Inhibition of ICa in single frog cardiac cells by quinidine, flecainide, ethmozin, and ethacizin.
The effects of four class I antiarrhythmic compounds on the Ca current (ICa), recorded with whole cell patch clamp in single isolated frog ventricular cells, were compared. Na and K currents were blocked by tetrodotoxin and Cs. Quinidine and flecainide induced an apparent tonic block with a 50% effective dose (ED50) at 10 and 20 microM, respectively; there was no clear use-dependent inhibition. Ethmozin and ethacizin, two phenothiazine derivatives, exhibited both tonic and use-dependent inhibition. Ethacizin was at least 10 times more potent than ethmozin; at 1 microM, it induced a 15% tonic block and 5, 35, and 42% use-dependent block at 0.125, 1, and 2 Hz, respectively. These compounds appeared only 3- to 10-fold less efficient on the ICa than on the Na current recorded in parallel experiments, with flecainide showing the largest different potency. All four compounds shifted the availability curves by a few millivolts toward hyperpolarization, had a clear voltage-dependent inhibition, and slowed reactivation, the latter effect being more marked with less negative holding potential. Consequently, the absence of use-dependence inhibition with quinidine and flecainide could be the consequence of a very fast association of the two compounds with the open channels that would be complete during the 200-ms depolarizing pulse. Since arrhythmias are frequently associated with tissue depolarization and can be related to Ca-dependent action potential and slow conduction, the inhibition of the ICa reported above should account, in part, both for the antiarrhythmic and the negative inotropic effects of these compounds.
Scamps
F
F
Laboratoire de Physiologie Cellulaire Cardiaque, INSERM U-241, Université Paris-Sud, Orsay, France.
Undrovinas
A
A
Vassort
G
G
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects / Q000502:physiology*; D005424:Flecainide / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects; D016293:Moricizine; D010640:Phenothiazines / Q000494:pharmacology*; D011802:Quinidine / Q000494:pharmacology*; D011893:Rana esculenta
D000889:Anti-Arrhythmia Agents; D015220:Calcium Channels; D010640:Phenothiazines; D016293:Moricizine; C046818:ethacizine; D011802:Quinidine; D005424:Flecainide