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PubMed2003

Desflurane affords greater protection than halothane against focal cerebral ischaemia in the rat.

BACKGROUND: We studied the potential neuroprotective effects of halothane and desflurane, compared with the awake state, on infarct size following 2 h of intraluminal middle cerebral artery occlusion (MCAo) and 22 h of reperfusion. METHODS: Male Sprague-Dawley rats were anaesthetized with desflurane or halothane, intubated, and mechanically ventilated. Mean arterial pressure (MAP), blood gases, and pH were controlled. Body temperature was maintained at 37.5-38 degrees C. Animals were assigned to one of four groups according to the anaesthetic type (halothane or desflurane) and the duration of anaesthesia: "short-duration", during the preparation only; "long-duration", during both preparation and ischaemia. Twenty-four hours after MCAo, infarcts were visualized by staining with 2,3,5-triphenyltetrazolium chloride. Two additional groups of rats were subjected to the same protocol as that of long-duration halothane and long-duration desflurane with additional pericranial temperature measurements made. RESULTS: Physiological parameters were comparable between the groups but MAP was higher (P<0.0001) in the short-duration groups. In the short-duration groups, cerebral infarct volumes were not significantly different between anaesthetics (short-duration halothane: 288 (61) mm(3), mean (SD); short-duration desflurane: 269 (71) mm(3), P>0.56). Compared with the awake state (short-duration groups), halothane and desflurane significantly reduced infarct volumes (long-duration halothane: 199 (54) mm(3), P<0.0047 vs short-duration halothane; long-duration desflurane: 121 (55) mm(3), P<0.0001 vs short-duration desflurane). The mean infarct volume in the long-duration desflurane group was significantly lower than that in the long-duration halothane group (P<0.0053). Pericranial temperatures were similar in the desflurane and halothane long-duration groups (P>0.17). CONCLUSIONS: In rats, desflurane-induced neuroprotection against focal cerebral ischaemia was greater than that conferred by halothane.

Analysis of Variance↗
PubMed1998

The effects of halothane on single human neuronal L-type calcium channels.

UNLABELLED: We investigated halothane's effects on the function of L-type Ca2+ channels in a human neuronal cell line, SH-SY5Y, by using the cell-attached patch voltage clamp configuration and Ba2+ as the charge carrier. In multiple-channel patches, halothane decreased the peak and persistent Ba2+ currents, accelerated the rate of inactivation, and slowed the rate of activation. Single-channel analysis showed that halothane (0.14-1.26 mM) increased the latency time for the first channel opening, increased the lifetime of nonconducting events, increased the proportion of short-lived open events, decreased the lifetime of the two open populations, and increased the percentage of current traces without channel activity. All of the observed halothane effects contribute to the halothane-induced decrease in macroscopic Ba2+ currents. The halothane concentration producing 50% reduction (IC50) of the peak Ba2+ current was 0.80 mM (approximately 1.9 hypothetical minimum alveolar anesthetic concentration [H-MAC] at 28 degrees C) and of the persistent Ba2+ current was 0.69 mM (approximately 1.7 H-MAC). The halothane effects did not always occur together, and the Hill slope of 1.6 suggested the presence of more than one interaction site or of more than one population of L-type Ca2+ channels. Halothane reduces L-type Ca2+ channel currents in human neuronal cells primarily through the stabilization of nonconducting states such as closed (before and after channel opening) and inactivated states. IMPLICATIONS: Calcium is a signaling molecule in neurons. We measured the effect of halothane on Ba2+ (a Ca2+ surrogate) movement into a human neuron-like cell electronically. Ba2+ entry through the L-type channel was depressed. Halothane decreased the likelihood of the channel opening and enhanced the rate at which the channel closed and inactivated. These actions of halothane are probably related to its anesthetic action.

Anesthetics, Inhalation↗
PubMed1999

The effect of a right-to-left intracardiac shunt on the rate of rise of arterial and end-tidal halothane in children.

