Modulation of Cardiac Sodium Current by α1-stimulation and Volatile Anesthetics

Background: alpha1 -adrenoceptor stimulation is known to produce electrophysiologic changes in cardiac tissues, which may involve modulations of the fast inward Na sup + current (INa). A direct prodysrhythmic alpha1 -mediated interaction between catecholamines and halothane has been demonstrated, supporting the hypothesis that generation of halothane-epinephrine dysrhythmias may involve slowed conduction, leading to reentry. In this study, we examined the effects of a selective alpha1 -adrenergic receptor agonist, methoxamine, on cardiac INa in the absence and presence of equianesthetic concentrations of halothane and isoflurane in single ventricular myocytes from adult guinea pig hearts. Methods: INa was recorded using the standard whole-cell configuration of the patch-clamp technique. Voltage clamp protocols initiated from two different holding potentials (VH) were applied to examine state-dependent effects of methoxamine in the presence of anesthetics. Steady state activation and inactivation and recovery from inactivation were characterized using standard protocols. Results: Methoxamine decreased INa in a concentration- and voltage-dependent manner, being more potent at the depolarized VH. Halothane and isoflurane interacted synergistically with methoxamine to suppress INa near the physiologic cardiac resting potential of -80 mV. The effect of methoxamine with anesthetics appeared to be additive when using a VH of -110 mV, a potential where no Na sup + channels are in the inactivated state. Methoxamine in the absence and presence of anesthetics significantly shifted the half maximal inactivation voltage in the hyperpolarizing direction but had no effect on steady-state activation. Conclusion: The present results show that methoxamine (alpha1 -adrenergic stimulation) decreases cardiac Na sup + current in a concentration- and voltage-dependent manner. Further, a form of synergistic interaction between methoxamine and inhalational anesthetics, halothane and isoflurane, was observed. This interaction appears to depend on the fraction of Na sup + channels in the inactivated state.