Halothane inhibits two components of calcium current in clonal (GH3) pituitary cells

Abstract

The effect of halothane on isolated calcium (Ca2+) current of clonal (GH3) pituitary cells was investigated using standard whole-cell clamp techniques at room temperature. Halothane (0.1–5.0 mM) reversibly reduced both the low-threshold, transient [low-voltage-activated (LVA)] component and the high-threshold [high-voltage-activated (HVA)] component of Ca2+ current. Halothane had little effect on the voltage dependence of activation or inactivation of either component of Ca2+ current. Inhibition of the peak high-threshold Ca2+ current was half- maximal at about 0.8 mM halothane, with maximal inhibition (100%) occurring with 5 mM halothane. When measured at the end of a 190-msec command step, half-maximal reduction of high-threshold current occurred at less than 0.5 mM halothane. The low-threshold transient current was less sensitive to halothane, with half-maximal inhibition of peak transient current activated at -30 mV occurring at approximately 1.3 mM. The effect of halothane on the HVA current was apparently not mediated by changes in intracellular Ca2+ concentration. The ability of halothane to inhibit Ca2+ current was unaffected by either the inclusion of the rapid Ca2+ buffer 1,2-bis(2-aminophenoxy)ethane N,N,N′,N′-tetraacetic acid (BAPTA) in the recording pipette or exposure of the cell to 10 mM caffeine. To assess the selectivity of the effect of halothane, the actions of halothane on two components of voltage- activated potassium (K+) current observed in the absence of extracellular Ca2+ and on voltage-dependent sodium (Na+) current were also examined. Halothane had no effect on the voltage-dependent, inactivating K+ current of GH3 cells at concentrations up to 1.2 mM. In contrast, the non-inactivating K+ current, though less sensitive to halothane than either Ca2+ current, was reduced by about 40% by 1.2 mM halothane at +20 mV. Peak Na+ current was also blocked by halothane, but 50% block required around 2.6 mM halothane with little effect at 1.6 mM. Reduction of Na+ current was associated with a substantial negative shift in the steady-state inactivation curve. Although the results indicate that a number of voltage-dependent ionic currents are sensitive to halothane, both components of Ca2+ current exhibit a greater sensitivity to halothane than any of three other voltage- dependent currents in GH3 cells. These results show that GH3 cell Ca2+ currents are selectively inhibited by clinically appropriate concentrations of halothane and that the reduction of Ca2+ current can account for the inhibition by halothane of TRH- or KCl-induced prolactin secretion in GH3 cells.

Calcium channel currents in bovine adrenal chromaffin cells and their modulation by anaesthetic agents.

“…see Terrar & Victory, 1988) and recent evidence shows that the L-and T-type currents of cardiac Purkinje fibres are affected by halogenated volatile anaesthetics to an approximately equal extent (Eskinder, Rusch, Supan, Kampine & Bosnjak, 1991). In clonal pituitary cells (GH3 cells) the lowthreshold current was resistant to halothane, while highthreshold calcium current was strongly inhibited (Herrington, Stern, Evers & Lingle, 1991). In this study the sustained component showed greater sensitivity than the inactivating current, possibly reflecting a greater sensitivity of L-type calcium channels.…”

Molecular Pharmacology of T-type Ca2+ Channels

“…Both isoflurane and halothane block T-type currents at therapeutically relevant concentrations of anesthetics (50). Block of high voltage-activated currents by halothane occurs at similar millimolar concentrations (51,52).…”

Novel Activation of Voltage-gated K+ Channels by Sevoflurane

“…Serotonin (5-HT3) receptors exhibit both inhibition and activation, which depends on the molecular volume of the anesthetic (6, 7, 16 -21). The interactions of voltage-gated ion channels with inhaled anesthetics are less well characterized and, to the best of our knowledge, the available studies of these targets report only inhibition by inhaled anesthetics (10,(22)(23)(24)(25)(26)(27)(28)(29). Previously, we characterized the inhibition of the archetypical Drosophila voltage-gated K ϩ (Kv) channel K-Shaw2 (a Kv3 homolog) by relevant concentrations of n-alcohols and inhaled anesthetics (12, 30 -33).…”