Oxygen tension modulates inhibition of L-type calcium currents by isoflurane in human atrial cardiomyocytes.

BACKGROUND: Myocardial L-type Ca(2+) currents (I(Ca,L)) are inhibited by isoflurane in the presence of a partial pressure of oxygen (P(O2)) of 150 mmHg. In guinea pig cardiomyocytes, I(Ca,L) are inhibited by reduced oxygen tensions. The authors therefore analyzed the effects of P(O2) on I(Ca,L) in human cardiomyocytes and the effects of isoflurane at reduced P(O2). METHODS: Atrial cardiomyocytes were prepared from specimens of patients undergoing open-heart surgery and superfused with either a high or a low P(O2) (150 or 12 +/- 1 mmHg) while I(Ca,L) were measured with the whole cell patch clamp technique. RESULTS: Basal I(Ca,L) were not changed by the P(O2) (range, 9-150 mmHg) at 21 degrees or 36 degrees C. The reducing agent 1,4-dithiothreitol (DTT) left I(Ca,L) unaffected, and the oxidizing agent 5,5'-dithio-bis(2-nitrobenzoic acid) (DTNB) irreversibly inhibited I(Ca,L). The P(O2) significantly affected the inhibition of I(Ca,L) by isoflurane (1 minimum alveolar concentration) that decreased I(Ca,L) by 17 +/- 2.0% at the high P(O2) but only by 5.8 +/- 2.9% (P = 0.037) at the low P(O2). The inhibition of I(Ca,L) by isoflurane was also significantly diminished (P = 0.018) by a low P(O2) when isoflurane effects at both P(O2) conditions were compared in the same cell. CONCLUSIONS: In contrast to the situation in guinea pigs, basal I(Ca,L) in human atrial cardiomyocytes was not sensitive to acute P(O2) changes over a wide range. This might be explained by a lack of oxygen-sensitive splice variants of L-type calcium channel subunits. The P(O2), however, has a decisive role for the effects of isoflurane on I(Ca,L).

Temperature-independent Inhibition of L-type calcium currents by halothane and sevoflurane in human atrial cardiomyocytes.

BACKGROUND: Cardiac L-type calcium currents (ICa,L) are affected by volatile anesthetics, possibly contributing to their side effects. Actions of anesthetics on ion channels are usually studied in vitro at room temperature. However, the solubility of anesthetic gases as well as ICa,L are markedly sensitive to the study temperature. Therefore, temperature-dependent effects of halothane and sevoflurane on cardiac ICa,L were analyzed. METHODS: ICa,L were studied at 21 degrees C and 36 degrees C with the patch clamp technique in isolated human atrial cardiomyocytes. Concentrations of anesthetics brought into solution by gassing at both temperatures were determined with gas chromatography. RESULTS: The aqueous concentrations of halothane and sevoflurane were linearly related to their concentration in the gas phase (1 to 3 minimum alveolar concentration [MAC]). At 21 degrees C, the slope of this relation was 0.52 and 0.12 mm/vol % for halothane and sevoflurane, respectively, and decreased at 36 degrees C to 0.29 and 0.09 mm/vol %, respectively. ICa,L displayed significantly higher current amplitudes at 36 degrees C than at 21 degrees C and significantly accelerated time-dependent inactivation. Halothane (1-2 MAC) and sevoflurane (1-3 MAC) evoked stronger inhibitions of ICa,L at 21 degrees C than at 36 degrees C. In spite of different temperature-dependent current amplitudes, the fractional (percent) inhibition of ICa,L showed the same linear relationship to the concentrations of halothane and sevoflurane in the bath medium at both temperatures, as revealed from present and previous experiments. CONCLUSIONS: Inhibition of ICa,L by halothane and sevoflurane is determined by the aqueous concentration of the anesthetics, independently of the temperature. Increased solubility may explain the stronger effects of the anesthetics at lower temperatures.

Effects of inhalational anesthetics on L-type Ca2+ currents in human atrial cardiomyocytes during beta-adrenergic stimulation.

BACKGROUND: Anesthetics may cause cardiac side effects by their action on L-type Ca2+ channels. Direct effects on the channels have not yet been discriminated from an interference with the beta-adrenergic channel regulation. The authors therefore studied the effects of halothane, sevoflurane, and xenon on human cardiac Ca2+ currents during stimulation with isoproterenol. METHODS: Currents through L-type Ca2+ channels were measured with the patch clamp technique in atrial cardiomyocytes obtained from patients undergoing cardiac surgery. Cells were superfused with solutions equilibrated with anesthetics at the desired concentrations. Ca2+ currents during pulses to 10 mV were evaluated with respect to their peak value (I(max)) and to the total moved charge (Q). RESULTS: In the absence and in the presence of isoproterenol (1 microm), sevoflurane (0.29 mm, 1 minimum alveolar concentration [MAC]) significantly depressed Q by 37.8 +/- 7.2% (mean +/- SD) and 40.8 +/- 10.3%, respectively. I(max) was not significantly affected in comparison with control cells never exposed to an anesthetic. Xenon (65%, 1 MAC) did not evoke significant effects. Exposure to halothane (0.39 mm, 1 MAC) during stimulation with isoproterenol significantly reduced Q by 31.3 +/- 23.3% (but not I(max)). After washout of halothane, Q was increased above the level prior to the application of halothane. Moreover, whereas Q promptly declined to baseline levels after washout of isoproterenol in controls, the previous exposure to halothane markedly delayed this decline, leaving Q significantly elevated for several minutes. CONCLUSIONS: Halothane exerts a dual effect on Ca2+ currents. The long-lasting stimulatory effect may contribute to the proarrhythmic potency of the drug that exceeds that of sevoflurane, which only depressed Ca2+ currents.