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PubMed1996

Isoflurane, but not halothane, improves indices of diastolic performance in dogs with rapid ventricular, pacing-induced cardiomyopathy.

BACKGROUND: The left ventricular (LV) mechanical effects of isoflurane and halothane were examined in dogs with rapid LV pacing-induced cardiomyopathy. These experiments tested the hypothesis that isoflurane and halothane differentially enhance indices of diastolic performance in dogs with moderate LV dysfunction. METHODS: Eight dogs were chronically instrumented for measurement of LV and aortic pressures, subendocardial segment length, and cardiac output. Contractility was quantified by preload recruitable stroke work (Mw). Diastolic function was evaluated with a time constant of isovolumic relaxation (tau), segment lengthening velocities and time-velocity integrals during early filling (dL/dtE and TVI-E) and atrial systole (dL/dtA and TVI-A), and a regional chamber stiffness constant (Kp). Hemodynamics and LV function were recorded in the conscious state before pacing. The left ventricles of the dogs were then continuously paced at ventricular rates between 220 and 240 beats.min-1 for 10 +/- 1 days and monitored on a daily basis. After the development of moderate LV dysfunction, pacing was temporarily discontinued, and dogs were studied in sinus rhythm in the conscious state and after 20 min equilibration at 1.1, 1.4, and 1.7 minimum alveolar concentration isoflurane and halothane on separate days. RESULTS: Chronic rapid pacing increased baseline (sinus rhythm) heart rate, LV end-diastolic pressure, and end-diastolic segment length and decreased mean arterial pressure, LV systolic pressure, and cardiac output. Mw decreased and tau and Kp increased, consistent with LV systolic and diastolic dysfunction. Reductions in dL/dtE/dL/dtA and TVI-E/A occurred, which indicated that LV filling was more dependent on atrial systole. In dogs with cardiomyopathy, isoflurane and halothane increased heart rate and decreased mean arterial pressure, LV systolic pressure, LV end-diastolic pressure, cardiac output, Mw, and Kp. Decreases in LV end-diastolic pressure were more pronounced in dogs anesthetized with 1.1 minimum alveolar concentration isoflurane compared with halothane. Halothane-induced decreases Mw were greater than those observed with equi-minimum alveolar concentration isoflurane. A reduction in tau and increases in TVI-E/TVI-A and the ratio of early to total LV filling were observed with isoflurane. In contrast, halothane caused dose-related reductions in dL/dtE, dL/dtA, TVI-E, and TVI-A, and did not improve the ratios of these variables. CONCLUSIONS: Isoflurane, but not halothane, improved several indices of diastolic performance in dogs with pacing-induced LV dysfunction, despite producing simultaneous negative inotropic effects. These findings can probably be attributed to favorable reductions in LV preload and not to direct lusitropic effects. Improvement of filling dynamics may partially offset the decrement in LV systolic function by isoflurane in the setting of LV dysfunction.

Anesthetics, Inhalation↗
PubMed1996

Sevoflurane depresses myocardial contractility less than halothane during induction of anesthesia in children.

BACKGROUND: Cardiovascular stability is an important prerequisite for any new volatile anesthetic. We compared echocardiographically derived indices of myocardial contractility during inhalation induction with sevoflurane and halothane in children. METHODS: Twenty children were randomized to receive either halothane or sevoflurane for inhalation induction of anesthesia. No preoperative medications were given. Myocardial contractility was evaluated at baseline and at sevoflurane and halothane end-tidal concentrations of 1.0 minimum alveolar concentration (MAC) and 1.5 MAC. RESULTS: There were no differences between groups in patient age, sex, physical status, weight, or height. Equilibration times and MAC multiples of sevoflurane and halothane were comparable. Vital signs remained stable throughout the study. Left ventricular end-systolic meridional wall stress increased with halothane but remained unchanged with sevoflurane. Systemic vascular resistance decreased from baseline to 1 MAC and 1.5 MAC with sevoflurane. Halothane depressed contractility as assessed by the stress-velocity index and stress-shortening index, whereas contractility remained within normal limits with sevoflurane. Total minute stress and normalized total mechanical energy expenditure, measures of myocardial oxygen consumption, did not change with either agent. CONCLUSIONS: Myocardial contractility was decreased less during inhalation induction of anesthesia with sevoflurane compared with halothane in children. Although the induction of anesthesia with sevoflurane or halothane was equally well tolerated, the preservation of myocardial contractility with sevoflurane makes it an attractive alternative for inducing anesthesia in children.

