Modulation of the Cardiac Sodium Current by Inhalational Anesthetics in the Absence and Presence of β-Stimulation

Background Cardiac dysrhythmias during inhalational anesthesia in association with catecholamines are well known, and halothane is more “sensitizing” than isoflurane. However, the underlying mechanisms of action of volatile anesthetics with or without catecholamines on cardiac Na channels are poorly understood. In this study, the authors investigated the effects of halothane and isoflurane in the absence and presence of beta-stimulation (isoproterenol) on the cardiac Na sup + current (INa) in ventricular myocytes enzymatically isolated from adult guinea pig hearts. Methods A standard whole-cell patch-clamp technique was used. The INa was elicited by depolarizing test pulses from a holding potential of -80 mV in reduced Na sup + solution (10 mM). Results Isoproterenol alone depressed peak INa significantly by 14.6 +/- 1.7% (means +/- SEM). Halothane (1.2 mM) and isoflurane (1.0 mM) also depressed peak INa significantly by 42.1 +/- 3.4% and 21.3 +/- 1.9%, respectively. In the presence of halothane, the effect of isoproterenol (1 micro Meter) was potentiated, further decreasing peak I sub Na by 34.7 +/- 4.1%. The halothane effect was less, although significant, in the presence of a G-protein inhibitor (GDP beta S) or a specific protein kinase A inhibitor [PKI-(6–22)-amide], reducing peak I sub Na by 24.2 +/- 3.3% and 24 +/- 2.4%, respectively. In combination with isoflurane, the effect of isoproterenol on INa inhibition was less pronounced, but significant, decreasing current by 12.6 +/- 3.9%. GDP beta S also reduced the inhibitory effect of isoflurane. In contrast, PKI-(6–22)-amide had no effect on isoflurane INa inhibition. Conclusions These results suggest two distinct pathways for volatile anesthetic modulation on the cardiac Na sup + current: (1) involvement of G proteins and a cyclic adenosine monophosphate (cAMP)-mediated pathway for halothane and, (2) a G-protein-dependent but cAMP-independent pathway for isoflurane. Furthermore, these studies show that the inhibition of cardiac INa by isoproterenol is enhanced in the presence of halothane, suggesting some form of synergistic interaction between halothane and isoproterenol.