Yamazaki K, Furukawa Y, Hirose M, Chiba S
Department of Pharmacology, Shinshu University School of Medicine, Matsumoto, Japan.
Eur J Pharmacol. 1997 Feb 5;320(1):21-7. doi: 10.1016/s0014-2999(96)00871-0.
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.
用于支气管哮喘的支气管扩张剂可降低呼吸阻力，但在一定程度上也会增加心率。对于老年患者和患有心脏病的患者而言，使用这类支气管扩张剂往往存在困难。我们研究的目的是调查一种特定的心动过缓药物扎替丁，是否能在不影响呼吸阻力的情况下抑制支气管扩张剂引起的心率增加。我们评估了扎替丁对麻醉并人工通气的犬体内，因支气管扩张剂异丙肾上腺素、丙卡特罗（一种β2-肾上腺素能受体激动剂）、6-(3-二甲基氨基丙酰基)-福斯高林、NKH 477（一种腺苷酸环化酶激活剂）和氨茶碱所导致的心率增加及呼吸阻力抑制的影响。当静脉注射剂量为0.05 - 1.5mg/kg的扎替丁降低心率而不影响动脉血压时，它能剂量依赖性地减弱对异丙肾上腺素、丙卡特罗、NKH 477和氨茶碱的心率增加反应，但不影响这些物质对组胺诱导的呼吸阻力增加的抑制作用。普萘洛尔（静脉注射剂量为0.01 - 0.3mg/kg）不仅能剂量依赖性地抑制心率增加，还能抑制异丙肾上腺素和丙卡特罗引起的呼吸阻力抑制。目前的结果表明，扎替丁在麻醉犬体内能选择性地抑制对环磷酸腺苷依赖性支气管扩张剂的心率增加反应，而不影响其支气管扩张作用，这表明扎替丁可能是一种用于预防支气管哮喘患者使用支气管扩张剂引起的心动过速的有用药物。
