Effect of acute and chronic administration of ceronapril on angiotensin converting enzyme in plasma, kidney, lung, brain regions and cerebrospinal fluid of rats

Abstract

Angiotensin converting enzyme (ACE) in brain, cerebrospinal fluid (C.S.F.) and peripheral tissues was studied ex vivo after oral administration of ceronapril (SQ 29,852) to male Sprague-Dawley rats. Angiotensin converting enzyme in tissue was measured by in vitro autoradiography or enzymatic assay. In in vitro experiments, ceronapril inhibited ACE in slices of brain with an IC 50, of approximately 34 nM, as measured by in vitro autoradiography. In C.S.F. ACE was inhibited with an IC 50, of approximately 34 nM, as assessed by a fluorimetric enzyme assay. Ceronapril (1OO mg/kg, p.o.) inhibited ACE in plasma, kidney and lung rapidly (3hr) after administration. Inhibition of ACE in kidney lasted up to 48 hr after administration of ceronapril, whereas the activity of ACE in plasma and lung recovered rapidly (8 hr). In lung and plasma ACE was increased at 72 hr after administration. Therefore, induction of ACE in plasma and lung by the drug may partly obscure the acute inhibition and may contribute to the different time-course of inhibition of ACE from kidney. Ceronapril inhibited ACE in vascular organ of the lamina terminals (OVLT) and subfornical organ (SFO) of the brain slowly (onset at 8 hr) but persistently (from 24 to 48 hr). However the drug did not inhibit ACE in structures of the brain within the blood-brain barrier, such as the caudate-putamen, choroid plexus, globus pallidus, supraoptic nucleus and paraventricular nucleus of the hypothalamus. In C.S.F. ACE was not detectably inhibited by ceronapril but was increased at 72 hr. After chronic treatment with ceronapril (100 mg/kg, p.o., twice daily), the results were similar to those seen in the acute experiments, with clear inhibition of ACE in the 2 circumventricular organs-the subfornical organ and the lamina terminals-but no change in other regions of the brain. Also, as in the acute experiments, no inhibition of ACE in C.S.F, was detected. These results show that ceronapril blocked ACE in peripheral sites acutely after a single dose. A slower onset, but more persistent, blockade of ACE occurred in the circumventricular organs of the brain. However, the drug did not appear to accumulate in brain tissue, within the blood-brain barrier or in C.S.F. Reports that very small doses of ceronapril might exert cognitive-enhancing effects in rats seem unlikely to be explained by accumulation of the drug in structures of the brain within the blood-brain barrier.