Abstract. We examined the involvement of the Na + /Ca 2+ exchanger in the automaticity of the pulmonary vein myocardium with a specific inhibitor, SEA0400. Action potentials were recorded from the myocardial layer of isolated guinea-pig pulmonary vein preparations, and Ca 2+transients were recorded from the cardiomyocytes. Spontaneous electrical activity was observed in 17.7% of the preparations, which was inhibited by either SEA0400 or ryanodine. In quiescent preparations, ouabain induced electrical activity and spontaneous Ca 2+ transients, which were inhibited by SEA0400, as well as ryanodine. These results provide pharmacological evidence that the Na + /Ca 2+ exchanger underlies the automaticity of the pulmonary vein myocardium.Keywords: pulmonary vein myocardium, NaPulmonary veins are considered to be involved in the initiation and maintenance of atrial fibrillation, one of the most frequent arrhythmias in clinical practice (1). Pulmonary veins contain a myocardial layer, whose electrical activity is considered to underlie their arrhythmogenic activity (2). The pulmonary vein myocardium has different electrophysiological properties from those of the working myocardium, including lower density of I K1 and a less negative resting membrane potential (3). The precise mechanisms of the pulmonary vein electrical activity as well as its pharmacological properties are now receiving attention as the basis to develop an effective therapeutic strategy against atrial fibrillation.The Na + /Ca 2+ exchanger (NCX) is involved in the physiological and pathophysiological regulation of Ca 2+ concentration in the myocardium. It functions both in the forward (Ca 2+ extrusion) and reverse (Ca 2+ influx) modes, and its functional role may vary with the region and the condition of the myocardium (4, 5). The forward mode NCX activity (inward current) is the major pathway for Ca 2+ extrusion from the cytoplasm and is also considered to be involved in the normal pacemaking of the rabbit sinoatrial node (6). It was postulated that the Ca 2+ released from the sarcoplasmic reticulum (SR) during the diastolic period is pumped out of the cell through the forward mode NCX, which generates an inward current that contributes to the diastolic depolarization of the pacemaker. Although it is possible that such a mechanism is involved in the automaticity of other myocardial regions including the pulmonary vein myocardium, pharmacological evidence is limited because of the lack of an NCX inhibitor with sufficient specificity. SEA0400 {2-[4-[(2,5-difluorophenyl) methoxy] phenoxy]-5-ethoxyaniline} is a potent and selective inhibitor of NCX in cultured neurons, astrocytes, microglia, dog sarcolemmal vesicles, and cultured rat myocytes with negligible affinities towards other transporters, ion channels, and receptors (7). We have previously shown that SEA0400 is a specific inhibitor of NCX in the myocardium (8, 9). SEA0400 (1 μM), which inhibited the NCX current by more than 80%, had no effect on the Na + current, L-type Ca 2+ current, delayed recti...

The electrophysiological properties underlying the automaticity of the guinea pig pulmonary vein myocardium were studied. About 30% of the isolated pulmonary vein tissue preparations showed spontaneous electrical activity, as shown by glass microelectrode recordings from their myocardial layer. The remaining quiescent preparations had a resting membrane potential less negative than that in the left atria. Blockade of the acetylcholine activated potassium current (I) by tertiapin induced a depolarizing shift of the resting membrane potential and automatic electrical activity in the pulmonary vein, but not in the atria. The tertiapin-induced electrical activity, as well as the spontaneous activity, was inhibited by the application of carbachol or by chelation of intracellular Ca by BAPTA. The isolated pulmonary vein cardiomyocytes had an I density similar to that of the atrial cardiomyocytes, but a lower density of the inwardly-rectifying potassium current (I). Spontaneous Ca transients were observed in about 30% of the isolated pulmonary vein cardiomyocytes, but not in atrial cardiomyocytes. The Ca transients in the pulmonary vein cardiomyocytes were induced by tertiapin and inhibited by carbachol. These results indicate that the pulmonary vein cardiomyocytes have a reduced density of the inwardly-rectifying potassium current, which plays a permissive role in their intracellular Ca-dependent automaticity.

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Abstract. The pulmonary vein is known as an important source of ectopic beats, initiating frequent paroxysms of atrial fibrillation. We analyzed electrophysiological and pharmacological characteristics of triggered activity elicited in the isolated pulmonary vein from the guinea pig. Immediately after the termination of train stimulation (pacing cycle length of 100 ms), spontaneous activities accompanied with phase-4 depolarization were detected in 43 out of 45 pulmonary vein preparations. Such triggered activities were not observed in the isolated left atrium. The incidence of triggered activity was higher at a shorter pacing cycle length (100 -200 ms), and the coupling interval was shorter at a shorter pacing cycle length. Verapamil (1 μM), ryanodine (0.1 μM), and pilsicainide (10 μM) suppressed the occurrence of triggered activities. The resting membrane potential of the pulmonary vein myocardium was more positive than that of the left atrium. Carbachol (0.3 μM) hyperpolarized the resting membrane potential and completely inhibited the occurrence of triggered activities. These results suggest that the pulmonary veins have more arrhythmogenic features than the left atrium, possibly through lower resting membrane potential. The electrophysiological and pharmacological characteristics of triggered activity elicited in the pulmonary vein myocardium were similar to those previously reported using ventricular tissues.