The Na(+)-activated K+ current was studied in inside-out patches and in whole cells isolated from the guinea-pig cardiac ventricle. The single channel conductance showed inward rectification for K+i less than K+e, but outward rectification for K+i greater than K+e. The open probability was dependent on Na+i and Na+,K(+)-pump activity. In the presence of pump blockade the channel remained active at low Na+i. Similar results were obtained in whole cells. These results suggest the existence of Na+ gradients depending on Na+,K(+)-pump activity and passive inward leak of Na+. The channel and whole cell current were blocked by R56865. The drug did not change the single channel conductance but markedly reduced open probability by shortening burst duration. The current may play an important role in action potential shortening during pump blockade.

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Arsenic trioxide (As 2 O 3 ; ATO) has recently been found to be very effective for relapsed acute promyelocytic leukemia. Several articles reported prolongation of QT interval or ventricular arrhythmias in patients receiving ATO. However, the QTprolonging effect has not been confirmed and the direct membrane effect of ATO has never been studied. In the present investigation, using conventional action potential recording technique, we found that ATO dose dependently prolonged action potential duration (APD) in guinea pig papillary muscle with a slow pacing frequency. Parenteral administration of ATO prolonged QT interval and APD in guinea pig hearts. Intravenous infusion of clinically relevant doses of ATO prolonged QT interval and APD dose dependently. These studies suggest that ATO IntroductionArsenic trioxide (As 2 O 3 ; ATO) has recently been found to be very effective in relapsed or refractory acute promyelocytic leukemia (APL). 1-3 Several articles have reported prolongation of the QT interval in patients receiving ATO for relapsed APL. 4,5 However, the conclusive evidence for ATP to prolong cardiac repolarization is lacking. Some of the reported cases with torsade de pointes have hypokalemia or hypomagnesemia or both. [4][5][6] Most of the patients with APL receiving ATO have been heavily treated with chemotherapeutic agents, including anthracycline and all-trans-retinoic acid. Thus, cardiac damage is likely to be universal before ATO therapy begins. 2,4,6 Some reported cases have monomorphic ventricular tachycardia instead of polymorphic tachycardia, which is a prototypical arrhythmia of QT prolongation. 4 Shen and colleagues did not report QT prolongation in 15 patients receiving ATO. 1 Thus, the causal relationship of the use of ATO and prolongation of QT interval is questionable. [7][8] There is a need to unravel the effect of ATO on cardiac repolarization.In the present study, we demonstrated that ATO prolonged action potential duration (APD) and QT interval in guinea pig heart. This is the first comprehensive study of effect of ATO on cardiac repolarization. Study design Action potential recordingThe care and handling of the animals in this study was in full compliance with the American Association for the Accreditation of Laboratory Animal Care. Adult Hartley guinea pigs (weighing 400-500 g) of either sex were used. Action potentials were recorded with conventional intracellular recording technique. 9 The action potential duration at 90% repolarization (APD 90 ) was measured. This is the most commonly measured parameter of action potential for the purpose of studying the effect of QT-prolonging agents 10-12 because this time period encompasses the interval from the beginning of phase 0 depolarization to the late repolarization, and the prolongation of the ADP 90 was usually accompanied by a parallel lengthening of the effective refractory period. 13 Effects of different concentrations of ATO (1, 10, and 25 M) under different stimulation frequencies (0.1, 1, and 2 Hz) were examined. ATO was purchase...

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In this experimental model, we provide reasonably convincing evidence to suggest that in endotoxic shock, an increase in nitric oxide activity may activate KATP, which plays a major role in the shortening of APD, presumably through a cGMP-dependent pathway.