Effect of neutral endopeptidase inhibitor on bradykinin-induced bronchoconstriction

To evaluate whether neutral endopeptidase (NEP) inhibitors have adverse res piratory effects, the influence of a NEP inhibitor on bradykinin (BK)-induc ed bronchoconstriction was investigated. In anesthetized and artificially v entilated guinea pigs, changes in airway opening pressure (Pao) were measur ed as an index of bronchoconstriction. An infusion of phosphoramidon (3 mg kg(-1) h(-1)), a NEP inhibitor, significantly enhanced the bronchoconstrict ion induced by high-dose BK (30 nmol kg(-1), i.v.). Capsaicin (0.1 mg kg(-1 ), i.v.) and SR48968 (0.3 mg kg(-1), i.v.), an NK2 receptor antagonist, sig nificantly inhibited the phosphoramidon-induced enhancement of BK-induced b ronchoconstriction, although FK888 (3 mg kg(-1), i.v.), an NK1 receptor ant agonist, did not. Both neurokinin A (NKA) (0.1-3 nmol kg(-1), i.v.) and sub stance P (SP) (0.1-3 nmol kg(-1), i.v.) induced dose-dependent bronchoconst riction which was enhanced by phosphoramidon infusion, although these enhan cements were more prominent in the NKA series. Phosphoramidon partially inh ibited BK degradation in lung homogenate, and both NKA and SP degradation i n the lung homogenate were significantly suppressed by phosphoramidon. In b ronchoalveolar lavage fluid (BALF), levels of NKA and SP were significantly elevated after a bolus of BK with a phosphoramidon infusion. These results suggest that NEP inhibitors may have adverse respiratory effects resulting from inhibition of the degradation of neurokinins, but mainly of NKA, when a large amount of BK is generated. (C) 2001 Elsevier Science Inc. All righ ts reserved.