UNLABELLED: In this prospective study, we evaluated the effect of a right-to-left intracardiac shunt on the rate of rise of end-tidal and arterial halothane concentration in children. Six children aged 23-43 mo undergoing surgical closure of atrial fenestration after Fontan procedure were given 0.8% inspired halothane. End-tidal halothane was recorded at 1-min intervals after the introduction of halothane. Arterial halothane concentrations were determined 0, 1, 3, 5, 10, and 15 min after the introduction of halothane. The sampling was performed before and after closure of the atrial fenestration. The ratio of pulmonary to systemic blood flow (Qp/Qs) increased in this patient population, from 0.58 +/- 0.04 to 0.88 +/- 0.12 (P = 0.01). The rate of rise of end-tidal halothane did not change significantly with a decrease in the magnitude of the right-to-left intracardiac shunt after closure of the atrial fenestration. The ratio of arterial to inspired halothane concentrations at 1, 3, 5, 10, and 15 min were lower before closure of the atrial fenestration compared with after closure (P < 0.05). We conclude that the presence of a right-to-left intracardiac shunt significantly slows the rate of rise of arterial halothane in the face of a constant inspired concentration. The rate of rise of end-tidal halothane is not significantly affected in the presence of a right-to-left intracardiac shunt. IMPLICATIONS: In this prospective study, we found a slower rate of rise of halothane in arterial blood in children with right-to-left intracardiac shunting. Induction of anesthesia by inhalation of volatile anesthetics may therefore be slower in these children.

Anesthesia, General↗
PubMed1982

Halothane and the carotid sinus reflex: evidence for multiple sites of action.

Baroreceptor reflexes have been found to be attenuated during halothane anesthesia in humans and experimental animals. The baroreceptor reflex arc is comprised for a number of components, including receptors, afferent and efferent nerve pathways, central integratory centers, peripheral ganglia, and effector organs, at which halothane might exert an inhibitory effect. This study was performed to determine the effect of halothane at each component in order to identify the site or sites of baroreflex attenuation due to halothane. The baroreflex effects on heart rate initiated by carotid sinus pressure changes were examined in conscious and anesthetized (0.0%, 0.75%, and 1.5% halothane in 50% N2O and O2, pls 25 mg/kg thiopental) dogs. In addition, carotid sinus afferent activity, cardiac sympathetic efferent activity and heart responses to direct sympathetic and parasympathetic efferent stimulation were examined in anesthetized dogs. Preganglionic and postganglionic sympathetic nerve activities were recorded simultaneously during baroreceptor activation to determine ganglionic effects of halothane. All levels of anesthesia significantly (P less than 0.05) attenuated reflex changes in heart rate produced by the pressure changes compared to conscious dogs. Significant decreases in cardiac sympathetic efferent activity were produced at 1.5% halothane (P less than 0.05). The depression in postganglionic activity was significantly greater than that or preganglionic activity, indicating a ganglionic-blocking effect by halothane. Cardiac chronotropic changes produced by direct efferent stimulation of sympathetic and vagal fibers were attenuated significantly by halothane (P less than 0.05). On the other hand, baroreceptor afferent activity was increased at 1.5% halothane. This sensitization of baroreceptors appeared to contribute to decreased levels of sympathetic tone, leading to blunted reflex changes in nerve activity. Therefore, halothane was found to have multiple sites of action, leading to depression of the baroreflex.

Animals↗
PubMed1988

Effects of halothane with and without histamine and/or epinephrine on automaticity, intracardiac conduction times, and development of dysrhythmias in the isolated guinea pig heart.