Anesthesia, Inhalation↗
PubMed1997

Halothane and enflurane attenuate pulmonary vasodilation mediated by adenosine triphosphate-sensitive potassium channels compared to the conscious state.

BACKGROUND: Adenosine triphosphate (ATP)-sensitive potassium (k+ATP) channels play an important role in pulmonary vasoregulation. However, the effects of volatile anesthetics on k+ATP channel-mediated pulmonary vasoregulation have not been elucidated. The purpose of the present study was to investigate the effects of halothane and enflurane anesthesia on the pulmonary vasodilator response to the selective k+ATP channel agonist lemakalim (BRJ38227) compared with that measured in the conscious state. The authors also investigated the extent to which endogenous neurohumoral vasoconstrictor mechanisms modulate the vasodilator response to k+ATP channel activation. METHOD: Nineteen conditioned, male mongrel dogs were chronically instrumented to measure the left pulmonary vascular pressure-flow (LPQ) relationship. LPQ plots were generated by continuously measuring the pulmonary vascular pressure gradient (pulmonary arterial pressure-left atrial pressure) and left pulmonary blood flow during gradula (approximately 1 min) inflation of a hydraulic occluder implanted around the right main pulmonary artery. After preconstriction with the thromboxane analog, U46619 (9,11-dideoxy-11 alpha, 9 alpha-epoxymethano-prostaglandin F2 alpha), the pulmonary vascular dose-response relationship for the k+ATP agonist lemakalim was assessed in the conscious and halothane-anesthetized states and also in the conscious and enflurane-anesthetized states. This protocol was repeated in conscious and halothane-anesthetized dogs after combined neurohumoral block with antagonists of sympathetic alpha 1 adrenoreceptors, arginine vasopressin V1-receptors, and angiotensin II receptors. The effect of the k+ATP antagonist glybenclamide on the baseline LPQ relationship and on the lemakalim dose-response relationship also was assessed in conscious dogs. RESULTS: Compared with the conscious state, halothane, enflurane and glybenclamide had no net effect on the baseline LPQ relationship. In contrast, halothane and enflurane attenuated (P < 0.05) the pulmonary vasodilator response to lemakalim compared with the conscious state. Glybenclamide also caused a rightward shift (P < 0.05) in the lemakalim dose-response relationship. Combined neurohumoral block did not modulate the vasodilator response to lemakalim in the conscious state. The halothane-induced attenuation of the vasodilator response to lemakalim was apparent after combined neurohumoral block. CONCLUSION: These results indicate that halothane and enflurane act to reduce the magnitude of K+ATP channel-mediated pulmonary vasodilation. Reflex pulmonary vasoconstriction resulting from K+ATP mediated systematic hypotension does not alter the magnitude of the pulmonary vasodilator response to lemakalim nor is it responsible for the attenuated response to K+ATP channel activation during halothane anesthesia.

Adenosine Triphosphate↗
PubMed1997

Isoflurane- and halothane-mediated dilation of distal bronchi in the rat depends on the epithelium.

BACKGROUND: Respiratory epithelium releases substance(s) that can modulate bronchoconstriction in response to constrictive agonists and enhance bronchodilation in response to certain bronchodilators. The hypothesis that the bronchodilatory effect of isoflurane and halothane depends on the epithelium was tested in rat distal bronchial segments. METHODS: Wistar rat bronchial segments of the fourth order (diameter approximately 100 microns) were dissected. After preconstriction with 5-hydroxytryptamine, each bronchial segment was exposed to increasing concentrations of 0% to 3% isoflurane or 0% to 3% halothane under four conditions: after epithelial rubbing, after pretreatment with the nitric oxide synthase inhibitor NG-nitro-L-arginine, after pretreatment with the cyclooxygenase inhibitor indomethacin, or with no preintervention (control). Changes in bronchial diameter were monitored using an in vitro video detection system. RESULTS: Both isoflurane and halothane produced concentration-dependent bronchodilation (P < 0.001 for either anesthetic; 40% +/- 11% [mean +/- SD] dilation for 3% isoflurane and 57% +/- 10% dilation for 3% halothane). For both anesthetics, bronchodilation was significantly but incompletely attenuated by epithelial rubbing (12% +/- 7% dilation for 3% isoflurane [P < 0.01] and 31% +/- 10% dilation for 3% halothane [P < 0.01]), by pretreatment with indomethacin (20% +/- 8% dilation for 3% isoflurane [P < 0.02] and 21% +/- 9% dilation for 3% halothane [P < 0.001]), or by L-NNA (9% +/- 7% dilation for 3% isoflurane [P < 0.005] and 39% +/- 12% dilation for 3% halothane [P < 0.05]). Epithelial rubbing did not impair nitroprusside-associated bronchodilation. CONCLUSIONS: Isoflurane- and halothane-mediated bronchodilation depends at least partially on the epithelium and may involve both a prostanoid and nitric oxide in distal rat bronchi.

