Pulmonary Mechanical Responses to Intravenously Administered Capsaicin in Guinea-pigs: Effect of Peptidase Inhibitors

Abstract

Summary: In order to examine the role of peptidases in modulating bronchoconstrictor responses to iv administered capsaicin, a potent C-fiber stimulant, we measured changes in pulmonary conductance ( G L ) and dynamic compliance ( C dyn) in anesthetized mechanically ventilated guinea-pigs. Control guinea-pigs, and guinea-pigs treated with the neutral endopeptidase (NEP) inhibitors thiorphan (1.7 mg/kg) or SCH32615 (1 mg/kg), the angiotensin converting enzyme (ACE) inhibitor captopril (5.7 mg/kg), or combinations of NEP and ACE inhibitors, were given increasing doses of capsaicin by rapid iv injection. The doses of capsaicin required to cause a 50% decrease in G L and C dyn (ED 50 G L and ED 50 C dyn respectively) were computed for each animal. None of the peptidase inhibitors, when given alone, had any effect on the changes in pulmonary mechanics induced by capsaicin. However, combined administration of thiorphan and captopril, or SCH32615 and captopril, caused a decrease in ED 50 C dyn for capsaicin, and prolonged the time during which the peak changes in G L induced by capsaicin persisted. These data support the hypothesis that substances whose degradation is inhibited by combined NEP and ACE inhibitors contribute to the bronchoconstriction induced by iv administered capsaicin. This profile of enzymatic degradation is consistent with the tachykinin, substance P.