Role of bradykinin and tachykinins in the potentiation by enalapril
Angiotensin-converting enzyme (ACE) inhibitors, such as enalapril, captopril and lisinopril, are drugs of choice for the treatment of hypertension and congestive heart disease in humans and dogs. Their use results notably in a lowering of blood pressure, without the adverse effects (decreased cardiac function and lipid metabolism) observed with some other vasodilators acting on the central nervous system. Yet it has been reported that in 1–33% of patients, these drugs can induce airway hyperreactivity and chronic dry cough.
The cough reflex is usually viewed as being elicited by stimulation of irritant receptors with myelinated afferent fibers, called rapidly adapting stretch receptors (RARs). It appears, however, that unmyelinated C-fibre endings may be involved. Inhaled capsaicin, predominantly a C-fibre ending stimulant, can cause coughing in humans and guinea pigs. This response involves sensory mechanisms, as it can be inhibited in guinea pigs by pretreatment with high doses of capsaicin, causing degeneration of sensory nerves. C-fibres contain tachykinins such as substance P, which can be released upon the action of citric acid]. Tachykinin receptor antagonists can inhibit the citric acid-induced cough reflex. The receptor types involved in the reaction depend on the species.
In humans treated with ACE inhibitors, the chronic dry cough occurring in some cases has been explained by increased levels of prostaglandins and thromboxane A2 in the airways. In guinea pigs pretreated with ACE inhibitors, bradykinin has also been reported repeatedly to play a role in sensitisation to a citric acid aerosol challenge. Yet in both guinea pigs and humans, an increase in the substance P level due to decreased ACE activity is also suspected as a mechanism that enhances the cough reflex induced by ACE inhibitors.
Thus, citric acid is thought to induce coughing through activation of the vanilloid channels of the sensory nerves by proton release, but other mechanisms involving bradykinin and prostanoids have also been identified. Bradykinin, well known to elicit bronchoconstriction and airway microvascular leakage, can also induce coughing or at least cause sensitisation of airway sensory nerves and enhancement of the cough reflex in guinea pigs. The inhibitory effects of Hoe140, a bradykinin B2 receptor antagonist, and of CH694, a kallikrein inhibitor, on citric-acid-induced coughing in guinea pigs and pigs suggests that citric acid acts also through release or activation of kallikrein, which leads to bradykinin production. Kinins, powerful stimulants of sensory nerves, elicit coughing through this way or through tachykinin release. But they can also exert their inflammatory action by causing production of prostanoids, also involved in the cough reflex. Both kinins and neurokinins are degraded by peptidases, especially neutral endopeptidase (NEP) and ACE, both highly active in the lungs. These peptidases are involved in airway inflammatory processes and differ by their location in lung tissues. ACE is predominantly located on the endothelial cells while NEP is found in epithelial cells. ACE plays a major physiological role in the control of arterial blood pressure through conversion of angiotensin I to angiotensin II. Like NEP, it also degrades bradykinin and substance P. In guinea pigs, blocking of ACE by ACE inhibitors or of NEP by phosphoramidon leads to enhancement of the citric-acid-induced cough reflex.
Given the role played by bradykinin and tachykinins such as substance P in pigs, the aim of this study was to investigate whether bradykinin and tachykinins play a role in enalapril-induced enhancement of the cough reflex elicited by citric acid aerosol challenge in these animals.
Filed under: Pulmonary