Studies on the Magnitude and the Mechanism of Cough Potentiation by Angiotensin-Converting Enzyme Inhibitors in Guinea-pigs: Involvement of Bradykinin in the Potentiation

Abstract

One adverse effect of the angiotensin-converting enzyme (ACE) inhibitors 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 studied in guinea-pigs. In normal guinea-pigs single and repeated dosing of imidapril at 0.1 to 100 mg kg-1 had no effect on capasaicin- or citric acid-induced coughs. Single and repeated dosing of enalapril and captopril at 10 to 30 mg kg-1, respectively, significantly increased the number of capsaicin-induced coughs. Repeated dosing of 1 mg kg-1 enalapril also significantly augmented the capsaicin cough. In bronchitic guinea-pigs imidapril also had no effect on the coughs induced by the two stimulants. Enalapril and captopril significantly increased the number of coughs induced not only by capsaicin but also by citric acid. Lower doses of enalapril were enough to augment the capsaicin-induced coughs, whereas medium to large doses failed to augment the cough irrespective of the protocol of administration. Bradykinin-induced discharges of the vegal afferents from the lower airway were significantly increased by enalaprilat but not by imidaprilat. Capsaicin-induced discharges of the afferents were, on the other hand, significantly depressed by enalaprilat, but not by imidaprilat. Interestingly, enalaprilat depression of the discharges was significantly reversed by Hoe-140, a bradykinin B2 receptor blocker. In guinea-pigs pretreated with a low dose of enalapril, arterial infusion of bradykinin significantly potentiated the coughs induced by capsaicin. The results indicated that imidapril was less potent than enalapril and captopril in potentiating 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 inhibitors.

Pharmacological Basis of Traditional Medicines and Health Supplements as Curatives

“…In our experiments, Bakumondo-to but not codeine completely inhibited ACE inhibitor-induced coughing (3,4). These effects are similar to those of steroidal antiinflammatory drugs.…”

Novel Antitussive Effect of Suplatast Tosilate in Guinea Pigs

“…We have previously speculated that BK plays a key role in the potentiation of coughs associated with ACE inhibitors [14], because the rate of BK-induced discharges of the vagal afferents of the lower airway is significantly increased by enalaprilat (an ACE inhibitor that strongly potentiates cough) but not by imidaprilat (an ACE inhibitor that weakly potentiates cough). The coughing induced by ACE inhibitors is often not responsive to antitussives.…”

“…The guinea pigs exposed to SO 2 under these conditions exhibited bronchitis characterized by an increase in the number of inflammatory cells in the bronchoalveolar lavage fluid, an increase in the sensitivity of the bronchial smooth muscle to acetylcholine and histamine, and a reduction of neutral endopeptidase activity in the trachea [14]. Some of these bronchitic animals coughed during SO 2 exposure but did not cough spontaneously after the exposure to SO 2 was terminated.…”

Ace inhibitors - activators of kinin receptors

“…Один из них, возникающий при хроническом применения иАПФ, -сухой кашель. Участие Б 2 Р в усилении кашля (индуцированного вдыханием стимулирующих агентов) на фоне приема иАПФ было продемонстрировано на морских свинках, у которых антагонист Б 2 Р (икатибант) подавлял развитие кашля [99,100]. Позднее было продемонстрировано вовлечение Б 1 Р в возникновении кашля, спонтанно развивающегося на фоне хронического приема иАПФ (эналаприла) [101].…”