Halothane and sevoflurane inhibit Na/Ca exchange current in rat ventricular myocytes.

BACKGROUND: The electrogenic Na+/Ca2+ exchanger (NCX) represents the main extrusion pathway for Ca2+ in ventricular muscle and therefore plays an important role in the regulation of cytosolic Ca2+ and contraction. Halothane and sevoflurane modulate cytosolic Ca2+ regulation and at steady state are negatively inotropic, however, the involvement of anaesthetic-induced changes in NCX activity in these effects requires further study. METHODS: Ventricular myocytes were isolated using a standard collagenase/protease dispersion technique and superfused with a physiological salt solution at 30 degrees C. Whole-cell patch-clamp technique was used to control membrane voltage. I(NCX) (identified as Ni2+ sensitive current) was recorded using a ramp clamp protocol under conditions to inhibit contaminating currents. RESULTS: With 0.6 mM sevoflurane, outward I(NCX) at positive voltages (> or = 0 mV) and inward I(NCX) at voltages negative to -60 mV was significantly reduced (P<0.05, n=13; I(NCX) reduced by 48% at +50 and 65% of control at -120 mV). Halothane (0.6 mM) inhibited outward I(NCX) at voltages positive to -10 mV and inward I(NCX) at voltages negative to -80 mV (P<0.05, n=10; I(NCX) reduced by 64% at +50 and 65% of control at -120 mV). Anaesthetic-induced inhibition of both inward and outward current was not voltage-dependent. CONCLUSIONS: Inhibition of Ca2+ efflux via NCX (i.e. inward I(NCX)) during an exposure to halothane or sevoflurane would be expected to limit the negative inotropic effects of these agents and help maintain SR Ca2+ content.

Transient and sustained changes in myofilament sensitivity to Ca2+ contribute to the inotropic effects of sevoflurane in rat ventricle.

BACKGROUND: The volatile anaesthetics isoflurane and sevoflurane induce both negative and positive inotropic effects in ventricular myocytes, the mechanisms of which are not fully understood. Previous data suggest that changes in myofilament Ca(2+) sensitivity contribute to their sustained negative inotropic effects. In this study, the role of changes in myofilament Ca(2+) sensitivity in both positive and negative inotropic effects of these agents was examined in intact ventricular myocytes. METHODS: Contractility and cytosolic Ca(2+) (fura-2) were recorded optically in ventricular myocytes stimulated electrically (1 Hz) at 30 degrees C. Myofilament Ca(2+) sensitivity was assessed from plots of cell length against fura-2 fluorescence ratio (Fr) from individual twitches at various points before, during and after a 1 or 4 min exposure to 0.6 mM anaesthetic. RESULTS: Isoflurane reduced mean (sd) myofilament Ca(2+) sensitivity from 10.3 (1.9) to 5.9 (1.6) microm Fr(-1) (P<0.001) throughout a 1 min exposure, which returned to control on removal. In contrast, on initial exposure to sevoflurane, Ca(2+) sensitivity was reduced from 10.8 (1.3) to 4.3 (0.9) microm Fr(-1) (P<0.001) but this recovered partially towards control over 3 min. On removal, sensitivity was increased above control (to 17.7 (2.2) microm Fr(-1); P<0.001) before preanaesthetic levels were restored. CONCLUSIONS: These data show that both isoflurane and sevoflurane reduce apparent myofilament Ca(2+) sensitivity at steady state. However, sevoflurane (but not isoflurane) induced transient changes in apparent myofilament Ca(2+) sensitivity, which would contribute to its inotropic profile.