Diminution by benzodiazepines of the chronotropic responses to noradrenaline in rat isolated atria

Abstract

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 μM, and the mixed agonist, diazepam 5, 10 and 50 μM, but not by the central benzodiazepine agonist, clonazepam 10 and 30 μM. The inhibitory effects of the benzodiazepines on the atrial responses to noradrenaline were not counteracted by either the peripheral benzodiazepine antagonist, PK 11195 10 μM, or the central benzodiazepine antagonist, Ro 15-1788 10 and 100 μM. Both 10 μM Ro 5-4864 and 10 μM 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 β-adrenoceptors.