NEUTRAL ENDOPEPTIDASE MODULATES VIP-INDUCED VASODILATION IN HAMSTER-CHEEK POUCH VESSELS IN-SITU

The purpose of this study was to determine whether vasoactive intestin al peptide (VIP) dilates resistance arterioles in the in situ systemic circulation and whether inhibitors of neutral endopeptidase (NEP) and angiotensin I-converting enzyme (ACE), two membrane-bound metalloenzy mes that are widely distributed in the microcirculation and cleave and inactivate VIP, potentiate this response. Using intravital microscopy , we found that VIP (0.05 and 0.1 nmol) induced significant vasodilati on in the hamster cheek. pouch (13 +/- 1 and 20 +/- 2% increase from b aseline, respectively; mean +/- SE; P < 0.05). These responses were si gnificantly potentiated by topical application of phosphoramidon and t hiorphan, two relatively selective NEP inhibitors, but not by captopri l, a relatively selective ACE inhibitor. Furthermore, suffusion of a m ixture of proteinase inhibitors consisting of leupeptin, Bestatin, and DL-2-mercaptomethyl-3-guanidinoethylthiopropanoic acid to inhibit ser ine proteinases, including mast cell tryptase, aminopeptidases, and ca rboxypeptidase N, respectively, had no significant effects on VIP-indu ced responses. These data indicate that VIP elicits vasodilation in th e in situ systemic microcirculation and that NEP modulates this respon se.