The Effect of Acute Angiotensin-Converting Enzyme and Neutral Endopeptidase 24.11 Inhibition on Plasma Extravasation in the Rat

Abstract

The effect of angiotensin-converting enzyme (ACE) and neutral endopeptidase (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 Ͼ55%. In contrast, the selective inhibition of renal NEP by Ͼ90% 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 omapatrilat, which produced Ͼ90% 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 that could be abolished by the bradykinin 2 (B2) receptor antagonist Hoe 140 (icatibant) or the neurokinin1 (NK1) antagonist CP99994 [(ϩ)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine], respectively. Bradykinin induced extravasation was also partially (ϳ40%) 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.Since their introduction nearly three decades ago, the angiotensin I-converting enzyme inhibitors (ACEIs) have become one of the more effective and highly used treatments for hypertension and heart failure. The therapeutic efficacy of these agents is derived in large part from their ability to inhibit the conversion of angiotensin I to angiotensin II, a vasoactive peptide whose direct vasoconstrictor and aldosterone-releasing actions promote increased blood pressure. There are some data to suggest that part of the therapeutic effect of these agents may be due to decreased breakdown of bradykinin (BK), which is also a substrate for ACE (Bao et al., 1992;Linz and Schölkens, 1992;Linz et al., 1995). In an attempt to provide even greater antihypertensive efficacy, efforts have been directed toward developing vasopeptidase inhibitors (VPI) that block not only ACE but also neutral endopeptidase (NEP). Inhibition of NEP should confer additional cardiovascular benefit by virtue of enhancing the hemodynamically favorable actions of the atrial natriuretic peptides, which are substrates for NEP (Robl et al., 1997;Burnett, 1999;Weber, 2001). Data from animal studies have indicated that the VPI omapatrilat does indeed confer greater cardiovascular benefit than ACE inhibitors alone (Trippodo et al., 1998;Bä cklund et al., 2001;Pu et al....

Mechanism of Vasopeptidase Inhibitor-Induced Plasma Extravasation: Comparison of Omapatrilat and the Novel Neutral Endopeptidase 24.11/Angiotensin-Converting Enzyme Inhibitor GW796406

“…We have demonstrated that captopril-induced plasma extravasation in this model was enhanced by concomitant inhibition of NEP (Sulpizio et al, 2004). These findings seem consistent with the report that C1 inhibitor deficiency in humans leads to spontaneous angioedema (Markovic et al, 2000).…”

“…Thus, it was evident that, for some unexplained reason, GW796406 had inherently less liability to increase extravasation than did omapatrilat. Interestingly, GW796406 also had less liability to increase extravasation than did combinations of ACEIs and ecadotril, which significantly increased plasma extravasation in spite of much lower levels of ACE inhibition than that produced by GW796406 (Sulpizio et al, 2004). This difference between the two agents was not observed at the higher dose regimen.…”

“…The observation that GW796406 when administered at the low-dose infusion protocol did not increase plasma extravasation in spite of profound inhibition of ACE and NEP was interesting since we previously reported that ecadotril, an NEP inhibitor, markedly worsened the extravasation liability of the selective ACE inhibitors captopril and lisinopril (Sulpizio et al, 2004). To investigate whether, under conditions of NEP inhibition comparable with that produced by GW796406, omapatrilat also remained free of extravasation liability, we tested omapatrilat in rats pretreated with a highly efficacious dose of ecadotril.…”

Dual ACE/NEP inhibitors – more than playing the ACE card

“…This effect has been attributed to firstly the rapid increase in bradykinin and its metabolite BK-8 by simultaneously blocking both BK degrading pathways and secondly by potentially a direct effect of the agent to promote extravasation. 13 Based on these findings and, in particular, the incidence of this potentially life threatening side effect it appears unlikely that omapatrilat will become routine medication for hypertension, especially in the Afro-American population.…”

“…Indeed, omapatrilat has recently been shown to induce extravasation in high doses. 13 As the various ACE/NEP inhibitors differ in their ability and relative potency to inhibit ACE versus NEP this may not only influence the magnitude of kinin production but also the antihypertensive, cardio vascular and antifibrotic effects.…”