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Effects of the Oral Converting Enzyme Inhibitor, SQ 14225, in a Model of Low Cardiac Output in Dogs

Dogs with thoracic caval constriction retain sodium and develop ascites and edema. The role of the renin-angiotensin-aldosterone system in this model of low output failure was evaluated before, during, and after administration of the new orally active converting enzyme inhibitor, 2-D-methyl-3-mercaptopropanoyl-L-proline (SQ 14225). The acute response to the initial oral dose of SQ 14225 (10 mg/kg) consisted of a striking fall in plasma aldosterone concentration (PAC) from 22.7 and 29.9 ng% to 10.7, 11.9, and 11.0 ng% (P < 0.05) after 67.5, 112.5, and 157.5 minutes; sodium excretion increased from 1.9 and 1.9 μEq/min to 19.9, 22.4, and 17.8 μEq/min. Arterial pressure and filtration fraction decreased (P< 0.05), and plasma renin activity (PRA) increased (P < 0.05) after the initial dose of SQ 14225; clearance of para-aminohippuric acid (PAH) and creatinine did not change significantly. The daily responses for 3-4 days to SQ 14225 (35 mg/kg per day, given as doses of 10,10, and 15 mg/kg) were a decrease in PAC from 50 ± 15 and 32 ± 10 ng% to 10 ± 4 ng% on the 4th day, a value not statistically different from normal (P > 0.05), and an increase in sodium excretion from 2.9 to 2.0 mEq/ day to 5.7, 10.0, 32.4, and 32.9 mEq/day on a sodium intake of 35 mEq/day (P < 0.05 for the last 2 days). Arterial pressure and creatinine clearance decreased (P < 0.05). PRA increased transiently on day 1 of SQ 14225 and then returned toward control levels, and clearance of PAH was unchanged. These data demonstrate an important role for aldosterone and the renin-angiotensin system in the retention of sodium and in ascites formation in dogs with thoracic caval constriction. Circ Res. 45: 540-545, 1979