Zatebradine inhibits tachycardia induced by bronchodilators without affecting respiratory resistance in dogs

Bronchodilators used for bronchial asthma reduce respiratory resistance but also increase heart rate to some extent. It is often difficult to use such bronchodilators with elderly patients and patients with heart disease. The object of our study was to investigate whether a specific bradycardic agent, zatebradine, inhibited the heart rate increased by bronchodilators without affecting respiratory resistance. We evaluated the effects of zatebradine on the increases in heart rate and inhibition of the respiratory resistance in response to the bronchodilators, isoproterenol, procaterol (a beta 2-adrenoceptor agonist), 6-(3-dimethylaminopropionyl)-forskolin, NKH 477 (an adenylyl cyclase activator) and aminophylline in the anesthetized and artificially ventilated dog. When zatebradine in doses of 0.05-1.5 mg/kg i.v. decreased heart rate without affecting arterial blood pressure, it dose dependently attenuated the increase in heart rate in response to isoproterenol, procaterol, NKH 477 and aminophylline but did not affect the inhibition by these substances of the increase in respiratory resistance induced by histamine. Propranolol (0.01-0.3 mg/kg i.v.) dose dependently inhibited not only the increase in heart rate but also the inhibition of the respiratory resistance induced by isoproterenol and procaterol. The present results indicate that zatebradine selectively inhibits the increase in heart rate in response to cyclic AMP-dependent bronchodilators without affecting their bronchodilator effects in anesthetized dogs and suggest that zatebradine may be a useful drug for prevention of the tachycardia induced by bronchodilators used for patients with bronchial asthma.