Histamine is released during allergic reactions, and is known to produce cardiac dysrhythmias. The authors compared the cardiac effects of histamine and epinephrine during exposure to halothane in the isolated perfused guinea pig heart. Responses studied were spontaneous sinus rate, intra-atrial conduction time, atrial-septal conduction time (ASCT), intraventricular conduction time (IVCT), and left ventricular pressure (LVP). The incidence and type of dysrhythmias with histamine and halothane and with epinephrine and halothane were analyzed from electrograms. The authors found that halothane alone (0.7 to 2.1 vol%) causes dose-dependent depressions of sinus rate and LVP, prolongs ASCT and IVCT, and produces atrioventricular (AV) block with junctional bradycardia. Histamine alone (.01-10 microM) increases sinus rate and LVP but, like halothane, prolongs ASCT. Halothane antagonizes the inotropic and chronotropic effects of histamine, but enhances ASCT compared with histamine alone. Histamine with halothane greatly increases the incidence of junctional tachycardia with AV dissociation from 0% with histamine alone up to 48%. Epinephrine alone (0.1-5 microM), like histamine, increases sinus rate and LVP, but does not cause a relative increase in ASCT. Halothane antagonizes the inotropic and chronotropic effects of epinephrine, but increases the incidence of ventricular tachycardia from 6% to 28%, and the incidence of premature ventricular excitations from 0% to 40%, compared with epinephrine alone. The authors' in vitro findings show that histamine and halothane, like epinephrine and halothane, can cause dysrhythmias, but that the genesis and type of dysrhythmias induced by these agents are dissimilar. Consequently, the release of histamine with an anaphylactoid reaction during halothane anesthesia, and the treatment of the reaction with epinephrine, could result in dangerous ventricular tachydysrhythmias.

Animals↗
PubMed1993

Effects of halothane and isoflurane on cytosolic calcium ion concentrations and contraction in the vascular smooth muscle of the rat aorta.

BACKGROUND: Halothane and isoflurane have been reported to suppress the contraction of vascular smooth muscle, although the exact mechanism has not been explained fully. This study examined the effect of halothane and isoflurane on cytosolic calcium ion (Ca2+) concentrations ([Ca2+]cyt), which was measured simultaneously with muscle tension in the vascular smooth muscle of the rat aorta to improve the understanding of the anesthetic's effect on vascular smooth muscle. METHODS: Isolated spiral strips of rat thoracic aorta were suspended for isometric tension recordings in physiologic salt solution. The [Ca2+]cyt was measured concomitantly by using fura-2-Ca2+ fluorescence. During exposure to 0%, 1%, 2%, or 3% halothane or 0%, 2%, or 4% isoflurane, increases in muscle tension and [Ca2+]cyt induced by 32.8 mM K+ or 30 nM norepinephrine were measured and compared with the reference values. In the other series, the 3% halothane-induced increase in [Ca2+]cyt was measured in Ca2+)-free solution without and with a pretreatment of ryanodine, caffeine, or norepinephrine. RESULTS: Halothane and isoflurane increased resting-state [Ca2+]cyt, although only 3% halothane elicited a transient increase in muscle tension during the resting state. By contrast, both anesthetic agents attenuated the high K(+)- and norepinephrine-induced increases in [Ca2+]cyt and muscle tension in a concentration-dependent manner. During 3% halothane or 4% isoflurane exposure, the pretreatment of the muscle strip with a 10(-6)-M dose of Bay K 8644 augmented the high K(+)-induced increase in [Ca2+]cyt to the level observed in the control (0% anesthetic exposure) state. However, the increase in muscle tension in the presence of Bay K 8644 was low; it was still attenuated from the control level during 3% halothane or 4% isoflurane administration. These results indicate that, not only [Ca2+]cyt-dependent, but also [Ca2+]cyt-independent, mechanisms are involved in the anesthetic-induced suppression of smooth muscle contraction. A 3% halothane-induced increase in [Ca2+]cyt was observed in the Ca(2+)-free solution even when the muscle strip was pretreated with a 10(-6)-M dose of ryanodine and a 20-mM dose of caffeine, whereas it was abolished completely after the muscle strip was pretreated with ryanodine, caffeine, and 100 nM norepinephrine. These results indicate that halothane can release Ca2+ from an intracellular Ca2+ store other than the caffeine-releasable site. CONCLUSIONS: Halothane and isoflurane have multiple effects on the [Ca2+]cyt and induce [Ca2+]cyt-dependent and [Ca2+]cyt-independent suppression of the contraction in the vascular smooth muscle.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1993

Effect of halothane on hypoxic toxicity and glutathione status in cultured rat hepatocytes.

