The effect of peptidase inhibitors on bradykinin-induced bronchoconstriction in guinea-pigs in vivo

Abstract

1 Bradykinin (BK) instilled directly into the airway lumen caused bronchoconstriction in anaesthetized, mechanically ventilated guinea-pigs in the presence of propranolol (1 mg kg⁻¹ i.v.) The geometric mean dose of BK required to produce 100% increase in airway opening pressure (PD₁₀₀) was 22.9 nmol (95% c.i. 11.7–44.6 nmol). 2 The dose-response curve for the effect of instilled BK was significantly shifted to the left by the angiotensin converting enzyme (ACE) inhibitor, captopril (5 and 50 nmol instillation, PD₁₀₀ = 3.0, 95% c.i. 0.98–8.9, and 2.0 nmol, 95% c.i. 0.65–6.2 nmol, respectively). 3 The neutral endopeptidase (NEP) inhibitor, phosphoramidon (5 and 50 nmol instillation) also shifted the dose-response curve for the effect of instilled BK; the PD₁₀₀ values = 2.2 (95% c.i. 0.40–11.7) and 1.8 nmol (95% c.i. 0.87–3.5 nmol), respectively. 4 After pretreatment with captopril (50 nmol) and phosphoramidon (50 nmol) in combination, the dose-response curve for the effect of instilled BK (PD₁₀₀ =1.1 nmol, 95% c.i. 0.37–3.2 nmol) was similar to that obtained in the presence of each inhibitor used alone. 5 The kininase I inhibitor, dl-2-mercaptomethyl-3-guanidinoethylthiopropionic acid (50 nmol instillation) failed to alter the dose-response curve to instilled BK (PD₁₀₀ = 14.6 nmol, 95% c.i. 6.7–32.0 nmol). 6 These data suggest that both ACE and NEP degrade BK in the airway lumen, but that kininase I is not involved.