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 (INa+) 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 microM) and the newer developed Sp-5,6-Dichloro-1-beta-D-ribofuranosylbenzimidazole- 3',5'-cyclic-monophosphorothioate (5,6-DCl-cBiMPS, 20 microM). The availability of INa+ 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+,max, the mid-point potential V1/2, and a steepness parameter alpha. Values are given by mean +/- SEM. 8-Br-cAMP showed a significant shift 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 INa+,max and alpha. In contrast, 5,6-DCl-cBiMPS had no significant effect on V1/2 but increased INa+,max by 8% +/- 2% versus control (n = 5, P < 0.05). In an intact muscle preparation we have found that 5,6-DCl-cBiMPS has a similar effect as that observed with the beta-adrenergic agonist ISO (100 nM), whereas 8-Br-cAMP exhibited a dissimilar action.(ABSTRACT TRUNCATED AT 250 WORDS)
Medizinische Universitätsklinik, Würzburg, Germany.
M
M
Kirstein
H
H
Langenfeld
A
A
Katzer
K
K
Kochsiek
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology*; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D004004:Dichlororibofuranosylbenzimidazole / Q000031:analogs & derivatives*; D004594:Electrophysiology; D005260:Female; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D009712:Nucleotides, Cyclic / Q000494:pharmacology*; D010210:Papillary Muscles / Q000187:drug effects* / Q000502:physiology; D018408:Patch-Clamp Techniques; D051381:Rats; D017208:Rats, Wistar; D015222:Sodium Channels / Q000187:drug effects* / Q000502:physiology; D013873:Thionucleotides / Q000494:pharmacology*
D009712:Nucleotides, Cyclic; D015222:Sodium Channels; D013873:Thionucleotides; C071644:5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole-3',5'-monophosphorothioate; D015124:8-Bromo Cyclic Adenosine Monophosphate; D004004:Dichlororibofuranosylbenzimidazole; D007545:Isoproterenol