Anesthetics, Inhalation↗
PubMed1997

Actions of phenylephrine, isoproterenol, and epinephrine with halothane on endocardial conduction and activation in canine left ventricular papillary muscles.

BACKGROUND: Myocardial sensitization by halothane to the arrhythmogenic effects of epinephrine involves synergistic actions mediated by alpha 1- and beta-adrenoceptors. Halothane potentiates a transient a1-adrenoceptor-mediated negative dromotropic effect of epinephrine on Purkinje fibers. This study examines how halothane alters the actions of alpha 1- and beta-agonists and epinephrine on endocardial conduction. METHODS: Superfused canine papillary muscles were mapped to locate a Purkinje-ventricular muscle junction (PVJ), and bipolar electrodes were placed to measure Purkinje and endocardial conduction velocity and PVJ conduction time during stimulation of the Purkinje layer. The effects of exposure to 5 microM phenylephrine, 1 microM isoproterenol, or 5 microM epinephrine on conduction were determined in the absence and presence of 0.4 mM halothane in three groups of 10 preparations. RESULTS: Isoproterenol slightly increased Purkinje conduction velocity and markedly improved conduction at the PVJ and in the endocardium similarly in the presence or absence of halothane. Phenylephrine depressed Purkinje velocity (-12%) only in the presence of halothane and did not slow conduction at the PVJ or in the myocardium. Epinephrine transiently depressed Purkinje velocity, more so with (-22%) than without (-12%) halothane (P < or = 0.01), and simultaneously facilitated conduction at the PVJ and in the myocardium. CONCLUSIONS: The prodysrhythmic actions of epinephrine with halothane may involve disparate effects on conduction, including speeding on conduction at the PVJ and in the myocardium, similar to that produced by isoproterenol, accompanied by simultaneous but transient alpha 1-mediated depression of conduction in the Purkinje system.

Adrenergic alpha-Agonists↗
PubMed1997

Halothane attenuates endothelium-dependent pulmonary vasorelaxant response to lemakalim, an adenosine triphosphate (ATP)-sensitive potassium channel agonist.

BACKGROUND: Lemakalim, an adenosine triphosphate (ATP)-sensitive potassium (K+(ATP)) channel agonist, causes profound pulmonary vasodilation in conscious dogs, which is attenuated during halothane anesthesia. The goal of the present study was to investigate the mechanism responsible for this attenuating effect of halothane. METHODS: Isolated canine pulmonary arterial rings were suspended for isometric tension recording in 25 ml organ baths. Rings with and without endothelium were contracted to 50% of their maximal response to phenylephrine, followed by the cumulative administration of lemakalim with or without exposure to halothane (0.5-1.5 minimum alveolar concentration [MAC] in dogs). Lemakalim dose-response curves were also generated in rings pretreated with the nitric oxide synthase inhibitor, Nw-nitro-L-arginine methyl ester (L-NAME); the cyclooxygenase inhibitor, indomethacin; or the K+(ATP) channel antagonist, glybenclamide. RESULTS: Compared with intact rings, the pulmonary vasorelaxant response to lemakalim was attenuated (P < 0.05) in endothelium-denuded rings. Halothane at 0.5 MAC had no effect on the vasorelaxant response to lemakalim. Halothane at 1 MAC attenuated (P < 0.05) the vasorelaxant response to lemakalim in intact rings, but not in endothelium-denuded rings. Halothane at 1.5 MAC attenuated (P < 0.05) the vasorelaxant response to lemakalim in both intact and endothelium-denuded rings. In endothelium-intact rings, indomethacin attenuated (P < 0.05) the vasorelaxant response to lemakalim, whereas L-NAME had no effect. Further, indomethacin, but not L-NAME, abolished the endothelium-dependent, halothane-induced attenuation of the lemakalim vasorelaxation response. Glybenclamide markedly attenuated (P < 0.05) lemakalim vasorelaxation at lemakalim doses less than 10(-6) M. CONCLUSIONS: Lemakalim-induced pulmonary vasorelaxation involves an endothelium-dependent and vascular smooth muscle component. Further, halothane attenuates the endothelium-dependent pulmonary vasorelaxant response to lemakalim via an inhibitory effect on vasodilator metabolites of the cyclooxygenase pathway.