BACKGROUND: In hypoxic rats, halothane causes hepatotoxicity at oxygen levels that would cause minimal hepatotoxicity in the absence of halothane. Using a model that excludes systemic and extrahepatic effects of halothane, the authors tested the hypothesis that halothane hepatotoxicity in the whole-rat model is caused by a direct hepatotoxic effect of halothane, which is mediated by halothane-derived free radicals. METHODS: Rat hepatocyte monolayer cultures were exposed to defined gas phases for 2 h. Three experimental variables were present or absent: hypoxia (1% O2), halothane (2%), and cytochrome P-450 induction (by phenobarbital). Two experimental outcomes were measured: aspartate aminotransferase release, a measure of cell death, and reduced glutathione, an endogenous free radical scavenger whose levels are decreased by physiologically significant free radical injury. RESULTS: As anticipated, hypoxia increased cell death. Cytochrome P-450 induction by itself increased cell death during hypoxia. However, halothane had no effect on cell death during hypoxia, with or without cytochrome P-450 induction. Halothane had no toxic effect, even when glutathione was depleted before the onset of hypoxia. Glutathione was decreased moderately by hypoxia alone. Neither halothane nor cytochrome P-450 induction had any effect on glutathione levels. CONCLUSIONS: Halothane was not toxic, and it did not generate a physiologically significant free radical insult during hypoxia in the isolated rat hepatocyte under the experimental conditions used in testing.

Animals↗
PubMed1993

Activation of brain noradrenergic neurons during recovery from halothane anesthesia. Persistence of phasic activation after clonidine.

BACKGROUND: alpha 2-Adrenoceptor agonists, known as antihypertensive agents, may be used during general anesthesia for their anesthetic sparing action and to reduce the occurrence of side effects. Previous studies have shown that the brain's noradrenergic nucleus, locus coeruleus, is an important target in mediating the hypnotic action of alpha 2 agonists. The authors studied the effects of recovery from halothane anesthesia on the electrical activity of locus coeruleus neurons to examine cellular substrates underlying the clinical effectiveness of alpha 2 agonists. METHODS: Experiments were performed in locally anesthetized rats, whose circulatory and acid-base stabilities were ensured by mechanical ventilation and volume infusion. Locus coeruleus neurons were recorded continuously while the rats were anesthetized with halothane (1%) and/or after the halothane was discontinued. RESULTS: Under the influence of halothane, locus coeruleus cells exhibited a slow, regular spontaneous discharge (1.95 +/- 0.23 Hz), and contralateral foot or tail pinch elicited a prominent, phasic activation in locus coeruleus neurons. Such phasic activation was blocked by local ejection of kynurenic acid, an excitatory amino acid antagonist, close to recorded neurons, but not by clonidine (up to 64 micrograms.kg-1). Thirty minutes after the halothane was discontinued, the mean firing rate of locus coeruleus neurons was increased by 87 +/- 20%. This excitation resulted from a prominent increase in bursting activity (21 +/- 5% of spikes in bursts vs. 4 +/- 1%) and was reversed by halothane readministration. This activation also was reduced by local ejection of kynurenic acid. Halothane discontinuance revealed the reactivity of locus coeruleus neurons to nonnoxious, sensory stimuli, and considerably reduced the apparent potency of intravenous administration of clonidine to inhibit locus coeruleus activity (effective dose for 50% of maximal effect (ED50), 25.48 +/- 8.26 micrograms.kg-1 vs. 4.81 +/- 0.80 micrograms.kg-1 under halothane). This decrease was caused by the persistence of bursting activity after the administration of clonidine, which was completely suppressed by readministration of halothane or local application of kynurenic acid. CONCLUSION: The data demonstrate: (1) that halothane withdrawal increases locus coeruleus neuronal activity via excitatory amino acid input, and this withdrawal-induced activity is characterized by a prominent burst (phasic) discharge; (2) that sedative doses of clonidine inhibit the tonic component of locus coeruleus activity but not the phasic activation of locus coeruleus neurons; and (3) that readministration of halothane or local ejection of an excitatory amino acid antagonist fully suppresses the bursting activity unaffected by clonidine.

Anesthesia Recovery Period↗
PubMed1994

Oral dexmedetomidine preserves baroreceptor function and decreases anesthetic requirements of halothane-anesthetized dogs.

