Received for publication December 10, 2003.
Revised February 6, 2004.
Accepted for publication February 9, 2004.

The Effect of Acute Angiotensin Converting Enzyme (ACE) and Neutral Endopeptidase 24.11 (NEP) Inhibition on Plasma Extravasation in the Rat

Abstract

The effect of ACE and NEP inhibition on microvascular plasma leakage (extravasation) was evaluated in a rat model. Progressive inhibition of ACE using captopril caused increased extravasation when lung ACE was inhibited by >55%. In contrast, the selective inhibition of renal NEP by >90% using ecadotril did not increase extravasation. In NEP inhibited rats, extravasation produced by the ACE inhibitors, captopril and lisinopril, was markedly enhanced. The dual ACE and NEP inhibitor, omapatrilat, at oral doses of 0.03, 0.1 and 0.3 mg/kg, selectively inhibited lung ACE by 19, 61 and 76%, respectively, and did not cause significant extravasation. Doses of 1 and 10 mg/kg of omapatrilat which produced >90% inhibition of ACE and also inhibited renal NEP by 54 and 78%, respectively, significantly increased extravasation. In this model, bradykinin and Substance P produced extravasation which could be abolished by the bradykinin 2 (B2) receptor antagonist, Hoe 140, or the neurokinin1 (NK1) antagonist, CP99994, respectively. Bradykinin induced extravasation was also partially (~40%) inhibited by CP99994, indicating that a portion of the response involves B2 receptor-mediated release of Substance P. In conclusion this study is the first to relate the degree of ACE and/or NEP inhibition to extravasation liability in the rat model. Our data clearly demonstrate that ACE inhibitor-induced plasma extravasation is enhanced by concomitant inhibition of NEP. In addition, this study provides further evidence for the role for B2 and NK1 receptors in mediating plasma extravasation in the rat.

Key words: Substance P, angioedema, angiotensin converting enzyme, bradykinin, extravasation, neutral endopeptidase

This article has been cited by other articles:

				J. B. Byrd, K. Touzin, S. Sile, J. V. Gainer, C. Yu, J. Nadeau, A. Adam, and N. J. Brown Dipeptidyl Peptidase IV in Angiotensin-Converting Enzyme Inhibitor Associated Angioedema Hypertension, January 1, 2008; 51(1): 141 - 147. [Abstract] [Full Text] [PDF]

				A. C. Sulpizio, M. A. Pullen, R. M. Edwards, J. B. Louttit, R. West, and D. P. Brooks Mechanism of Vasopeptidase Inhibitor-Induced Plasma Extravasation: Comparison of Omapatrilat and the Novel Neutral Endopeptidase 24.11/Angiotensin-Converting Enzyme Inhibitor GW796406 J. Pharmacol. Exp. Ther., December 1, 2005; 315(3): 1306 - 1313. [Abstract] [Full Text] [PDF]

				L. M. F. Leeb-Lundberg, F. Marceau, W. Muller-Esterl, D. J. Pettibone, and B. L. Zuraw International Union of Pharmacology. XLV. Classification of the Kinin Receptor Family: from Molecular Mechanisms to Pathophysiological Consequences Pharmacol. Rev., March 1, 2005; 57(1): 27 - 77. [Abstract] [Full Text] [PDF]