Adenosine Triphosphate↗
PubMed1997

The effect of halothane on the recirculatory pharmacokinetics of physiologic markers.

BACKGROUND: The cardiovascular effects of halothane are well recognized, but little is known of how this affects drug distribution. The effect of halothane anesthesia on physiologic factors that affect drug disposition from the moment of injection was investigated. METHODS: The dispositions of markers of intravascular space and blood flow (indocyanine green), extracellular space and free water diffusion (inulin), and total body water and tissue perfusion (antipyrine) were determined in four purpose-bred coonhounds. The dogs were studied while awake and while anesthetized with 1%, 1.5%, and 2% halothane in a randomized order determined by a repeated measures Latin square experimental design. Marker dispositions were described by recirculatory pharmacokinetic models based on frequent early and less frequent later arterial blood samples. These models characterize the role of cardiac output and its distribution on drug disposition. RESULTS: Halothane caused a significant and dose-dependent decrease in cardiac output. The disposition of antipyrine was most profoundly affected by halothane anesthesia, which increased both nondistributive intercompartmental clearance and volume while decreasing fast and slow tissue clearances and elimination clearance in a halothane dose-dependent manner. CONCLUSIONS: Halothane-induced changes in blood flow to the compartments of the antipyrine recirculatory model were not proportional to changes in cardiac output. Halothane anesthesia significantly increased (to more than double) the area under the drug concentration versus time curve due to an increase in the apparent peripheral blood flow not involved in drug distribution, despite a dose-dependent cardiac output decrease. Recirculatory pharmacokinetic models include the best aspects of traditional compartmental and physiologic pharmacokinetic models while offering advantages over both.

Anesthesia, Inhalation↗
PubMed1997

Effects of halothane on the phrenic nerve responses to carbon dioxide mediated by carotid body chemoreceptors in vagotomized dogs.

BACKGROUND: Previous studies in dogs showed that the phrenic nerve response to an acute hypoxic stimulus was dose dependently depressed by 0.5-2.0 minimum alveolar concentration (MAC) of halothane but not abolished. Because a carbon dioxide stimulus is transduced by a different mechanism in the carotid body chemoreceptors (CBCRs) than is a hypoxic stimulus, inhalational anesthetics may preferentially depress one of these transduction processes, the central neuronal processing, or both, of the integrated responses to these two types of inputs. METHODS: Carotid body chemoreceptor stimulation was produced by short (1-1.5 s), bilateral, 100% carbon dioxide in saline infusions into the carotid arteries during neural inspiration in unpremedicated, halothane-anesthetized, paralyzed, vagotomized dogs during constant mechanical ventilation. The phrenic neurogram quantified the neural inspiratory response. Four protocols were performed in the study: (1) the dose-dependent effects of halothane anesthesia (0.5-2.0 MAC) during hyperoxic hypercapnia on phrenic nerve activity, (2) the effects of three background levels of the partial pressure of carbon dioxide (PaCO2) on the magnitude of the carbon dioxide infusion responses at 1 MAC halothane, (3) the effects of anesthetic type on the magnitude of the carbon dioxide infusion response, and (4) the effects of CBCR denervation. RESULTS: Peak phrenic nerve activity (PPA) increased significantly during the carbon dioxide-stimulated phrenic burst in protocols 1-3; after denervation there was no response (protocol 4). Halothane produced a dose-dependent reduction in the PPA of control and carbon dioxide infusion-stimulated phrenic bursts and in the net carbon dioxide response. The net PPA responses for the different PaCO2 background levels were not different but were somewhat larger for sodium thiopental anesthesia than for 1.0 MAC halothane. CONCLUSIONS: The phrenic nerve response to an acute, severe carbon dioxide stimulus was dose dependently depressed by surgical doses of halothane. The observed responses to carbon dioxide infusion were mediated by the CBCRs because they were eliminated by CBCR denervation. These results suggest that the CBCR transduction and central transmission of the carbon dioxide signal in terms of inspiratory excitatory drive are not abolished at surgical levels of halothane anesthesia.

