Cough is the most common symptom reported by patients in a primary care setting and is one of the most frequent secondary effects recorded during treatment with angiotensin-converting enzyme (ACE) inhibitors. The aim of the current study was to analyze potential differences in cough induction between 2 structurally different ACE inhibitors, namely zofenopril, which has a sulphydryl moiety, and ramipril, which has a carboxyl moiety. The cough reflex was induced by chemical (citric acid) and/or mechanical stimulation of the tracheobronchial tree in awake and anesthetized rabbits. Intravenous injection of the active compounds of the 2 ACE inhibitors, zofenoprilat (288 nmol/kg) and ramiprilat (129 nmol/kg), caused similar hypotensive effects in anesthetized rabbits. None of the studied cough-related variables changed in response to ACE inhibitor administration, with the exception of the number of coughs. Ramiprilat, but not zofenoprilat, increased the cough response induced by both mechanical and chemical stimulation (1 mol/L citric acid aerosol) of the tracheobronchial tree. In awake animals, zofenoprilat- or vehicle-treated rabbits did not show any significant changes in the number of coughs induced by 1 mol/L citric acid aerosol compared to their respective basal values (from 15.2 ± 2.3 to 13.1 ± 1.3 and from 16.1 ± 4.9 to 15.8 ± 4.3, respectively). Conversely, ramiprilat resulted in a significant increase in the number of coughs (from 21.1 ± 2.6 to 34.9 ± 3.5; P < .01). These findings confirm that there are differences in the cough potentiation effect induced by different ACE inhibitors. The low rate of cough seen with zofenoprilat may be related to its ability to induce a lower accumulation of bradykinin and prostaglandins at the lung level.
Korpás J., Tomori Z.Cough and other respiratory reflexes. Basel, Switzerland: Karger;1979.
2.
Lee LY, Pisarri TEAfferent properties and reflex functions of bronchopulmonary C-fibers . Respir Physiol. 2001;125(1-2): 47-65.
3.
Mutolo D., Bongianni F., Cinelli E., Fontana GA, Pantaleo T.Modulation of the cough reflex by antitussive agents within the caudal aspect of the nucleus tractus solitarii in the rabbit. Am J Physiol Regul Integr Comp Physiol. 2008;295(1):R243-R251.
4.
Mutolo D., Bongianni F., Cinelli E., Pantaleo T.Role of excitatory amino acids in the mediation of tracheobronchial cough induced by citric acid inhalation in the rabbit. Brain Res Bull.2009; 80(1-2):22-29.
5.
Mutolo D., Bongianni F., Fontana GA, Pantaleo T.The role of excitatory amino acids and substance P in the mediation of the cough reflex within the nucleus tractus solitarii of the rabbit. Brain Res Bull. 2007;74(4):284-293.
Widdicombe JGAfferent receptors in the airways and cough . Respir Physiol. 1998;114(1):5-15.
8.
Canning BJ, Mazzone SB, Meeker SN, Mori N., Reynolds SM, Undem BJIdentification of the tracheal and laryngeal afferent neurones mediating cough in anaesthetized guinea-pigs. J Physiol. 2004 ;557(pt 2):543-558.
9.
Chou YL, Scarupa MD, Mori N., Canning BJDifferential effects of airway afferent nerve subtypes on cough and respiration in anesthetized guinea pigs. Am J Physiol Regul Integr Comp Physiol. 2008;295(5):R1572-R1584.
Amir M., Khan B., Tahir M.Incidence of angiotensin converting enzyme inhibitor induced cough . Professional Med J. 2005; 12(4):435-439.
14.
Takahama K. , Fuchikami J., Suzuki A., Tabata T., Kai H., Miyata T.Differences in the mode of cough augmentation by four angiotensin-converting enzyme inhibitors in guinea-pigs. J Pharm Pharmacol. 1993;45(11):1003-1005.
Evangelista S., Manzini S.Antioxidant and cardioprotective properties of the sulphydryl angiotensin-converting enzyme inhibitor zofenopril . J Int Med Res. 2005;33(1):42-54.
17.
Vasmant D., Bender N.The renin-angiotensin system and ramipril, a new converting enzyme inhibitor . J Cardiovasc Pharmacol. 1989;14(suppl 4):S46-S52.
18.
Bongianni F. , Mutolo D., Nardone F., Pantaleo T.Ionotropic glutamate receptors mediate excitatory drive to caudal medullary expiratory neurons in the rabbit. Brain Res. 2005;1056(2):145-157.
19.
Bongianni F. , Mutolo D., Fontana GA, Pantaleo T.Discharge patterns of Botzinger complex neurons during cough in the cat. Am J Physiol. 1998 ;274(4 pt 2):R1015-R1024.
20.
Mutolo D., Bongianni F., Pantaleo T.Effects of lignocaine blockades and kainic acid lesions in the Botzinger complex on spontaneous expiratory activity and cough reflex responses in the rabbit . Neurosci Lett. 2002;332(3):175-179.
21.
Cushman DW, Wang FL, Fung WC, et al. Comparisons in vitro, ex vivo, and in vivo of the actions of seven structurally diverse inhibitors of angiotensin converting enzyme (ACE) . Br J Clin Pharmacol. 1989;28(suppl 2):115S-130S; discussion 30S-31S..
22.
Opie LHACE inhibitors: specific agents and pharmacokinetics. In: Opie LH, ed. ACE Inhibitors: Scientific Basis for Clinical Use. 2nd ed. New York, NY: Authors Publishing House; 1995:171-217.
23.
