Journal of Applied Physiology, Vol 66, Issue 5 2338-2343, Copyright © 1989 by American Physiological Society
Neutral endopeptidase modulates neurotensin-induced airway contraction
T. D. Djokic, D. J. Dusser, D. B. Borson and J. A. Nadel
Cardiovascular Research Institute, University of California, San Francisco 94143.
To determine the role of endogenous neutral endopeptidase (NEP) (also
called enkephalinase, EC 3.4.24.11) in regulating neurotensin-induced
airway contraction, we used phosphoramidon, a specific NEP inhibitor, in
the guinea pig. In studies in vitro, neurotensin and the COOH-terminal
fragment neurotensin-(8-13) contracted strips of bronchial smooth muscle in
a concentration-dependent fashion (P less than 0.001). In contrast, the
NH2-terminal fragment neurotensin-(1-11) and the COOH-terminal fragment
neurotensin-(12-13), the main fragments of neurotensin hydrolysis by NEP,
had no effect. Phosphoramidon (10(-5) M) did not change resting tension but
shifted the concentration-response curves to neurotensin to lower
concentrations (P less than 0.001), whereas inhibitors of kininase II,
aminopeptidases, serine proteases, and carboxypeptidase N were without
effect. Removing the epithelium increased the contractile response to
neurotensin (P less than 0.001), and phosphoramidon further increased the
response to neurotensin in these tissues (P less than 0.001). Similar
results were obtained in studies in vivo using aerosolized neurotensin and
phosphoramidon. These results suggest that endogenous NEP in the airways
modulates the effects of neurotensin on airway smooth muscle contraction by
inactivating the peptide.