Anesthetics, Inhalation↗
PubMed1998

Differential effect of halothane and forskolin on platelet cytosolic Ca2+ mobilization and aggregation.

BACKGROUND: Previous works have suggested that the impairment of platelet aggregation by halothane was partly related to a stimulation of cyclic adenosine monophosphate (cAMP) production, to an inhibitory effect on Ca2+ signaling, or both. Intracellular Ca2+ measurements therefore were undertaken, first to determine the critical steps in the platelet CaZ+ signaling cascade most likely to be affected by halothane or by an increase in cAMP production, and second to establish if the effect of halothane involves aggregation-related biochemical pathways triggered by an increase in internal Ca2+. METHODS: Human washed platelets were treated with halothane or forskolin for 5 min before application of either platelet-activating factor, thrombin, U46619, or thapsigargin. The cytosolic Ca2+ concentration ([Ca2+]i) was measured with the fluorescent Ca2+ indicator fura-2. Nephelometric measurements were also performed to assay the aggregation process. RESULTS: Our results indicate that pretreating platelets with halothane leads to a partial impairment of the [Ca2+]i increase induced either by U46619, thrombin, or platelet-activating factor, but this had no significant effect on the [Ca2+]i response triggered by thapsigargin. In addition, our results show that halothane inhibits platelet aggregation triggered by U46619, but not by thapsigargin. Conversely, forskolin completely inhibited the [Ca2+]i response to U46619 and thapsigargin and prevented platelet aggregation induced by both agonists. CONCLUSIONS: These results suggest that halothane and cAMP exert their effects on platelet aggregation and Ca2+ signaling through different mechanisms, and that halothane cannot impair platelet aggregation independently of phospholipase C stimulation.

Anesthetics, Inhalation↗
PubMed1999

Halothane induces calcium release from human skinned masseter muscle fibers.

BACKGROUND: An increase in masseter muscle tone in response to halothane or succinylcholine anesthesia (or both) can be observed in healthy persons. Thus the authors compared the fiber-type halothane and succinylcholine sensitivities in human masseter and vastus lateralis muscles. METHODS: Masseter and vastus lateralis muscle segments were obtained from 13 and 9 healthy persons, respectively. After chemical skinning of a single fiber and loading the sarcoplasmic reticulum with Ca++ 0.16 microM solution, halothane (0.5-4 vol% bubbled in the incubating solution), succinylcholine (0.1 microM to 10 mM), or both sensitivities were defined as the concentration inducing more than 10% of the maximum tension obtained by application of 16 microM Ca++ solution. The myofilament response to Ca++ was studied with and without halothane by observing the isometric tension of skinned masseter fibers challenged with increasing concentrations of Ca++. Muscle fiber type was determined by the difference in strontium-induced tension measurements. RESULTS: A significant difference in halothane sensitivity was found between type 1 masseter fibers (0.6+/-0.2 vol%; mean +/- SD) versus type 1 (2.7+/-0.6 vol%) and type 2 vastus lateralis muscle (2.5+/-0.4 vol%). Succinylcholine did not induce Ca++ release by the sarcoplasmic reticulum. In the masseter muscle, 0.75 vol% halothane decreased the maximal activated tension by 40% but did not change the Ca++ concentration that yields 50% of the maximal tension. CONCLUSIONS: The very low halothane threshold for Ca++ release from the masseter muscle usually could be counteracted by a direct negative inotropic effect on contractile proteins. However, halothane may increase the sensitivity of the sarcoplasmic reticulum Ca++ release to succinylcholine-induced depolarization, leading to an increase in masseter muscle tone.

Adult↗
PubMed1999

Effects of halothane on synaptic neurotransmission to medullary expiratory neurons in the ventral respiratory group of dogs.

