Differential effects of class I antiarrhythmic drugs on the guinea pig pulmonary vein myocardium: Inhibition of automatic activity correlates with blockade of a diastolic sodium current component.

The effects of class I antiarrhythmic drugs on the automaticity of isolated guinea pig pulmonary vein myocardia were investigated using microelectrode and voltage clamp methods. All of the drugs examined reduced the maximum rate of rise of automatic action potentials. The firing frequency and rate of diastolic depolarization were decreased by aprindine, flecainide and propafenone, but not by cibenzoline, disopyramide and pilsicainide, which correlated with blockade of the sodium current component induced by ramp depolarization mimicking the diastolic depolarization. In conclusion, class I antiarrhythmic drugs which block the diastolic sodium current component inhibit the automaticity of the pulmonary vein myocardium.

Involvement of the persistent Na+ current in the diastolic depolarization and automaticity of the guinea pig pulmonary vein myocardium.

The role of the Na+ current in the automaticity of the pulmonary vein myocardium was examined in isolated guinea pig pulmonary vein cardiomyocytes and tissue preparations. Tetrodotoxin inhibited the automaticity of pulmonary vein tissue preparations by suppressing the diastolic depolarization of the action potential. ATX-II, which increased the density of persistent component of the Na+ current (late INa), induced a depolarization of the resting membrane potential followed by spontaneous firing of action potentials. GS-458967, which inhibited the late INa, suppressed the diastolic depolarization and the firing of action potentials. Pilsicainide, which inhibited only the transient component of Na+ current (peak INa), had no effect on the firing frequency. GS-458967 had no effect on the contractile force of the working myocardium. In conclusion, late INa is involved in the diastolic depolarization and automaticity of the pulmonary vein myocardium. Late INa inhibitors appear to be effective therapeutic agents for atrial fibrillation with minimum adverse effects on the working myocardium.

Permissive role of reduced inwardly-rectifying potassium current density in the automaticity of the guinea pig pulmonary vein myocardium.

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 (IK-ACh) 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 Ca2+ by BAPTA. The isolated pulmonary vein cardiomyocytes had an IK-ACh density similar to that of the atrial cardiomyocytes, but a lower density of the inwardly-rectifying potassium current (IK1). Spontaneous Ca2+ transients were observed in about 30% of the isolated pulmonary vein cardiomyocytes, but not in atrial cardiomyocytes. The Ca2+ 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 Ca2+-dependent automaticity.

Involvement of alpha- and beta-adrenoceptors in the automaticity of the isolated guinea pig pulmonary vein myocardium.

We examined the involvement of adrenoceptors in the automaticity of the pulmonary vein myocardium, which probably plays a crucial role in the generation of atrial fibrillation. The automatic activity of the myocardium in guinea pig pulmonary vein tissue preparations were monitored by contractile force or membrane potential measurement. In quiescent preparations, application of noradrenaline induced an automatic activity. The firing frequency was reduced by prazosin or atenolol. Methoxamine induced an automatic activity of low frequency, which was accelerated by further application of isoproterenol. In preparations driven at a constant frequency, noradrenaline, in the presence of atenolol, caused a depolarizing shift of the resting membrane potential and an increase in the slope of the diastolic depolarization. In contrast, in the presence of prazosin, noradrenaline had no effect on the slope, but caused acceleration of the late repolarization and a hyperpolarizing shift of the maximum diastolic potential. At clinically relevant concentrations, carvedilol significantly inhibited the noradrenaline-induced activity but bisoprolol did not. It was concluded that α1- and ß1-adrenoceptor stimulation enhance automaticity through different mechanisms in the guinea pig pulmonary vein myocardium. Dual blockade of these adrenoceptors appears to be effective for suppressing noradrenaline-induced pulmonary vein automaticity and probably atrial fibrillation.

Manifestation of automaticity in the pulmonary-vein myocardium of rats with abdominal aorto-venocaval shunt.

Effect of abdominal aorto-venocaval shunt (AVS) on the automaticity of the pulmonary-vein myocardium was studied in the rat. Spontaneous electrical activity was observed in one third of the isolated pulmonary-vein preparations from the AVS rats, but scarcely in those from sham-operated rats; the activity was induced by tertiapin and suppressed by carbachol or chelation of intracellular Ca(2+). The evoked action potentials in AVS rats had less negative resting membrane potential and longer action potential duration than those in sham-operated rats. These results suggest that the automaticity of the rat pulmonary-vein myocardium is manifested under chronic volume overload.