kidney and in sera of spontaneously hypertensive rats (SHR) both with respect to potencies of their active moieties as inhibitors of angiotensin‐converting enzyme (ACE), and, where applicable, rates of hydrolysis of their prodrug ester functions. 2. In ex vivo dose‐response and time‐course studies, the inhibitory effects of the seven drugs on tissue ACEs and their relative distributions to SHR tissues were compared following oral administration. 3. The relative potencies of the inhibitory moieties of the drugs (in parentheses) and the normalized ‘equiactive’ oral doses employed for time‐course studies were: SQ 29,852 (1.0), 100 mg kg‐1; captopril (3.5), 30 mg kg‐1; enalapril (12), 20 mg kg‐1; fosinopril (13), 25 mg kg‐1; zofenopril (20), 10 mg kg‐1; lisinopril (24), 10 mg kg‐1; and ramipril (51), 5 mg kg‐1. 4. Following oral administration of the drugs to SHR, the degree and duration of ACE inhibition in aorta and lung correlated with the antihypertensive actions, with ramipril, lisinopril, and zofenopril producing effects of the greatest magnitude and duration. 5. Ramipril and enalapril did not inhibit brain ACE ex vivo; captopril and zofenopril had modest but short‐lasting effects; and fosinopril, lisinopril, and SQ 29,852 had long‐lasting inhibitory actions, which, with the latter two, were delayed in onset. 6. All of the drugs produced significant inhibition of kidney ACE, with ramipril and fosinopril having somewhat weaker effects, perhaps due to biliary routes of excretion. 7. Captopril, fosinopril, and particularly zofenopril inhibited cardiac ACE ex vivo with degrees and durations that were marked compared with those of the other drugs; preliminary studies with isolated hearts suggest a possible relationship between inhibition of cardiac ACE and preservation of cardiac function subsequent to ischaemia.

Targeting of Captopril to the Kidney Reduces Renal Angiotensin-Converting Enzyme Activity without Affecting Systemic Blood Pressure

“…filtration and tubular secretion (Kubo and Cody, 1985;Cushman et al, 1989). Since the conjugate displayed less plasma ACE inhibition but a similar or higher renal ACE inhibition than free captopril, the RSI of the conjugate was increased at all time points (significant from t ϭ 15 min).…”

Antirenin immunization versus angiotensin converting enzyme inhibition in rats.

“…27 - 28 However, it has been recently shown that brain ACE was not consistently decreased by most of the ACE inhibitors. 29 In addition, antirenin immunization also tended to increase the baroreceptor reflex sensitivity. Therefore, the differences observed between SHR-I and SHR-P could be due to the lower SBP of SHR-P, which allows in the measurement of the baroreceptor reflex sensitivity a greater proportion of the linear steep part of the relation between SBP and heart period to be studied.…”

ACE Inhibition Reduces Infarction in Normotensive but Not Hypertensive Rats: Correlation with Cortical ACE Activity

“…The two ACE inhibitors were selected because ramipril (1 mg/kg) is lipophilic and is thought to cross the blood-brain barrier, whereas lisinopril (10 mg/kg) is hydrophilic and is less likely to do so. The doses were selected as Cushman et al (1989) showed that they were normalized equivalent oral doses, and they have also been shown to induce renin-angiotensin system manipulation in the brain (Cushman et al, 1989;Lu et al, 2005;Sakaguchi et al, 1988). Separate cohorts received either 7 (short-term) or 42 days (long-term) of treatment until and including the day of surgery.…”