Palytoxin is a coral toxin that seriously impairs heart function, but its effects on excitation-contraction (E-C) coupling have remained elusive. Therefore, we studied the effects of palytoxin on mechanisms involved in atrial E-C coupling. In field-stimulated cat atrial myocytes, palytoxin caused elevation of diastolic intracellular Ca 2ϩ concentration ([Ca 2ϩ ]i), a decrease in [Ca 2ϩ ]i transient amplitude, Ca 2ϩ alternans followed by [Ca 2ϩ ]i waves, and failures of Ca 2ϩ release. The

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... e in [Ca 2ϩ ]i transient amplitude occurred despite high sarcoplasmic reticulum (SR) Ca 2ϩ load. In voltage-clamped myocytes, palytoxin induced a current with a linear current-voltage relationship (reversal potential ϳ5 mV) that was blocked by ouabain. Whole cell Ca 2ϩ current and ryanodine receptor Ca 2ϩ release channel function remained unaffected by the toxin. However, palytoxin significantly reduced Ca 2ϩ pumping of isolated SR vesicles. In currentclamped myocytes stimulated at 1 Hz, palytoxin induced a depolarization of the resting membrane potential that was accompanied by delayed afterdepolarizations. No major changes of action potential configuration were observed. The results demonstrate that palytoxin interferes with the function of the sarcolemmal Na ϩ -K ϩ pump and the SR Ca 2ϩ pump. The suggested mode of palytoxin toxicity in the atrium involves the conversion of Na ϩ -K ϩ pumps into nonselective cation channels as a primary event followed by depolarization, Na ϩ accumulation, and Ca 2ϩ overload, which, in turn, causes arrhythmogenic [Ca 2ϩ ]i waves and delayed afterdepolarizations.