Modulating L-type calcium current affects discontinuous cardiac action potential conduction.
We have used pairs of cardiac cells (i.e., one real guinea pig ventricular cell and a real-time simulation of a numerical model of a guinea pig ventricular cell) to evaluate the effects on action potential conduction of a variable coupling conductance in combination with agents that either increase or decrease the magnitude of the L-type calcium current. For the cell pairs studied, we applied a direct repetitive stimulation to the real cell, making it the "leader" cell of the cell pair. We have demonstrated that significant delays in action potential conduction for a cell pair can occur either with a decreased value of coupling conductance or with an asymmetry in size such that the follower cell is larger than the leader cell. In both conditions we have shown that isoproterenol, applied to the real cell at very low concentrations, can reversibly decrease the critical coupling conductance (below which action potential conduction fails) for a cell pair with fixed cell sizes, or, for a fixed value of coupling conductance, increase the maximum allowable asymmetry in cell size for successful conduction. For either of these effects, we were able to show that treatment of the real cell with BayK 8644, which more specifically increases the magnitude of the L-type calcium current, was able to mimic the actions of isoproterenol. Treatment of the leader cell of the cell pair (the real cell) with nifedipine, which selectively lowers the magnitude of the L-type calcium current, had effects opposite those of isoproterenol or BayK 8644. The actions of nifedipine, isoproterenol, and BayK 8644 are all limited to conditions in which the conduction delay is on the order of 5 ms or more, whether this delay is caused by limited coupling conductance or by asymmetry in size of the cells. This limitation is consistent with the time course of the L-type calcium current and suggests that the effects of calcium channel blockers or beta-adrenergic blocking drugs, in addition to being selective for regions of the heart that depend on the L-type calcium current for the upstroke of the action potential, would also be somewhat selective for regions of the heart that have discontinuous conduction, either normally or because of some pathological condition.
Joyner
R W
RW
Todd Franklin Cardiac Research Laboratory, Children's Heart Center, Department of Pediatrics, Emory University, Atlanta, Georgia 30322, USA. rjoyner@anatomy.emory.edu
Kumar
R
R
Wilders
R
R
Jongsma
H J
HJ
Verheijck
E E
EE
Golod
D A
DA
Van Ginneken
A C
AC
Wagner
M B
MB
Goolsby
W N
WN
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D055592:Biophysical Phenomena; D001703:Biophysics; D002120:Calcium Channel Agonists / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism*; D020746:Calcium Channels, L-Type; D004553:Electric Conductivity; D004558:Electric Stimulation; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000166:cytology / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology; D008955:Models, Cardiovascular; D009206:Myocardium / Q000378:metabolism*; D009543:Nifedipine / Q000494:pharmacology
D000318:Adrenergic beta-Agonists; D002120:Calcium Channel Agonists; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D009543:Nifedipine; D007545:Isoproterenol