Voltage-dependent inhibition of the ATP-sensitive K+ current by the class Ia agent disopyramide in cat ventricular myocytes.
The inhibition of the adenosine triphosphate-sensitive K+ (KATP) current by disopyramide, a class Ia antiarrhythmic drug, was studied using whole cell voltage clamp in cat ventricular myocytes at 37 degrees C and was compared to that seen with quinidine, a prototypical class Ia drug. The inhibition of the levcromakalim-induced KATP current was concentration dependent, with Ki, at -20 mV, of 4.9 +/- 0.6 and 1.5 +/- 0.1 microM for disopyramide and quinidine, respectively. Disopyramide also inhibited the KATP current elicited during the metabolic inhibition induced by the uncoupler CCCP. Disopyramide (9 microM) produced a 75% inhibition in comparison to the 82% inhibition of the levcromakalim-elicited current. The degree of inhibition increased with depolarization. This effect was quantified using the fractional electrical distance (delta) as an index of the voltage dependence, yielding equivalent voltage dependency values of 0.48 +/- 0.02 and 0.51 +/- 0.08 for disopyramide and quinidine, respectively. Depolarizing and repolarizing voltage steps in presence of tetrodotoxin (5-30 microM), nitrendipine (1 microM), and 4-aminopyridine (1.5 microM) failed to reveal clear kinetics of block and unblock, suggesting either a very fast block (< 3 ms) or a tonic (i.e., time-independent) inhibition. The preferential inhibition of KATP channels at depolarized potentials during metabolic inhibition may contribute to preserve the ability of class Ia agents to prolong action potential duration without compromising resting potential.
Wyeth-Ayerst Research, Cardiovascular and Diabetes Division, Princeton, New Jersey.
F G
FG
de Lorenzi
T R
TR
Bridal
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W
Spinelli
D000200:Action Potentials / Q000187:drug effects; D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000818:Animals; D002415:Cats; D004206:Disopyramide / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D017202:Myocardial Ischemia / Q000503:physiopathology; D026902:Potassium Channel Blockers; D011802:Quinidine / Q000494:pharmacology
D026902:Potassium Channel Blockers; D000255:Adenosine Triphosphate; D004206:Disopyramide; D011802:Quinidine