Differentiation of Angiotensin–Converting Enzyme (ACE) Inhibitors by Their Selective Inhibition of ACE in Physiologically Important Target Organs

Abstract

Seven ACE inhibitors were studied for possible differences in distribution to aorta, brain, heart, lung, and kidney after administration of single oral doses to spontaneously hypertensive rats (SHR). Doses, normalized for differences in inhibitory potency and molecular weight, were expected to deliver equivalent levels of ACE-inhibitory activity to the circulation, and this was confirmed by preliminary dose-response studies. The relative potencies of the active moieties of the seven drugs and the normalized oral doses used were: SQ 29,852 (1.0), 100 mg/kg; captopril (3.5), 30 mg/kg; enalapril (12), 20 mg/kg; fosinopril (13), 25 mg/kg; zofenopril (20), 10 mg/kg; lisinopril (24), 10 mg/kg; and ramipril (51), 5 mg/kg. In these ex vivo studies, ACE activities were determined fluorometrically in SHR sera and in uncentrifuged homogenates of the solid tissues at various times after oral dosing with the ACE inhibitors. As expected, the normalized oral doses of the seven inhibitors had equivalent effects on serum ACE. In lung, where ACE has a vascular endothelial localization, and in aorta, where ACE inhibition correlates with antihypertensive action, ramipril, lisinopril, and zofenopril were distinguished by the magnitude and duration (three to four days) of their effects. In the brain, where ACE may affect central regulation of blood pressure and participate in the degradation of certain neuropeptides, ramipril and enalapril had no effect; captopril and zofenopril had modest, short-lasting effects, and fosinopril, lisinopril, and SQ 29,852 had delayed but long-lasting inhibitory actions. In the kidney, where ACE inhibition may have positive or negative effects on renal function, ramipril and fosinopril could be distinguished by their weak actions, perhaps associated with biliary routes of excretion. In the heart, where ACE inhibitors may prevent ischemic damage to the myocardium, single oral doses of captopril, fosinopril, and particularly zofenopril produced striking and long-lasting inhibition, whereas equivalent doses of ramipril and enalapril produced barely detectable inhibition.

Angiotensin-converting enzyme inhibitors and incidence of mild cognitive impairment. The Italian Longitudinal Study on Aging

“…However, the cognitive outcomes were defined differently in the CHS (incident dementia, cognitive decline, or disability) (Sink et al 2009) and in the ILSA (incident MCI). Furthermore, conflicting evidence exists around the central action of lisinopril (Jackson et al 1987;Cushman et al 1989;Furberg and Pitt 2001) and ramipril (Furberg and Pitt 2001;Jouquey et al 1995). Clearly, the classification by either chemical structure or BBB penetrability has some limitations.…”

“…Indeed, in some cases, these drugs are not only structurally similar but have similar potency (e.g., IC 50 on ACE0enalapril 1.9 nM and lisinopril 1.5 nM) (Brown and Vaughan 1998). However, some studies have sub-grouped these drugs for analytical purposes according to their penetrance of the blood brain barrier (BBB) which would be expected to be important for diseases such as AD, but there are conflicting reports on the penetration of some ACE-Is (Jackson et al 1987;Gohlke et al 1989;Cushman et al 1989;Tan et al 2005), questioning the validity of this manner of sub-grouping ). Instead, in the present study, we opted to subgroup drugs according to their chemical structures, which offers less ambiguity in some respects, although the potential for differential pharmacological profiles remains (Thind 1990;Ranadive et al 1992).…”

Combination antihypertensive therapy in patients with arterial hypertension and coronary heart disease

“…Это высокая липофильность, высокое сродство к тканевой РААС и, как следствие, выраженное и продолжительное ингибирование АПФ в периферических тканях и в сердце, а значит, продолжительный антиише-мический, а также органопротективный эф фекты. Особое значение имеет сульфгидрильная SH-группа, наличие которой снижает превращение NO в эндогенный оксидант пероксинитрит и продук-цию эндотелина-1 [9,10]. Последний, как маркер эндотелиальной дисфункции, имеет важное про-гностическое значение при сердечно-сосудистых заболеваниях.…”

Early initiation of ACE inhibitor treatment after acute myocardial infarction - a missed therapeutic opportunity?

“…The high incidence of severe hypotension in these studies may have been exaggerated by reperfusion injury associated with thrombolytic treatment, not administered to patients participating in the SMILE study. Alternatively, beneficial ancillary properties of zofenopril, such as high selectivity of myocardial tissue uptake, 33 may have made an important contribution to the favourable blood pressure profile found in SMILE. This may become clearer when the results of SMILE-2 are available; this is a randomised, double-blind outcome study of early intervention with zofenopril or lisinopril after myocardial infarction in patients eligible to receive thrombolytic and other secondary prevention treatment.…”