Inhibition of pulmonary endothelial angiotensin converting enzyme activity by trandolaprilat in vivo

✍ Scribed by Attila Cziraki; James Parkerson; Eugene Fisher; John D. Catravas

• Publisher: John Wiley and Sons
• Year: 1997
• Tongue: English
• Weight: 142 KB
• Volume: 41
• Category: Article
• ISSN: 0272-4391
• DOI: 10.1002/(sici)1098-2299(199705)41:1<22::aid-ddr3>3.0.co;2-u

✦ Synopsis

The purpose of the present study was to contrast a commonly used ACE inhibitor (enalaprilat) with a novel ACE inhibitor (trandolaprilat) in their ability to inhibit 1) pulmonary capillary endothelialbound ACE activity in vivo, 2) arterial pressure responses to i.v. angiotensin I and bradykinin, and 3) selected tissue ACE activity ex vivo, in rabbits. Pulmonary capillary endothelium-bound ACE activity in vivo was estimated via the single pass transpulmonary hydrolysis of the substrate 3 H-Benzoyl-Phenylalanyl-Alanyl-Proline (BPAP). Doses of acutely administered trandolaprilat (8 µg/kg) or enalaprilat (10 µg/kg) were equieffective in reducing the pressor response to angiotensin I. At these doses, trandolaprilat produced a greater inhibition of pulmonary capillary endothelial-bound ACE activity (66.5 ± 4.7% reduction of baseline BPAP metabolism vs. 52.7 ± 4.2% by enalaprilat, P < 0.05). Chronically administered trandolaprilat (8 µkg/ day for 8 days) was more effective than enalaprilat (either 8 µg/kg/day or 10 µg/kg/day for 8 days) in reducing the angiotensin-1 induced increase in mean arterial 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 activities in the aorta, left ventricle, and lung, respectively. We conclude that trandolaprilat is a more potent, longer acting, and more tissue-selective ACE inhibitor than enalaprilat, and that the method outlined here can be used to aid in the development of tissue-specific ACE inhibitors. Drug Dev. Res.