Augmentation of spontaneous cough by enalapril through up-regulation of bradykinin B1 receptors in guinea pigs

Studies of angiotensin-converting enzyme inhibitor-induced cough have involved extensive use of experimental models in which guinea pigs are exposed to an inhaled stimulus such as capsaicin or citric acid. In the present study, we examined enalapril-induced potentiation of spontaneous cough in guinea pigs, without an inhaled stimulus. Daily oral administration of enalapril (3 mg/kg) for 20 to 30 days enhanced spontaneous cough. This enhancement of cough was inhibited by the bradykinin B-1 receptor antagonist des-Arg(10)-[Leu(9)]kallidm, but not by the bradykinin B-2 receptor antagonist icatibant. The amount of the bradykinin B-1 receptor agonist [H-3]des-Arg(10)-kallidin specifically bound to membrane fractions from the trachea and larynx was increased by prolongation of the enalapril treatment, and positively correlated well with coughing frequency. In conclusion, the present results indicate that enalapril-induced cough is mediated by up-regulation of bradykinin B-1 receptors. (C) 2003 Elsevier B.V. All rights reserved.