Substance P-induced bronchoconstriction in the guinea pig. Enhancement by inhibitors of neutral metalloendopeptidase and angiotensin-converting enzyme.
We tested the effects of the neutral metalloendopeptidase (NEP) inhibitor, thiorphan (0.17, 0.5, and 1.7 mg i.v), and the angiotensin-converting enzyme (ACE) inhibitor, captopril (0.5, 1.7, and 5.0 mg i.v.), on the bronchoconstrictor response to rapid intravenous infusions of substance P (0.1 to 30 nmol/kg) in anesthetized, mechanically ventilated guinea pigs. The decreases in pulmonary conductance and dynamic compliance caused by substance P were greater in animals treated with either thiorphan or captopril than in control animals. Thiorphan (0.5 mg) had no effect on airway responsiveness to intravenously administered methacholine, whereas captopril (1.7 mg) caused a small increase in methacholine responsiveness. Both drugs significantly increased the recovery of immunoreactive substance P in arterial plasma after exogenous administration of the peptide. We conclude that degradation of substance P by both NEP and ACE is important for determining the magnitude of the bronchoconstriction caused by intravenous administration of this neuropeptide. These data suggest that conditions associated with diminished peptidase activity could result in enhanced responses to stimuli which cause the release of endogenous substance P.
D000603:Amino Acids, Sulfur / Q000494:pharmacology*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001980:Bronchi / Q000187:drug effects*; D002216:Captopril / Q000494:pharmacology; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006168:Guinea Pigs; D008297:Male; D016210:Methacholine Chloride; D008688:Methacholine Compounds / Q000494:pharmacology; D010993:Plethysmography, Whole Body; D011480:Protease Inhibitors / Q000494:pharmacology*; D012121:Respiration, Artificial; D013373:Substance P / Q000097:blood / Q000494:pharmacology*; D015244:Thiorphan; D013997:Time Factors; D008625:Tiopronin / Q000031:analogs & derivatives / Q000494:pharmacology*
D000603:Amino Acids, Sulfur; D000806:Angiotensin-Converting Enzyme Inhibitors; D008688:Methacholine Compounds; D011480:Protease Inhibitors; D016210:Methacholine Chloride; D013373:Substance P; D002216:Captopril; D015244:Thiorphan; D008625:Tiopronin; D004121:Dimethyl Sulfoxide