Central cardiovascular effects of SQ 14,225, an angiotensin-converting enzyme inhibitor in chloralose-anesthetized cats

Abstract

Experiments were conducted in chloralose-anesthetized cats to investigate the central and peripheral cardiovascular effects of a new orally active angiotensin-converting inhibitor, SQ 14,225 (3-mercapto-2-D-methylpropanoyl-L-proline). I.v. administration of SQ 14,225 (0.31-3100 microgram/kg) antagonized the pressor responses to angiotensin I (AI) (310 ng/kg) i.v. in a dose-related manner but did not alter responses to angiotensin II (AII) (200 ng/kg) i.v. Similarly, intracerebroventricularly (i.c.v.) administered SQ 14,225 (0.31-310 microgram/kg perfused over 10 min) produced dose-related decreases in the centrally mediated pressor responses and heart increases elicited by AI (310 ng/kg) i.c.v. The central responses to AII (200 ng/kg) i.c.v. were not affected by SQ 14,225. Passage of SQ 14,225 out of the ventricular system into the systemic circulation was detected, but only at doses greater than that required to antagonize central AI responses. Doses of SQ 14,225 (310 microgram/kg and 3.1 mg/kg) i.v. which maximally inhibited i.v. AI responses, had no effect upon central AI activity. This finding suggests that passage of SQ 14,225 across the blood brain barrier into the central nervous system is restricted. Peripheral or central administration of SQ 14,225 produced only minimal transient decreases in blood pressure (less than 10 mm Hg). The results of these studies indicate that SQ 14,225 is a potent inhibitor of AI conversion in the brain as well as in the peripheral circulation.