Sensitization of the Cardiac Na Channel to α1-Adrenergic Stimulation by Inhalation Anesthetics Evidence for Distinct Modulatory Pathways

Background: α 1 -Adrenergic receptor stimulation has been shown to inhibit cardiac Na + current (I Na ). Furthermore, some form of synergistic interaction of α 1 -adrenergic effects on I Na in combination with volatile anesthetics has been reported. In this study, the authors investigated the possible role of G proteins and protein kinase C in the effects of halothane and isoflurane in the absence and presence of α 1 -adrenergic stimulation on the cardiac I Na . Methods: The standard whole-cell configuration of the patch-clamp technique was used. I Na was elicited by depolarizing test pulses from a holding potential of - 80 mV in reduced Na + solution (10 mM). The experiments were conducted on ventricular myocytes enzymatically isolated from adult guinea pig hearts. Results: The inhibitory effect of halothane (1.2 mM) and isoflurane (1 mM) on peak I Na was significantly diminished in the presence of guanosine 5'-O-[2-thiodiphosphate (GDPβS). In myocytes pretreated with pertussis toxin (PTX), the potency of halothane was significantly enhanced, but the isoflurane effect was unchanged. In the presence of the protein kinase C (PKC) inhibitor bisindolylmaleimide (BIS), the effect of halothane was unchanged. In contrast, the effect of isoflurane on I Na in the presence of BIS was significantly enhanced. The positive interaction between methoxamine and halothane was evident in the presence of G protein and PKC inhibitors. In contrast, the effect of methoxamine with isoflurane was additive in the presence of GDPβS or BIS. Conclusions: Different second messenger systems are involved in the regulation of cardiac Na + current by volatile anesthetics. The effect of halothane involves a complex interaction with G proteins but is independent of regulation by PKC. In contrast, PKC is involved in the modulation of cardiac I Na by isoflurane. In addition, non-PTX-sensitive G proteins may contribute to the effects of isoflurane. The positive interaction between methoxamine and anesthetics are independent of G proteins and PKC for halothane. In the case of isoflurane, the positive interaction with methoxamine is coupled to PTX-insensitive G proteins and PKC.