METABOLISM OF BRADYKININ BY PEPTIDASES IN THE LUNG

We investigated the release of carboxypeptidase M (CPM), neutral endopeptidase 24.11 (enkephalinase, NEP), and angiotensin I converting enzyme (kininase II, ACE) and their contribution to bradykinin metabolism in the rat lung. The P3, membrane-enriched fraction of the homogenized lung was rich in all three peptidases. The activities of CPM and NEP were high in bronchoalveolar lavage fluid but lower in alveolar macrophages indicating that they originate from other cells present on the alveolar surface. In situ perfusion of rat lung with buffer that contained either deoxycholate or melittin or compound 48/80, produced lung edema. CPM, NEP, and ACE activities were recovered both in edema and perfusate fluid. The level of CPM and NEP was higher in edema fluid whereas, in contrast, more ACE activity was released into the perfusate. To evaluate the effect of peptidase inhibitors on changes in vascular permeability induced by bradykinin in the in situ perfused rat lung we measured the increase in lung weight as an index of increased vascular permeability or edema. Combined inhibition of either ACE plus NEP or ACE plus CPM augmented the effect of a subthreshold dose of bradykinin. Inhibitors of ACE, NEP, or CPM given alone and a combination of NEP plus CPM inhibitors did not enhance the bradykinin effect. Our results indicate that CPM, NEP, and ACE although present on different lung cells, synergistically modulate bradykinin effects. The different ratios of distribution of these enzymes in the perfusate and in edema fluid may not be due only to their presence on different pulmonary cells but also to their different anchoring mechanisms to plasma membranes. Thus, CPM and NEP participate in the inactivation of bradykinin in the lung, which could be of special importance after administration of ACE inhibitors.