STUDIES ON THE MAGNITUDE AND THE MECHANISM OF COUGH POTENTIATION BY ANGIOTENSIN-CONVERTING ENZYME-INHIBITORS IN GUINEA-PIGS - INVOLVEMENT OF BRADYKININ IN THE POTENTIATION

One adverse effect of the angiotensin-converting enzyme (ACE) inhibito rs used for treatment of hypertension and congestive heart failure is the production of dry coughs. Imidapril is a new type of ACE inhibitor with a very low incidence of coughs. The magnitude and the mechanism of cough potentiation of imidapril and other ACE inhibitors has been s tudied in guinea-pigs. In normal guinea-pigs single and repeated dosin g of imidapril at 0 . 1 to 100 mg kg(-1) had no effect on capsaicin- o r citric acid-induced coughs. Single and repeated dosing of enalapril and captopril at 10 to 30 mg kg(-1), respectively, significantly incre ased the number of capsaicin-induced coughs. Repeated dosing of 1 mg k g(-1) enalapril also significantly augmented the capsaicin cough. In b ronchitic guinea-pigs imidapril also had no effect on the coughs induc ed by the two stimulants. Enalapril and captopril significantly increa sed the number of coughs induced not only by capsaicin but also by cit ric acid. Lower doses of enalapril were enough to augment the capsaici n-induced coughs, whereas medium to large doses failed to augment the cough irrespective of the protocol of administration. Bradykinin-induc ed discharges of the vagal afferents from the lower airway were signif icantly increased by enalaprilat but not by imidaprilat. Capsaicin-ind uced discharges of the afferents were, on the other hand, significantl y depressed by enalaprilat, but not by imidaprilat. Interestingly, ena laprilat depression of the discharges was significantly reversed by Ho e-140, a bradykinin B-2 receptor blocker. In guinea-pigs pretreated wi th a low dose of enalapril, arterial infusion of bradykinin significan tly potentiated the coughs induced by capsaicin. The results indicated that imidapril was less potent than enalapril and captopril in potent iating cough responses induced by capsaicin and citric acid in guinea- pigs, and further suggest that bradykinin might be a key substance in the mechanism of the potentiation of coughs associated with ACE inhibi tors.