INHIBITION OF PULMONARY ENDOTHELIAL ANGIOTENSIN-CONVERTING ENZYME-ACTIVITY BY TRANDOLAPRILAT IN-VIVO

The purpose of the present study was to contrast a commonly used ACE i nhibitor (enalaprilat) with a novel ACE inhibitor (trandolaprilat) in their ability to inhibit 1) pulmonary capillary endothelial-bound ACE activity in vivo, 2) arterial pressure responses to i.v. angiotensin 1 and bradykinin, and 3) selected tissue ACE activity ex vivo, in rabbi ts. Pulmonary capillary endothelium-bound ACE activity in vivo was est imated via the single pass transpulmonary hydrolysis of the substrate H-3-Benzoyl-Phenylalanyl-Alanyl-Proline (BPAP). Doses of acutely admin istered trandolaprilat (8 mu g/kg) or enalaprilat (10 mu g/kg) were eq uieffective in reducing the presser response to angiotensin 1. At thes e doses, trandolaprilat produced a greater inhibition of pulmonary cap illary endothelial-bound ACE activity (66.5 +/- 4.7% reduction of base line BPAP metabolism vs. 52.7 +/- 4.2% by enalaprilat, P < 0.05). Chro nically administered trandolaprilat (8 mu kg/ day for 8 days) was more effective than enalaprilat (either 8 mu g/kg/day or 10 mu g/kg/day fo r 8 days) in reducing the angiotensin-1 induced increase in mean arter ial pressure (increases of 9.7 +/- 1.4 mmHg vs. 20.3 +/- 2.3 mmHg and 19.1 +/- 5.7 mmHg respectively; P< 0.01), as well as in reducing BPAP metabolism. in agreement with in vivo data, trandolaprilat was 5.5-, 3 .6-, and 2.5-times more effective than enalaprilat in reducing ACE act ivities in the aorta, left ventricle, and lung, respectively We conclu de that trandolaprilat is a more potent, longer acting, and more tissu e-selective ACE inhibitor than enalaprilat, and that the method outlin ed here can be used to aid in the development of tissue-specific ACE i nhibitors. (C) 1997 Wiley-Liss, Inc.