Dissimilar Action of Two Cyclic Adenosine-Monophosphate Analogues on the Sodium Current in Intact Rat Papillary Muscle

In intact papillary muscles from rat we have found with the loose-patch-clamp technique an increase of the fast cardiac sodium current (I_Na⁺) by isoproterenol (ISO). In this study we have tested two membrane permeable analogues of the intracellular second messenger cyclic adenosine-monophosphate (cAMP) to investigate the intracellular pathway: 8-Br-cAMP (50 μM) and the newer developed S_p5,6-Dichloro-1-β-D-ribofuranosylbenzimidazole-3′, 5′-cyclic-monophosphor-othioate (5,6-DCl-cBiMPS, 20 μM). The availability of I_Na⁺ was determined with test pulses to ± 0 mV every 3.5 seconds after 2.5-second conditioning between -130 mV and-50 mV and a holding potential at the resting potential of the cell under examination, and after wash-in of either compound. The peak currents were fit to a Boltzmann equation, and expressed by the maximal attainable current INa⁺_Na,max the mid-point potential V½, and a steepness parameter a. Values are given by mean ± SEM. 8-Br-cAMP showed a significant shift of the availability curve in the hyperpolarized direction (V½= -82 ± 2 mV vs - 66 ± 2 mV, n = 5, P < 0.05) with only minor changes of I⁺_No,max and a. In contrast, 5,6-DCI-cBiMPS had no significant effect on V½ but increased I⁺_Na,max by 8%± 2% versus control (n = 5. P < 0.05). In an intact muscle preparation we have found that 5,6-DCI-cBiMPS has a similar effect as that observed with the β-adrenergic agonist ISO (100 nM), whereas 8-Br-cAMP exhibited a dissimilar action. This indicates, that ihe effects of ISO are transmitted by the cAMP system. On the other hand, 8-Br-cAMP, which is not as permeable and specific an activator of the cAMP dependent proteinkinase, may have other effects on the sodium channel, perhaps mediated through purinergic receptors.