Do different ACE inhibitors exhibit selective inhibition of ACE in physiologically important target organs in spontaneously hypertensive rats?
ACE inhibitors exhibit distinct tissue-specific profiles of ACE inhibition in spontaneously hypertensive rats despite equivalent serum ACE inhibition, suggesting potential differences in organ-specific effects.
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.
Cushman et al. (1989) studied this question.