Na+ channel blockade by cyclic AMP and other 6-aminopurines in neonatal rat heart.
Elementary Na+ currents were recorded at 19 degrees C in cell attached and inside-out patches from cultured neonatal rat cardiocytes in order to study the effect of cAMP and other 6-aminopurines. The treatment of the cardiocytes with db-cAMP (1 x 10(-3) mol/liter) led to a decline of reconstructed macroscopic peak INa to 62 +/- 7.6% of the initial control value. This reduction in NPo was mostly accompanied by a decrease in burst activity. Open-state kinetics were preserved even in DPI-modified, noninactivating Na+ channels. Since the stimulator of the adenylate cyclase, forskolin (1 x 10(-6) mol/liter), evoked a similar pattern of response, the NPo decrease can be considered as the functional correlate of Na+ channel phosphorylation brought about by cAMP-dependent protein kinase. As found in inside-out patches, cAMP (1 x 10(-3) mol/liter) remained effective under cell-free conditions and reduced reconstructed macroscopic peak INa to about 50% of the initial control value when the absence of Mg-ATP at the cytoplasmic membrane surface prevents phosphorylation reactions. A very similar response developed in the cytoplasmic presence of other 6-aminopurines including ATP (1 x 10(3) mol/liter), adenosine (1 x 10(-4) mol/liter), adenine (1 x 10(-5) mol/liter) and hypoxanthine (1 x 10(-5) mol/liter). This susceptibility to adenine suggests that cardiac Na+ channels in situ could sense intracellular fluctuations of adenine nucleotides, most likely of ATP.
Herzig
J W
JW
Physiological Institute, University of Freiburg, Federal Republic of Germany.
Kohlhardt
M
M
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000494:pharmacology*; D004553:Electric Conductivity; D007700:Kinetics; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D011687:Purines / Q000494:pharmacology*; D051381:Rats; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism*
D011687:Purines; D015222:Sodium Channels; D005576:Colforsin; D000255:Adenosine Triphosphate; D000242:Cyclic AMP