MODULATION OF CARDIAC SODIUM CURRENT BY ALPHA(1)-STIMULATION AND VOLATILE ANESTHETICS

Background: alpha(1)-adrenoceptor stimulation is known to produce elec trophysiologic changes in cardiac tissues, which may involve modulatio ns of the fast inward Na+ current (I-Na). A direct prodysrhythmic alph a(1)-mediated interaction between catecholamines and halothane has bee n demonstrated, supporting the hypothesis that generation of halothane -epinephrine dysrhythmias may involve slowed conduction, leading to re entry. In this study, we examined the effects of a selective alpha(1)- adrenergic receptor agonist, methoxamine, on cardiac I-Na in the absen ce and presence of equianesthetic concentrations of halothane and isof lurane in single ventricular myocytes from adult guinea pig hearts. Me thods: I-Na was recorded using the standard whole-cell configuration o f the patch-clamp technique, Voltage clamp protocols initiated from tw o different holding potentials (V-H) were applied to examine state-dep endent effects of methoxamine in the presence of anesthetics, Steady s tate activation and inactivation and recovery from inactivation were c haracterized using standard protocols.Results: Methoxamine decreased I -Na in a concentration- and voltage-dependent manner, being more poten t at the depolarized V-H. Halothane and isoflurane interacted synergis tically with methoxamine to suppress I-Na near the physiologic cardiac resting potential of -80 mV, The effect of methoxamine with anestheti cs appeared to be additive when using a V-H of -110 mV, a potential wh ere no Na+ channels are in the inactivated state. Methoxamine in the a bsence and presence of anesthetics significantly shifted the half maxi mal inactivation voltage age in the hyperpolarizing direction but had no effect on steady-state activation. Conclusion: The present results show that methoxamine (alpha(1)-adrenergic stimulation) decreases card iac Na+ current in a concentration-and voltage-dependent manner. Furth er, a form of synergistic interaction between methoxamine and inhalati onal anesthetics, halothane and isoflurane, was observed. This interac tion appears to depend on the fraction of Na+ channels in the inactiva ted state.