BACKGROUND: The alpha 2-adrenergic agonist, dexmedetomidine, alters hemodynamics by diminishing sympathetic and/or augmenting parasympathetic neurogenic tone to the heart and peripheral vasculature. However, the specific actions of dexmedetomidine on baroreceptor function are unknown. The purpose of the current investigation was to determine baroreceptor function during an anesthetic state produced by halothane and a similar anesthetic state produced by halothane after dexmedetomidine pretreatment. METHODS: Dogs were instrumented for measurement of arterial and left ventricular pressures, coronary blood flow velocity, segment shortening and cardiac output. Five experimental conditions were studied in the same dogs (n = 8). Measurements of baroreceptor sensitivity (via abrupt decreases and increases in arterial pressure resulting in changes in the cardiac cycle) and hemodynamics were made in the conscious state in dogs in conditions 1 and 2 before and after 25 and 50 micrograms.kg-1 of oral dexmedetomidine, respectively. Dogs in conditions 3 and 4 received the same doses of dexmedetomidine and were then anesthetized with halothane. Baroreceptor sensitivity was determined after 60 min of halothane anesthesia. For comparison, dogs in condition 5 had baroreceptor sensitivity measured after 60 min of halothane anesthesia in the absence of dexmedetomidine. RESULTS: Dexmedetomidine decreased heart rate, rate-pressure product, rate of increase of left ventricular pressure at 50 mmHg, cardiac output and percent segment shortening. Diastolic coronary vascular resistance and systemic vascular resistance were increased with both oral doses. In addition, diastolic coronary blood flow velocity and stroke volume were significantly reduced by the high dose of dexmedetomidine. Anesthesia with halothane increased heart rate and decreased mean arterial pressure, left ventricular systolic pressure, rate of increase of left ventricular pressure at 50 mmHg, stroke volume and segment shortening. Administration of dexmedetomidine before halothane anesthesia in dogs pretreated with dexmedetomidine resulted in small increases in heart rate and decreases mean arterial pressure and left ventricular systolic pressure. Both doses of dexmedetomidine demonstrated anesthetic-sparing effects. The end-tidal concentration of halothane to maintain dogs unconscious and unresponsive was reduced by 30% and 40% (1.03 +/- 0.08% to 0.67 +/- 0.09% and to 0.58 +/- 0.06% end-tidal, respectively) at 25 and 50 micrograms.kg-1, respectively. Baroreceptor sensitivity was profoundly depressed by halothane alone. Dexmedetomidine did not significantly change the slope of the baroreflex response when compared with conscious control measurements. After pretreatment with dexmedetomidine, the reduction in halothane concentration required for a comparable level of anesthesia resulted in significant preservation of baroreceptor sensitivity. CONCLUSIONS: The results indicate that dexmedetomidine alone does not alter baroreflex sensitivity. In addition, possibly through an anesthetic-sparing action, dexmedetomidine preserves baroreflex responses during halothane anesthesia. Such a preservation of the baroreceptor reflex by dexmedetomidine might provide an important mechanism for maintenance of cardiovascular stability by retaining buffer reflexes during general anesthesia.

Administration, Oral↗
PubMed1996

Pontine cholinergic mechanisms modulate the cortical electroencephalographic spindles of halothane anesthesia.

BACKGROUND: Halothane anesthesia causes spindles in the electroencephalogram (EEG), but the cellular and molecular mechanisms generating these spindles remain incompletely understood. The current study tested the hypothesis that halothane-induced EEG spindles are regulated, in part, by pontine cholinergic mechanisms. METHODS: Adult male cats were implanted with EEG electrodes and trained to sleep in the laboratory. Approximately 1 month after surgery, animals were anesthetized with halothane and a microdialysis probe was stereotaxically placed in the medial pontine reticular formation (mPRF). Simultaneous measurements were made of mPRF acetylcholine release and number of cortical EEG spindles during halothane anesthesia and subsequent wakefulness. In additional experiments, carbachol (88 mM) ws microinjected in the the mPRF before halothane anesthesia to determine whether enhanced cholinergic neurotransmission in the MPRF would block the ability of halothane to induce cortical EEG spindles. RESULTS: During wakefulness, mPRF acetylcholine release averaged 0.43 pmol/10 min of dialysis. Halothane at 1 minimum alveolar concentration decreased acetylcholine release (0.25 pmol/10 min) while significantly increasing the number of cortical EEG spindles. Cortical EEG spindles caused by 1 minimum alveolar concentration halothane were not significantly different in waveform, amplitude, or number from the EEG spindles of nonrapid eye movement sleep. Microinjection of carbachol into the mPRF before halothane administration caused a significant reduction in number of halothane-induced EEG spindles. CONCLUSIONS: Laterodorsal and pedunculopontine tegmental neurons, which provide cholinergic input to the mPRF, play a causal role in generating the EEG spindles of halothane anesthesia.

