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Background: Cardioprotection by volatile anesthetic-induced preconditioning is known to involve intracellular signaling pathways. Recent studies have shown that protein kinase C (PKC) plays an important role in anesthetic-induced preconditioning. In this study, the effects of the activation of specific isozymes of PKC, specifically PKC-epsilon and -delta, on the modulation of the sarcolemmal adenosine triphosphate-sensitive potassium (sarcKATP) channel by isoflurane were investigated., Methods: The sarcKATP current was measured in ventricular myocytes isolated from guinea pig hearts using the whole cell configuration of the patch clamp technique. Peptides that induced the translocation of specific PKC isozymes were used to activate PKC-epsilon and PKC-delta., Results: Under whole cell conditions, isoflurane alone was unable to elicit the opening of the sarcKATP channel. Pretreatment with the specific PKC-epsilon activator, PP106, primed the sarcKATP channel to open in the presence of isoflurane. The resulting sarcKATP current densities in the presence of 0.88 mm isoflurane were 6.5 +/- 6.0 pA/pF (n = 7) and 40.4 +/- 18.2 pA/pF (n = 7) after pretreatment with 100 and 200 nm PP106, respectively. The PKC-epsilon antagonist PP93 abolished this effect. A scrambled peptide of the PKC-epsilon activator PP105 did not prime the sarcKATP channel. The PKC-delta activator PP114 was significantly less effective in priming the sarcKATP channel. 5-Hydroxydecanoate significantly attenuated the effect of the PKC-epdsilon activator on the sarcKATP channel. In addition, immunohistochemical analysis showed that the PKC-epsilon isoform translocated to both the mitochondria and sarcolemma after anesthetic-induced preconditioning, whereas the PKC-delta isoform translocated to the mitochondria., Conclusion: The PKC-epsilon isozyme primed the sarcKATP channel to open in the presence of isoflurane. The PKC-delta isozyme was significantly less effective in modulating the isoflurane effect on this channel.

Background: Halothane more so than isoflurane potentiates an alpha1-adrenoceptor (alpha1-AR)-mediated action of epinephrine that abnormally slows conduction in Purkinje fibers and may facilitate reentrant arrhythmias. This adverse drug interaction was further evaluated by examining conduction responses to epinephrine in combination with thiopental and propofol, which "sensitize" or reduce the dose of epinephrine required to induce arrhythmias in the heart, and with etomidate, which does not, and responses to epinephrine with verapamil, lidocaine, and l-palmitoyl carnitine, a potential ischemic metabolite., Methods: Action potentials and conduction times were measured in vitro using two microelectrodes in groups of canine Purkinje fibers stimulated at 150 pulses/min. Conduction was evaluated each minute after exposure to 5 microm epinephrine (or phenylephrine) alone or with the test drugs. Changes in the rate of phase 0 depolarization (Vmax) and the electrotonic spread of intracellular current were measured during exposure to epinephrine with octanol to evaluate the role of inhibition of active and passive (intercellular coupling) membrane properties in the transient depression of conduction velocity., Results: Lidocaine (20 microm) and octanol (0.2 mm) potentiated alpha1-AR-induced conduction depression like halothane (0.4 mm), with maximum depression at 3-5 min of agonist exposure, no decrease of Vmax, and little accentuation at a rapid (250 vs. 150 pulses/min) stimulation rate. Thiopental (95 microm), propofol (50 microm), and verapamil (2 microm) similarly potentiated epinephrine responses, whereas etomidate (10 microm) did not. Between groups, the decrease of velocity induced by epinephrine in the presence of (10 microm) l-palmitoyl carnitine (-18%) was significantly greater than that resulting from epinephrine alone (-6%; 0.05

Cardiac dysrhythmias during inhaled anesthesia are well documented and may, in part, involve depression of the fast inward Na+ current (INa) during the action potential upstroke. In this study, we examined the effects of halothane, isoflurane, and sevoflurane at clinically relevant concentrations on INa in single ventricular myocytes isolated enzymatically from adult guinea pig hearts. INa was recorded using standard whole-cell configuration of the patch clamp technique. Halothane at 0.6 mM and 1.2 mM produced significant (P < 0.05) depressions of peak INa of 12.3% +/- 1.8% and 24.4% +/- 4.1% (mean +/- SEM, n = 12), respectively. Isoflurane (0.5 mM, n = 12; 1.0 mM, n = 15) and sevoflurane (0.6 mM, n = 14; 1.2 mM, n = 12) were less potent than halothane, decreasing peak INa by 4.8% +/- 1.1% and 11.4% +/- 1.4% (isoflurane) and 3.0% +/- 0.7% and 10.7% +/- 3.9% (sevoflurane). The depressant effects on INa were reversible in all cases. For all anesthetics tested, the degree of block increased at more depolarizing potentials. Anesthetics induced significant shifts in the steady-state inactivation and activation of the channel toward more hyperpolarizing potentials. The present findings indicate that volatile anesthetics at clinical concentrations decrease the cardiac INa in a dose- and voltage-dependent manner. At approximately equianesthetic concentrations, the decrease of INa caused by halothane was twice that observed with isoflurane or sevoflurane.