BACKGROUND: The activity of canine expiratory neurons is primarily dependent on N-methyl-D-aspartic acid (NMDA)-receptor mediated excitatory chemodrive inputs and a powerful inhibitory gain modulatory mechanism mediated via gamma-aminobutyric acidA (GABA(A)) receptors. We examined whether the depressant effect of halothane on expiratory neuronal activity is primarily caused by a reduction in glutamatergic excitation or a potentiation of the inhibitory mechanism. METHODS: Experiments were performed in halothane-anesthetized, vagotomized, paralyzed, and mechanically ventilated dogs during hypercapnic hyperoxia. The effect of a halothane dose increase from one minimum alveolar concentration (MAC) to 2 MAC on extracellularly recorded expiratory neuronal activity was studied before and during complete GABA(A) receptor blockade by localized picoejection of bicuculline close to the neuron. Complete blockade of the inhibitory mechanism allowed differentiation between the effects of halothane on overall NMDA-mediated excitation and on GABA(A)-mediated inhibition. RESULTS: The spontaneous activity of 12 expiratory neurons was significantly depressed (18.1%) by the 1-MAC halothane dose increase. Overall glutamatergic excitation was depressed 38.3+/-12.3% (mean +/- SD) by the 1-MAC halothane increase. The prevailing GABA(A)ergic attenuation of neuronal output decreased significantly from 49.5+/-10 to 32.0+/-10.4%. Thus overall inhibition was reduced by halothane by 33.5+/-17.2%. CONCLUSIONS: These results suggest that the depressive effect of a 1-MAC halothane dose increase on expiratory neuronal activity in our in vivo preparation with an intact neural network was mainly caused by a reduction of synaptic excitatory mechanisms and not an enhancement of synaptic inhibitory mechanisms.

Anesthetics, Inhalation↗
PubMed1999

Halothane and isoflurane increase spontaneous but reduce the N-methyl-D-aspartate-evoked dopamine release in rat striatal slices: evidence for direct presynaptic effects.

BACKGROUND: Experimental data suggest that volatile anesthetics induce significant changes in extracellular dopamine concentrations in the striatum, a restricted but functionally important brain area. In the present study, the authors used a superfused slice preparation to examine the effects of halothane and isoflurane on both spontaneous and N-methyl-D-aspartate (NMDA)-evoked dopamine release in the striatum, and whether these effects involved actions of these anesthetics mediated by gamma-aminobutyric acid receptors in this structure. METHODS: Radioactivity collected from 5-min fractions was compared in the absence (basal release) or presence (evoked release) of NMDA alone and combined with various pharmacologic or anesthetic agents in slices of the dorsolateral striatum and synaptosomes of the whole striatum preloaded with 3H-dopamine and superfused with artificial cerebrospinal fluid. RESULTS: In tetrodotoxin-treated striatal slices, halothane and isoflurane significantly increased dopamine basal release (EC50 = 0.33 mM and 0.41 mM for halothane and isoflurane, respectively). Both agents decreased the NMDA-evoked dopamine release in both the absence (IC50 = 0.15 mM and 0.14 mM for halothane and isoflurane, respectively) and presence (IC50 = 0.15 mM for both halothane and isoflurane) of tetrodotoxin in slices, and in synaptosomes (IC50 = 0.19 mM for both halothane and isoflurane). NMDA-induced dopamine release was significantly enhanced by bicuculline, a gamma-aminobutyric acid receptor antagonist. Halothane and isoflurane inhibitory effects on NMDA-evoked dopamine release were significantly reduced in the presence of bicuculline. CONCLUSION: These results indicate that halothane and isoflurane decrease the NMDA-evoked dopamine release by acting directly at dopamine terminals in striatal slices. They support the involvement of both depression of presynaptic NMDA receptor-mediated responses and enhancement of gamma-aminobutyric acid receptor-mediated responses in these effects.

Algorithms↗
PubMed2000

Comparative contractile effects of halothane and sevoflurane in rat aorta.

BACKGROUND: Volatile anesthetic agents have been shown to have contractile effects in vascular tissues during specific conditions. This study compared contractile effects of halothane and sevoflurane in rat aorta treated with verapamil. This study also tried to elucidate the mechanism of the contraction. METHODS: Endothelium-denuded rat thoracic aorta was used for recording of isometric tension and measurement of influx of 45Ca2+. All experiments were performed in the presence of verapamil. In recording of tension, rings were precontracted with a submaximum dose of phenylephrine, followed by exposure to halothane or sevoflurane. For measurement of influx of 45Ca2+, rat aortic strips were exposed to phenylephrine and then to additional halothane or sevoflurane. Influx of Ca2+ was estimated by incubating the strips in 45Ca2+-labeled solution for 2 min. RESULTS: Halothane (0.5-4.0%) induced contraction in a dose-dependent manner, whereas sevoflurane (1-4%) had no effect on tension. Influx of 45Ca2+ was strongly enhanced by halothane at 1% and 2%, but only slightly at 4%, and was not affected by 1-4% sevoflurane. SK&F 96365, a blocker of voltage-independent Ca2+ channels, abolished contraction and influx of 45Ca2+ by 1% halothane. Depletion of Ca2+ from the sarcoplasmic reticulum with ryanodine or thapsigargin reduced the contraction induced by halothane at 4% but not that at 1% and 2%. CONCLUSION: Halothane is suggested to cause contraction by enhancing influx of Ca2+ via voltage-independent Ca2+ channels at concentrations up to 2% and by inducing release of Ca2+ at 4%. Sevoflurane (1-4%) is devoid of these contractile effects.