Acetylcholine↗
PubMed1996

Direct inhibitory mechanisms of halothane on human platelet aggregation.

BACKGROUND: Although halothane directly inhibits platelet aggregation, the mechanisms of this effect are still unknown. The current study aimed to clarify the inhibitory mechanisms of halothane on thrombin-induced human platelet aggregation by measuring (1) platelet-surface glycoprotein Ib expression, (2) the concentration of intracellular free Ca2+ ([Ca2+]i) measured simultaneously with aggregation, (3) the concentration of intracellular inositol 1,4,5-triphosphate, and (4) the concentration of intracellular cyclic 3',5'-adenosine monophosphate ([cAMP]i). METHODS: Washed platelet suspensions, obtained from healthy volunteers, were preincubated with halothane (0-2 mM) for 2 min and then exposed to 0.02 units/ml thrombin for 3 min. The glycoprotein Ib bound to fluorescein-labeled antibody was measured by fluorescence flow cytometry. [Ca2+]i was measured, simultaneously with aggregation, in Fura-2 (Ca2+ indicator)-loaded platelets by use of a fluorometer. Inositol 1,4,5-triphosphate and [cAMP]i were measured by radioimmunoassay. RESULTS: Halothane had no effect on glycoprotein Ib expression with or without thrombin. Halothane decreased the thrombin stimulated [Ca2+]i transient and inhibited platelet aggregation in a dose-dependent manner, both in the presence and in the absence of external Ca2+. Isoflurane had no apparent effect on either platelet aggregation or [Ca2+]i in the absence of external Ca2+. Halothane inhibited the increase in inositol 1,4,5-triphosphate induced by thrombin. Halothane moderately but significantly increased [cAMP]i, but the adenylate cyclase activator forskolin (which has the same inhibitory ability on aggregation as halothane) increased [cAMP]i to a much greater extent than did halothane. CONCLUSIONS: Halothane inhibits thrombin-induced human platelet aggregation by decreasing [Ca2+]i without inhibiting agonist-receptor binding; the inhibitory effect of halothane on [Ca2+]i might be mediated by a decrease in inositol 1,4,5 triphosphate and in part by an increase in [cAMP]i.

Adult↗
PubMed1997

Halothane-induced dilatation of intraparenchymal arterioles in rat brain slices: a comparison to sodium nitroprusside.

