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Estimation of the dissociation constants for pulmonary endothelial angiotensin converting enzyme reactions with trandolaprilat and enalaprilat in vivo
Author(s) -
Orfanos Stylianos E.,
Parkerson James,
Fisher Eugene,
Catravas John D.
Publication year - 1998
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/(sici)1098-2299(199806/07)44:2/3<80::aid-ddr5>3.0.co;2-6
Subject(s) - enalaprilat , verapamil , chemistry , angiotensin converting enzyme , enzyme inhibitor , dissociation constant , ace inhibitor , in vivo , enzyme , pharmacology , ramipril , medicine , endocrinology , biochemistry , calcium , receptor , biology , blood pressure , microbiology and biotechnology , organic chemistry
We estimated the activity of pulmonary capillary endothelium‐bound (PCEB) angiotensin converting enzyme (ACE) in the rabbit in vivo, before and at 20 min and 2 h postadministration of the ACE inhibitors trandolaprilat (8 μg/kg) and enalaprilat (10 μg/kg), alone and in combination with the calcium channel blocker verapamil (100 μg/kg). PCEB ACE activity was assessed from the single‐pass transpulmonary hydrolysis of the synthetic substrate 3 H‐benzoyl‐Phe‐Ala‐Pro (BPAP). We then calculated the modified kinetic parameter A max / Km and the dissociation constants (k ‐1 ) of the two inhibitors from PCEB ACE. Trandolaprilat reduced PCEB ACE activity less than enalaprilat, but its action was more sustained. Verapamil did not influence the immediate inhibitory action 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 × 10 –5 &sol/sec). Co‐injection of verapamil did not significantly affect the k ‐1 of enalaprilat (86.3 ± 5.2 × 10 –5 /sec) but moderately increased that of trandolaprilat (45.2 ± 6 × 10 –5 /sec). We conclude that 1) trandolaprilat confers a longer‐lasting enzyme inhibition than enalaprilat, and 2) although the trandolaprilat‐verapamil treatment moderately reduces the duration of the trandolaprilat‐induced inhibition, it still offers a longer enzyme inhibition than enalaprilat alone or in combination with verapamil. Drug Dev. Res. 44:80–86, 1998. © 1998 Wiley‐Liss, Inc.