Anesthetics, Inhalation↗
PubMed2002

Kinetic modulation of HERG potassium channels by the volatile anesthetic halothane.

BACKGROUND: (human ether-a-gogo related gene) encodes the cardiac rapidly activating delayed rectifier potassium currents (I(kr)), which play an important role in cardiac action potential repolarization. General anesthetics, like halothane, can prolong Q-T interval, suggesting that they act on myocellular repolarization, possibly involving HERG channels. Evidence for direct modulation of HERG channels by halothane is still lacking. To gain insight on HERG channel modulation by halothane the authors recorded macroscopic currents expressed in Xenopus oocytes and conducted non-stationary noise analysis to evaluate single channel parameters modified by the anesthetic. METHODS: Macroscopic currents were recorded in 120 mM K(+) internal-5 mM K(+) external solutions with the cut open oocyte technique. Macropatch recordings for non-stationary noise analysis of HERG tail currents were made in symmetrical 120 mM K(+) solutions. Pulse protocols designed for HERG current recording were elicited from a holding potential of -80 mV. Halothane was delivered via gravity-fed perfusion. RESULTS: Halothane (0.7%, 1.5%, and 3%) decreased macroscopic currents in a concentration-dependent manner (average reduction by 14%, 22%, and 35% in the range of -40 mV to 40 mV) irrespective of potential. HERG currents had slower activation and accelerated deactivation and inactivation. Non-stationary noise analysis revealed that halothane, 1.5%, decreased channel P(o) by 27%, whereas single-channel current amplitudes and number of channels in the patch remained unchanged. CONCLUSIONS: Halothane inhibits HERG currents expressed in oocytes in a concentration-dependent manner. It slowed down activation and accelerated deactivation and inactivation of HERG channels. The authors' results demonstrate that halothane decreased HERG currents by modulating kinetic properties of HERG channels, decreasing their open probability. Partial block of I(kr) currents could contribute to delayed myocellular repolarization and altered cardiac electrophysiology.

Anesthetics, Inhalation↗
PubMed2003

Effect of halothane on the guanosine 5' triphosphate binding activity of G-protein alphai subunits.

BACKGROUND: Receptor-mediated increases in the force produced by airway smooth muscle are attenuated by anesthetics such as halothane. Guanosine 5'-triphosphate (GTP) binding protein alpha subunits (Galpha(i)) are known to participate in the regulation of force in airway smooth muscle. The authors hypothesized that halothane would inhibit the ability of Galpha(i) subunits to bind a nonhydrolyzable analog of GTP (GTPgammaS). METHODS: The effect of halothane on both GTPase-specific activity and [35S]GTPgammaS binding were assayed using purified, recombinant Galpha(i1). In separate experiments, [35S]GTPgammaS binding to Galpha(i) in crude airway smooth muscle membrane preparations was assayed using an immunoprecipitation technique in the presence and absence of halothane. RESULTS: The steady state GTPase-specific activity of the recombinant Galpha(i1) was 0.033 +/- 0.018 (mean +/- SD) mole P(i) mole Galpha(i1)-1 min-1 under control conditions and 0.035 +/- 0.015 mole P(i) mole Galpha(i1)-1 min-1 in the presence of 1.1 +/- 0.2 mm halothane, a difference that is not significant. The mole fractions of recombinant Galpha(i1) bound to [35S]GTPgammaS were 0.49 +/- 0.02 and 0.60 +/- 0.02 at 10 and 20 min, respectively. The addition of halothane (1.26 +/- 0.07 mm) did not significantly change these values. Halothane did not affect the binding of [35S]GTPgammaS to Galpha(i) subunits in membrane fractions of airway smooth muscle as measured using immunoprecipitation. Validity of the assays was confirmed using suramin, an inhibitor of GTP binding. CONCLUSION: These results suggest that halothane, which inhibits receptor-activated Galpha(i)-coupled pathways in intact airway smooth muscle, must functionally target a component of the G protein-coupled receptor complex other than Galpha(i).

