ESTIMATION OF THE DISSOCIATION-CONSTANTS FOR PULMONARY ENDOTHELIAL ANGIOTENSIN-CONVERTING ENZYME-REACTIONS WITH TRANDOLAPRILAT AND ENALAPRILAT IN-VIVO

We estimated the activity of pulmonary capillary endothelium-bound (PC EB) angiotensin converting enzyme (ACE) in the rabbit in vivo, before and at 20 min and 2 h postadministration of the ACE inhibitors trandol aprilat (8 mu g/kg) and enalaprilat (10 mu g/kg), alone and in combina tion with the calcium channel blocker verapamil (100 mu g/kg). PCEB AC E activity was assessed from the single-pass transpulmonary hydrolysis of the synthetic substrate H-3-benzoyl-Phe-Ala-Pro (BPAP). We then ca lculated the modified kinetic parameter A(max)/K-m and the dissociatio n constants (k(-1)) of the two inhibitors from PCEB ACE. Trandolaprila t reduced PCEB ACE activity less than enalaprilat, but its action was more sustained. Verapamil did not influence the immediate inhibitory a ction of either inhibitor. Enalaprilat exhibited more than a threefold higher k(-1) than trandolaprilat from PCEB ACE (77.9 +/- 9.2 vs. 25.2 +/- 4.3 x 10(-5)/sec). Go-injection of verapamil did not significantl y affect the k(-1) of enalaprilat (86.3 +/- 5.2 x 10(-5)/sec) but mode rately increased that of trandolaprilat (45.2 +/- 6 x 10(-5)/sec). We conclude that 1) trandolaprilat confers a longer-lasting enzyme inhibi tion than enalaprilat, and 2) although the trandolaprilat-verapamil tr eatment moderately reduces the duration of the trandolaprilat-induced inhibition, it still offers a longer enzyme inhibition than enalaprila t alone or in combination with verapamil. Drug Dev. Res. 44:80-86, 199 8. (C) 1998 Wiley-Liss, Inc.