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CARDIOVASCULAR

An Increase in Late Sodium Current Potentiates the Proarrhythmic Activities of Low-Risk QT-Prolonging Drugs in Female Rabbit Hearts

Pharmacological Sciences, CV Therapeutics, Inc., Palo Alto, California (L.W., J.C.S., L.B.); and Department of Medicine, University of Florida, Gainesville, Florida (Y.S.)

Assessment of the proarrhythmic risk associated with drugs that prolong the QT interval is difficult. We hypothesized that the proarrhythmic activities of drugs with very low to moderate risk of causing torsades de pointes would be well differentiated when the late sodium current (I_NaL) was greater than normal. The effects of selected QT-prolonging drugs on electrical activity of female rabbit isolated hearts were determined in the absence and presence of sea anemone toxin (ATX-II; an enhancer of I_NaL). I_NaL recorded from ventricular myocytes isolated from female rabbit hearts was slightly increased by 1 and 3 nM ATX-II (n = 13, P < 0.01). ATX-II (1 nM) prolonged the duration of the monophasic action potential (MAPD₉₀) the isolated heart by of 19 ± 3% (P < 0.001, n = 31) and shifted the concentration-response relationships for cisapride (1-30 nM), ziprasidone (0.01-3 µM), quinidine (0.1-1 µM), and moxifloxacin (0.01-1 µM) to prolong MAPD to the left by 2- to 12-fold. In contrast, the increases in MAPD₉₀ caused by 1 nM ATX-II and pentobarbital were only additive, and the increases in MAPD₉₀ caused by ATX-II and ranolazine [(±)-N-(2,6-dimethylphenyl)-(4[2-hydroxy-3-(2-methoxyphenoxy)propyl]-1-piperazine] were less than additive. Episodes of arrhythmic activity were commonly observed, and beat-to-beat variability of action potential duration was increased, during exposure of hearts to cisapride, ziprasidone, quinidine, and moxifloxacin but not during exposure of hearts to ranolazine or pentobarbital, in the presence of ATX-II. Thus, in the female rabbit heart, ATX-II potentiated the effects of QT-prolonging drugs to increase MAPD₉₀ and unmasked the proarrhythmic activities of these drugs at clinically relevant drug concentrations.

Address correspondence to: Lin Wu, CV Therapeutics, Inc., 3172 Porter Drive, Palo Alto, CA 94304. E-mail: lin.wu{at}cvt.com

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