DISSIMILAR ACTION OF 2 CYCLIC ADENOSINE-MONOPHOSPHATE ANALOGS ON THE SODIUM CURRENT IN INTACT RAT PAPILLARY-MUSCLE

In intact papillary muscles from rat we have found with the loose-patc h-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 aden osine-monophosphate (cAMP) to investigate the intracellular pathway: 8 -Br-cAMP (50 mu M) and the newer developed sylbenzimidazole-3',5'-cycl ic-monophosphorothioate (5,6-DCl-cBiMPS, 20 mu M) 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 Bol tzmann equation, and expressed by the maximal attainable current I-Na ,max,(+) the mid-point potential V1/2, and a steepness parameter alpha . Values are given by mean +/- SEM. 8-Br-cAMP showed a significant shi ft of the availability curve in the hyperpolarized direction (V1/2 = - 82 +/- 2 mV vs -86 +/- 2 mV, n = 5, P < 0.05) with only minor changes of I-Na ,I-max(+) and alpha. In contrast, 5,6-DCl-cBiMPS had no signif icant effect on V1/2, but increased I-Na ,max(+) by 8% +/- 2% versus c ontrol (n = 5, P < 0.05). In an intact muscle preparation we have foun d that 5,6-DCl-cBiMPS has a similar effect as that observed with the b eta-adrenergic agonist ISO (100 nM), whereas 8-Br-cAMP exhibited a dis similar action. This indicates, that the effects of ISO are transmitte d by the cAMP system. On the other hand, 8-Br-cAMP, which is not as pe rmeable and specific an activator of the cAMP dependent protein kinase , may have other effects on the sodium channel, perhaps mediated throu gh purinergic receptors.