Adenosine Triphosphatases↗
PubMed1989

Cardiopulmonary effects of ephedrine in halothane-anesthetized horses.

The cardiopulmonary effects of intravenous (i.v.) administration of the sympathomimetic drug ephedrine during two different levels of halothane anesthesia [end-tidal concentration of 1.37% (light anesthesia) and 2.1% (deep anesthesia)] were studied in eight horses. Anesthesia was induced and maintained using only halothane in O2. Ventilation was controlled to maintain a Paco2 of 38-42 mmHg. Following instrumentation and stabilization of the horse at the halothane concentration being studied, baseline measurements of cardiac output (Q), arterial blood pressure (AP), pulmonary artery pressure, heart rate, Pao2, Paco2 and pH were made. Ephedrine was then administered (0.06 mg/kg i.v.) and these measurements repeated at 10, 20, 30, 45 and 60 min after injection. At both doses of halothane there was a significant (P less than 0.05) increase in Q, stroke volume (SV), and systolic AP following ephedrine administration. In addition, at 2.1% halothane, ephedrine administration resulted in a significant (P less than 0.05) increase in mean AP and Pao2 and a decrease in total peripheral resistance. The increase in systolic AP, Q, and SV was significantly (P less than 0.05) greater at 2.1% halothane than at 1.37% halothane. Ephedrine administration to horses during both light and deep halothane anesthesia results in an increase in AP that is due to an increase in Q and SV.

Animals↗
PubMed1976

Effects of halothane on the metabolism of human adipose tissue.

The metabolism of specimens of human adipose tissue exposed to different concentrations of halothane was studied. Halothane was added to the incubation medium directly or via the gas phase above the medium. The basal lipolysis was significantly increased by low concentrations of halothane. Higher concentrations clearly diminished the lipolysis, but here, in spite of the inhibitory effect on the basal lipolysis, the lipolytic effect of noradrenaline expressed as percent increment was increased. The rate of lipid synthesis from glucose was reduced when halothane was present in the gas phase. The effect of insulin on glucose metabolism was not affected by the presence of halothane, while the antilipolytic action was abolished by high concentrations of halothane. The results show that halothane may exert dual effects on the mobilization of lipids from human adipose tissue; at low concentrations halothane enhances the basal lipolysis, while at higher concentrations it exerts inhibitory effects.

Adipose Tissue↗
PubMed1977

The need for halothane supplementation of N2O-O2-relaxant anaesthesia in chronic alcoholics.

The demand for intermittant halothane supplementation during N2O-O2-relaxant anaesthesia was studied in 25 alcohlics (annual consumption over 15 1 pure alcohol) scheduled for biliary or gastric surgery. The controls were 45 non-alcoholics and 43 patients with an annual consumption of between 1 to 15 1. Thiopental (3 mg/kg/min) was given for induction. After intubation, halothane supplementation was given in 0.5% concentration for 10-min periods. Standardized criteria for halothane supplementation were various motor and autonomic responses to painful stimuli. Muscular relaxation was kept fairly constant (roughly 90%), as assessed visually with the aid of a peripheral nerve stimulator. The total time for which halothane supplementation was given, expressed as a percentage of the total anaesthesia time, was used as an indication of the need for halothane supplementation. The need for thiopental for induction was not increased to a statistically significant extent in alcoholics, but signs of excitation did occur in 40% as compared with 11% in non-alcoholics (P less than 0.01). The demand for halothane supplementation was higher in alcoholics (47 +/- 4.8%, s.e. mean) than in non-alcoholics (33 +/- 2.3%). This difference, however, was partly due to the higher incidence of gastric surgery, which required more supplementation than biliary surgery. Analysis of the different criteria indicating the need for halothane supplementation revealed that an increase in blood pressure or heart rate was more common in non-alcoholics, whereas motor irritability, sweating and lacrimation were more frequent in alcoholics. Management of the anaesthetic posed no special difficulties in the alcoholics with an estimated mean annual consumption of 32 +/- 4 (s.e. mean) litres of absolute alcohol. Three patients (5% of the alcohol consumers) reported dreams or recollections, suggesting that this mode of halothane supplementation does not guarantee an adequate anaesthetic depth. The difficulties and biases associated with this type of analysis are discussed.

Alcoholism↗