The effects of halothane (0.45 and 0.9 mM, equivalent to 0.7 and 1.5 vol%, respectively) and isoflurane (0.56 and 1.23 mM, equivalent to 0.9 and 2.0 vol%) on slowly inactivating Na+ current were examined by whole-cell voltage-clamp techniques. This approach allows evaluation of the role of anesthetic inhibition of inward Na+ current on the action potentials of canine Purkinje fibers isolated from the false tendons. Cells were superfused with Tyrode's solution containing nifedipine and Ni2+ to block Ca2+ channel currents and internally dialyzed with Cs+ to block outward K+ currents. Veratridine (0.5 microM) was used throughout the experiments to enhance the slow Na+ current. Na+ current was elicited by depolarizing pulses from a holding potential of -100 mV to stepwise (10 mV increments) more positive membrane potentials and measured at 200 ms after initiation of the voltage pulse before, during, and after exposure to anesthetics. Slowly inactivating Na+ current showed threshold activation at -80 mV and peak activation around -55 to -40 mV. This current was abolished by 5 microM tetrodotoxin, showing the characteristic feature of Na+ channel current. Halothane and isoflurane depressed the amplitude of slowly inactivating Na+ current in a concentration-dependent manner and did not shift the current-voltage relationship for slow Na+ current activation. There was no significant difference between the sensitivities of slow Na+ current to halothane or isoflurane at equianesthetic concentrations. Inhibition of slow inward Na+ current may contribute to the marked decrease of action potential duration produced by volatile anesthetics in false tendon Purkinje fibers but does not account for the larger decreases of duration produced by isoflurane than halothane.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of inhalation anesthetics halothane, enflurane, and isoflurane on spontaneous impulse initiation (automaticity) and triggered sustained rhythmic activity were examined in Purkinje fibers derived from normal (n = 38) and 24-h-old infarcted canine hearts (n = 27) to further understanding of their influence on the cellular mechanisms underlying generation of cardiac arrhythmias. Purkinje fibers from normal or infarcted hearts were superfused with modified Krebs' solution (37 degrees C) with or without epinephrine (2 or 15 microM) and equilibrated with a 97% O2-3% CO2 gas mixture (control). Transmembrane action potentials were recorded using conventional microelectrode techniques, and Purkinje fibers were exposed to anesthetic concentrations equivalent to 2.0 MAC. Normal Purkinje fibers were not spontaneously active unless exposed to epinephrine. All anesthetics (enflurane greater than halothane, isoflurane; P less than 0.05) increased automaticity of normal Purkinje fibers exposed to either epinephrine concentration. Partially depolarized Purkinje fibers from infarcted hearts were either spontaneously active or were quiescent. For ischemic fibers that beat spontaneously, abnormal automaticity was sustained (duration greater than 300 s) or periodic (duration less than 300 s). Sustained abnormal automaticity was elicited by epinephrine (15 microM) in some quiescent partially depolarized fibers. None of the anesthetics affected the rate of sustained abnormal automaticity, regardless of whether the induction of such automaticity required epinephrine, nor did anesthetics significantly affect the duration of trains of periodic abnormal automaticity. Finally, quiescent, partially depolarized Purkinje fibers were tested for triggered rhythmic activity during pacing at a cycle length of 800 ms.(ABSTRACT TRUNCATED AT 250 WORDS)

The authors investigated the effects of halothane (HAL) and isoflurane (ISO) on cardiac depression produced by global hypoxia and the recovery of function following reoxygenation is isolated guinea pig hearts perfused with Krebs' solution at constant pressure. Isovolumetric left ventricular systolic (LVSP) and end-diastolic pressures (LVEDP) were measured by placing a saline filled, latex balloon into the left ventricle. Bipolar electrodes were placed in the right atrium and right ventricle for measurements of heart rate (HR), atrioventricular conduction time (AVCT), and determination of the incidence and severity of dysrhythmias occurring during hypoxia and reoxygenation. Hearts were divided into three groups: control (n = 20), halothane (n = 12), and isoflurane (n = 13). All hearts were exposed in sequence to oxygenated perfusate (PO2, 530 mmHg), moderately hypoxic perfusate (PO2, 91 mmHg) for 30 min, and then to oxygenated perfusate for 40 min. Halothane (1%, 0.4 mM) or isoflurane (1.5%, 0.5 mM) were administered 10 min before hypoxia, during hypoxia, and during the first 10 min of reoxygenation. Exposure to halothane and isoflurane before hypoxia produced a 14 and 11% decrease in heart rate, a 32 and 23% increase in AVCT, and a 47 and 28% decrease in LVSP (all P less than or equal to 0.001) for halothane and isoflurane, respectively, and no significant change in LVEDP. During hypoxia, HR decreased and AVCT increased similarly in both groups. Left ventricular systolic pressure (LVSP) decreased sharply with a narrowing of the prehypoxic differences among the groups. In the control and isoflurane groups, LVEDP increased during hypoxia but remained unchanged in the halothane group.(ABSTRACT TRUNCATED AT 250 WORDS)