Tonic and phasic Vmax block induced by 5-hydroxypropafenone in guinea pig ventricular muscles.
The effects of 5-hydroxypropafenone (5-OH-P) on transmembrane action potentials were studied in isolated guinea pig papillary muscles. 5-Hydroxypropafenone, 10(-7) M to 5 X 10(-5) M, produced a dose-dependent decrease in the Vmax and amplitude of the action potential and a depolarization of the resting membrane potential, whereas the action potential duration was not affected by the drug. In the presence of 5-OH-P, trains of stimuli at rates between 0.2 and 2 Hz led to an exponential decline in Vmax (onset rate at 1 Hz 0.07 +/- 0.01 per action potential) to a new steady-state level. This phasic, use-dependent Vmax block was augmented at higher stimulation frequencies. The time constant for the recovery of Vmax from the phasic block (offset) was 200.0 +/- 9.3 s. In papillary muscles depolarized with 10 mM K the inhibitory effect of 5-OH-P on Vmax of the first action potential after a long quiescent period (tonic block) was markedly increased, but the rates of onset and offset of the phasic block were similar to those found in normally polarized fibers under 5.4 mM K. 5-OH-P also shifted the curves relating membrane potential and Vmax in the hyperpolarizing direction. These findings suggest that 5-OH-P exhibited similar phasic inhibitory action of the fast sodium channels than other class Ic antiarrhythmic drugs. This phasic Vmax block, and its greater inhibition of Vmax in depolarized muscles through the increase of tonic block, would play a major role for the antiarrhythmic effect of the drug.
Valenzuela
C
C
Department of Pharmacology, School of Medicine, Universidad Complutense, Madrid, Spain.
Delpón
E
E
Tamargo
J
J
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D004558:Electric Stimulation; D005260:Female; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D010210:Papillary Muscles / Q000187:drug effects; D011405:Propafenone / Q000031:analogs & derivatives* / Q000494:pharmacology
D000889:Anti-Arrhythmia Agents; D011405:Propafenone; C044307:5-hydroxypropafenone