Elgoyhen B, Adler-Graschinsky E
Instituto de Investigaciones Farmacológicas, CONICET, Buenos Aires, Argentina.
Eur J Pharmacol. 1989 May 30;164(3):467-78. doi: 10.1016/0014-2999(89)90254-9.
The effects of various benzodiazepines on chronotropic responses were assayed in spontaneously beating rat isolated atria. The increases in atrial rate obtained from concentration-response curves to noradrenaline were reduced dose dependently by both the peripheral agonist, Ro 5-4864 5 and 10 microM, and the mixed agonist, diazepam 5, 10 and 50 microM, but not by the central benzodiazepine agonist, clonazepam 10 and 30 microM. The inhibitory effects of the benzodiazepines on the atrial responses to noradrenaline were not counteracted by either the peripheral benzodiazepine antagonist, PK 11195 10 microM, or the central benzodiazepine antagonist, Ro 15-1788 10 and 100 microM. Both 10 microM Ro 5-4864 and 10 microM diazepam also reduced the increases in atrial rate produced by either the phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine, or the adenylate cyclase activator, forskolin. On the contrary, diazepam and Ro 5-4864 did not modify the chronotropic responses of the atria either to direct exposure to CaCl2 or to the calcium agonist, BAY K 8644. The increases in the intracellular levels of cAMP induced by noradrenaline were not modified by Ro 5-4864 and were even increased by 50% in the presence of diazepam. It is concluded that benzodiazepines probably reduce the chronotropic responses to noradrenaline in rat isolated atria through the interaction with the cAMP-linked chain of events that follows the activation of beta-adrenoceptors.
在自发搏动的大鼠离体心房中测定了各种苯二氮䓬类药物对变时反应的影响。外周激动剂Ro 5-4864（5和10微摩尔）和混合激动剂地西泮（5、10和50微摩尔）可剂量依赖性地降低从去甲肾上腺素浓度-反应曲线获得的心房率增加，但中枢苯二氮䓬类激动剂氯硝西泮（10和30微摩尔）则无此作用。苯二氮䓬类药物对心房对去甲肾上腺素反应的抑制作用，既不能被外周苯二氮䓬类拮抗剂PK 11195（10微摩尔）抵消，也不能被中枢苯二氮䓬类拮抗剂Ro 15-1788（10和100微摩尔）抵消。10微摩尔的Ro 5-4864和10微摩尔的地西泮还降低了磷酸二酯酶抑制剂3-异丁基-1-甲基黄嘌呤或腺苷酸环化酶激活剂福司可林引起的心房率增加。相反，地西泮和Ro 5-4864既不改变心房对直接暴露于氯化钙或钙激动剂BAY K 8644的变时反应。Ro 5-4864不改变去甲肾上腺素诱导的细胞内cAMP水平升高，而在存在地西泮的情况下，cAMP水平甚至升高50%。结论是，苯二氮䓬类药物可能通过与β-肾上腺素能受体激活后cAMP相关事件链相互作用，降低大鼠离体心房对去甲肾上腺素的变时反应。
