Affiliation:
1. Department of Pharmacological Sciences, Faculty of Pharmaceutical Sciences, Kumamoto University, 5-1 Oehonmachi, Kumamoto 862
2. Laboratory of Pharmacokinetics and Pharmacology, Panapharm Laboratories Co. Ltd, Uto, Kumamoto 869-04, Japan
Abstract
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 capsaicin- 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 vagal 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.
Publisher
Oxford University Press (OUP)
Subject
Pharmaceutical Science,Pharmacology
Reference35 articles.
1. Carboxylterminal tripeptidyl hydrolysis of substance P by purified rabbit lung angiotensin converting enzyme and the potentiation of substance P activity in vivo by captopril and MK-422;Cascieri;Mol. Pharmacol.,1984
2. Sensitivity of the human cough reflex: effect of inflammatory mediators, prostaglandin E2, bradykinin and histamine;Choudry;Am. Rev. Respir. Dis.,1989
3. Separation of cough and reflex bronchoconstriction by inhaled local anaesthetics;Choudry;Eur. Respir. J.,1990
4. Cough associated with captopril and enalapril;Coulter;Br. Med. J.,1987
5. Spectrophotometric assay and properties of the angiotensin-converting enzyme of rabbit lung;Cushman;Biochem. Pharmacol.,1971
Cited by
24 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献