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

Attila Cziraki, James Parkerson, Lyle E Fisher, John D. Catravas

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

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 endothelial-bound 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 3H-Benzoyl-Phenylalanyl-Alanyl-Proline (BPAP), Doses of acutely administered trandolaprilat (8 μg/kg) or enalaprilat (10 μg/kg) were equieffective in reducing the presser 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.

Original languageEnglish (US)
Pages (from-to)22-30
Number of pages9
JournalDrug Development Research
Volume41
Issue number1
DOIs
StatePublished - May 1 1997

Keywords

  • ACE inhibitors
  • Angiotensin converting enzyme
  • Enalaprilat
  • Hypertension
  • Pulmonary capillary endothelium
  • Tissue ACE activity
  • Trandolaprilat

ASJC Scopus subject areas

  • Drug Discovery

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