Modulation by stimulation rate of basal and cAMP-elevated Ca2+ channel current in guinea pig ventricular cardiomyocytes.
The modulation of L-type Ca2+ current (ICa) by changes in stimulation frequency was investigated in single ventricular cardiomyocytes isolated from guinea pig hearts. Electrical recordings were carried out at 21-25 degrees C and at 33-37 degrees C with the whole-cell patch clamp method, under K(+)-free conditions. A comparison is made between the response to frequency changes for ICa in the basal state and after the application of drugs which elevate the level of adenosine-3',5'-cyclic monophosphate (cAMP) within the cells. Peak basal ICa was reduced with an increase in stimulation rate from 0.5 Hz to 1, 2, 3, 4, or 5 Hz. This frequency-induced reduction of ICa was enhanced by reduced temperature, was unchanged when Na+ or Ba2+ carried the basal Ca2+ channel current, and was greatly enhanced after elevating cAMP levels with forskolin, isoprenaline, or 8-(4-chlorophenylthio)-cyclic AMP. We examined the mechanism of the enhancement of the frequency-induced reduction of ICa by cAMP, and found two conditions which abolished it: (a) application of isoprenaline when Na+ carried the Ca2+ channel current in Ca(2+)-free solution, or (b) application of 3-isobutyl-1-methylxanthine, a broad-spectrum phosphodiesterase inhibitor. It was further shown that an elevation of both ICa and cAMP (induced by isoprenaline), and not an increase of ICa alone (induced by Bay K 8644), is required to produce the extra component of reduction by frequency. It is concluded that Ca2+ entry results in feedback regulation of ICa, through the activation of Ca(2+)-dependent phosphodiesterase(s). This is important in the context of sympathetic stimulation, which produces the companion conditions of an elevated heart rate and increases in cAMP levels and Ca2+ entry.
Department of Physiology and Biophysics, Dalhousie University, Halifax, Nova Scotia, Canada.
S P
SP
Kaspar
D J
DJ
Pelzer
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism*; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D066298:In Vitro Techniques; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology*; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials; D018408:Patch-Clamp Techniques
D000318:Adrenergic beta-Agonists; D015220:Calcium Channels; D000242:Cyclic AMP; D007545:Isoproterenol; D002118:Calcium