Neutral Endopeptidase Inhibitors and the Pulmonary Circulation

1. Neutral endopeptidase (NEP) EC 3.4.24.11 is a zinc-metallopeptidase which is partly responsible for the degradation of atrial natriuretic peptide (ANP) in vivo. 2. ANP inhibits vascular smooth muscle cell proliferation, and elicits vasorelaxation of the systemic and, more potently, the pulmonary vasculature. Plasma ANP levels are elevated in human disease states characterized by pulmonary hypertension, and in animal models of these diseases. 3. However, the short in vivo half-life of ANP suggests that it has limited therapeutic potential. Therefore, it has been hypothesized that inhibition of the metabolism of ANP may prove successful in the treatment of pulmonary hypertension. 4. Several inhibitors of NEP have been shown to reduce the development of pulmonary hypertension secondary to chronic hypoxia in rats. In addition, the inhibitor SCH 42495, partially reversed the established cardio-pulmonary remodelling associated with this disease model, without elevating plasma ANP levels. 5. The physiological actions of ANP are many of the properties desirable in a treatment for pulmonary hypertension. Thus, attenuating the metabolism of this peptide using NEP inhibitors, should potentially enhance the effects of ANP, either by maintaining plasma levels or at a local, tissue level.