Bolser DC, Hey JA, Chapman RWInfluence of central antitussive drugs on the cough motor pattern . J Appl Physiol. 1999; 86(3):1017-1024.
24.
Tatar M., Hanacek J., Widdicombe J.The expiration reflex from the trachea and bronchi. Eur Respir J. 2008;31(2):385-390.
25.
Widdicombe J., Fontana G. Cough: what’s in a name?Eur Respir J. 2006;28(1):10-15.
26.
Widdicombe JGRespiratory reflexes from the trachea and bronchi of the cat. J Physiol. 1954;123(1):55-70.
27.
Lalloo UG, Fox AJ, Belvisi MG, Chung KF, Barnes PJCapsazepine inhibits cough induced by capsaicin and citric acid but not by hypertonic saline in guinea pigs. J Appl Physiol. 1995;79(4):1082-1087.
28.
Moreaux B., Advenier C., Gustin P.Role of bradykinin and tachykinins in the potentiation by enalapril of coughing induced by citric acid in pigs. Fundam Clin Pharmacol . 2001;15(1):23-29.
29.
Moreaux B., Beerens D., Gustin P.Development of a cough induction test in pigs: effects of SR 48968 and enalapril . J Vet Pharmacol Ther. 1999 ;22(6):387-389.
30.
Karlsson JA , Fuller RWPharmacological regulation of the cough reflex-from experimental models to antitussive effects in Man. Pulm Pharmacol Ther. 1999;12(4):215-228.
31.
Canning BJ, Farmer DG, Mori N.Mechanistic studies of acid-evoked coughing in anesthetized guinea pigs. Am J Physiol Regul Integr Comp Physiol. 2006;291(2):R454-R463.
32.
Karlsson JA , Sant’Ambrogio FB, Forsberg K., Palecek F., Mathew OP, Sant’Ambrogio G.Respiratory and cardiovascular effects of inhaled and intravenous bradykinin, PGE2, and PGF2 alpha in dogs. J Appl Physiol. 1993;74(5):2380-2386.
33.
Yang HY, Erdos EG, Levin Y.A dipeptidyl carboxypeptidase that converts angiotensin I and inactivates bradykinin. Biochim Biophys Acta. 1970;214(2):374-376.
34.
Israili ZH, Hall WDCough and angioneurotic edema associated with angiotensin-converting enzyme inhibitor therapy. A review of the literature and pathophysiology. Ann Intern Med. 1992; 117(3):234-242.
35.
Semple PFPutative mechanisms of cough after treatment with angiotensin converting enzyme inhibitors. J Hypertens Suppl. 1995 ;13(3):S17-S21.
36.
Takahama K. , Araki T., Fuchikami J., Kohjimoto Y., Miyata T.Studies on the magnitude and the mechanism of cough potentiation by angiotensin-converting enzyme inhibitors in guinea-pigs: involvement of bradykinin in the potentiation . J Pharm Pharmacol . 1996;48(10):1027-1033.
37.
Trifilieff A., Da Silva A., Gies JPKinins and respiratory tract diseases. Eur Respir J.1993;6(4):576-587.
38.
Wallace JLDistribution and expression of cyclooxygenase (COX) isoenzymes, their physiological roles, and the categorization of non-steroidal anti-inflammatory drugs (NSAIDs) . Am J Med. 1999; 107(6A):11S-16S; discussion 16S-17S.
39.
Kawikova I. , Arakawa H., Lofdahl CG, Skoogh BE, Lotvall J.Bradykinin-induced airflow obstruction and airway plasma exudation: effects of drugs that inhibit acetylcholine, thromboxane A2 or leukotrienes. Br J Pharmacol . 1993;110(2):657-664.
40.
Maher SA, Birrell MA, Belvisi MGProstaglandin E2 mediates cough via the EP3 receptor: implications for future disease therapy. Am J Respir Crit Care Med. 2009;180(10):923-928.
41.
Kim SY, Chang YJ, Cho HM, Hwang YW, Moon YSNon-steroidal anti-inflammatory drugs for the common cold. Cochrane Database Syst Rev. 2009;3:CD006362.
42.
Swartz SL, Williams GHAngiotensin-converting enzyme inhibition and prostaglandins. Am J Cardiol. 1982;49(6): 1405-1409.
43.
Kohlstedt K. , Busse R., Fleming I.Signaling via the angiotensin-converting enzyme enhances the expression of cyclooxygenase-2 in endothelial cells. Hypertension. 2005; 45(1):126-132.
44.
Przyklenk K. , Kloner RAAngiotensin converting enzyme inhibitors improve contractile function of stunned myocardium by different mechanisms of action . Am Heart J. 1991;121(5): 1319-1330.
45.
Pasini AF, Garbin U., Nava MC, et al. Effect of sulfhydryl and non-sulfhydryl angiotensin-converting enzyme inhibitors on endothelial function in essential hypertensive patients . Am J Hypertens. 2007;20(4):443-450.
46.
Borghi C., Bacchelli S., Degli Esposti D., Ambrosioni E.A review of the angiotensin-converting enzyme inhibitor, zofenopril , in the treatment of cardiovascular diseases. Expert Opin Pharmacother. 2004;5(9):1965-1977.
47.
Omboni S., Malacco E., Parati G.Zofenopril plus hydrochlorothiazide fixed combination in the treatment of hypertension and associated clinical conditions. Cardiovasc Ther.2009; 27(4):275-288.
48.
Yusuf S., Teo KK, Pogue J., et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med. 2008; 358(15):1547-1559.
