Differential angiotensin-converting enzyme inhibition in brain after oral administration of perindopril demonstrated by quantitative in vitro autoradiography.
To help elucidate potential sites for the central actions of a new angiotensin-converting enzyme (ACE) inhibitor, perindopril, ACE levels were measured in the brain of Sprague-Dawley rats by quantitative in vitro autoradiography after administration of the drug. Following acute oral administration of 1 mg/kg perindopril, ACE in the two circumventricular organs, the subfornical organ and organum vasculosum of the lamina terminalis, was markedly inhibited and had only partially recovered after 24 h. The ACE inhibition in the circumventricular organs did not correlate with the inhibition of ACE in plasma but with that of pressor response to intravenous angiotensin I. No or little change in ACE was observed in other brain structures which are rich in the enzyme, including the choroid plexus and basal ganglia. However, large doses of perindopril (up to 16 mg/kg) did progressively inhibit ACE in all brain structures measured, including the basal ganglia. These findings fit with the deficient blood-brain barrier known to occur in the circumventricular organs. These regions are rich in ACE and angiotensin II receptors and exhibit physiological responses to angiotensin II with effects on fluid, electrolyte, and blood pressure homeostasis. Combined with current observations, the circumventricular organs are potential targets for the centrally mediated actions of ACE inhibitors.
Sakaguchi
K
K
University of Melbourne, Department of Medicine, Austin Hospital, Heidelberg, Vic., Australia.
Chai
S Y
SY
Jackson
B
B
Johnston
C I
CI
Mendelsohn
F A
FA
D000803:Angiotensin I / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors; D000818:Animals; D001345:Autoradiography; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000201:enzymology*; D007031:Hypothalamus / Q000201:enzymology; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D007703:Peptidyl-Dipeptidase A / Q000097:blood / Q000378:metabolism*; D020913:Perindopril; D051381:Rats; D011919:Rats, Inbred Strains; D013356:Subfornical Organ / Q000201:enzymology
D000806:Angiotensin-Converting Enzyme Inhibitors; D007211:Indoles; D000803:Angiotensin I; D007703:Peptidyl-Dipeptidase A; D020913:Perindopril