BACKGROUND: Halothane is a potent dilator of cerebral arteries. The predominant site of cerebrovascular resistance is thought to be intracerebral arterioles, and the effects of halothane on these vessels were not previously examined. This study compared the effects of halothane with those of the vasodilator and nitric oxide donor, sodium nitroprusside, on intraparenchymal microvessel responsiveness in a brain slice preparation. METHODS: Anesthetized Sprague-Dawley rats underwent thoracotomy and intracardiac perfusion and then were decapitated. Hippocampal brain slices were prepared and placed in a perfusion/recording chamber and superfused with artificial cerebrospinal fluid. An arteriole was located within the brain parenchyma and its diameter was monitored with videomicroscopy before, during, and after various concentrations of halothane or sodium nitroprusside were equilibrated in the perfusate. All vessels were preconstricted with prostaglandin F2 alpha before halothane or sodium nitroprusside treatment. An observer blinded to treatment analyzed vessel diameter changes with a computerized videomicrometer. RESULTS: Baseline microvessel diameter was 18 +/- 2 microns in the halothane group (n = 14) and 15 +/- 1 microns in the sodium nitroprusside group (n = 15). Prostaglandin F2 alpha (0.5 micron) preconstricted vessels by approximately 15% from resting diameter in both groups. Halothane significantly and dose dependently dilated intracerebral microvessels by 54% +/- 6%, 74% +/- 8%, 108% +/- 13%, and 132% +/- 7% (normalized to the preconstricted diameter) at 0.5%, 1.0%, and 2.5% halothane, respectively. This dilatation corresponds to a decrease in a calculated index of cerebrovascular resistance index of up to 117% +/- 2% at 2.5% halothane. Sodium nitroprusside, in concentrations ranging from 10(-8) to 10(-3)M, also dose dependently dilated these intraparenchymal vessels by 129% +/- 7% at the highest concentration. These alterations in microvessel diameter corresponded to a decrease in the cerebrovascular resistance index of up to 116 +/- 4% for the largest dose. CONCLUSIONS: Halothane produces dose-dependent vasodilatation of intraparenchymal cerebral microvessels, thus predicting marked decreases in cerebrovascular resistance in this in vitro brain slice preparation. The effects of halothane on these cerebral microvessels are similar to those of the potent vasodilator sodium nitroprusside. These findings suggest that direct effects of halathane on cerebral microvessels diameter contribute substantially to alterations in cerebrovascular resistance and flow produced by this agent.

Anesthetics, Inhalation↗
PubMed1998

Role of intracellular Ca2+ stores in the inhibitory effect of halothane on airway smooth muscle contraction.

BACKGROUND: Halothane directly inhibits contraction of airway smooth muscle, mainly by decreasing the intracellular concentration of free Ca2+ ([Ca2+]i). The role of intracellular Ca2+ stores, sarcoplasmic reticulum, is still unclear. We investigated the role of sarcoplasmic reticulum in the inhibitory effect of halothane on contraction of airway smooth muscle by measuring [Ca2+]i and intracellular concentration of inositol 1,4,5-triphosphate ([IP3]i), a second messenger for release of Ca2+ from sarcoplasmic reticulum. METHODS: [Ca2+]i was monitored by measuring the 500-nm light emission ratio (F340/F380) of a Ca2+ indicator fura-2 with isometric tension of canine tracheal smooth muscle strip. During Ca2+-free conditions, carbachol (10(-5) M) was introduced with pretreatment of halothane (0-3%). During Ca2+-free conditions, 20 mM caffeine, a Ca2+-induced Ca2+ release channel opener, was introduced with or without halothane. We measured [IP3]i during exposure to carbachol and halothane by radioimmunoassay technique. RESULTS: Pretreatment with halothane significantly diminished carbachol-induced increases in [Ca2+]i by 77% and muscle tension by 83% in a dose-dependent manner. Simultaneous administration of halothane significantly enhanced caffeine-induced transient increases in [Ca2+]i and muscle tension in a dose-dependent manner, by 97% and 69%, respectively. Pretreatment with halothane abolished these responses. Rapid increase in [IP3]i produced by carbachol was significantly inhibited by 32% by halothane in a dose-dependent manner. CONCLUSIONS: Halothane, during Ca2+-free conditions, inhibits transient contraction of airway smooth muscle induced by muscarinic receptor stimulation, mainly by attenuating the increase in [Ca2+]i. Depletion of Ca2+ from sarcoplasmic reticulum via Ca2+-induced Ca2+ release channels also may contribute to the attenuation of the increase in [Ca2+]i by halothane.

Anesthetics, Inhalation↗
PubMed2000

Effects of halothane on excitatory neurotransmission to medullary expiratory neurons in a decerebrate dog model.

BACKGROUND: The activity of canine expiratory (E) neurons in the caudal ventral respiratory group is primarily dependent on N-methyl-D-aspartic acid (NMDA) receptor-mediated excitatory chemodrive inputs and modulated by an inhibitory mechanism mediated via gamma-aminobutyric acidA (GABA(A)) receptors. In an intact canine preparation, halothane depressed the activity of these neurons mainly by reduction in overall glutamatergic excitation. A new decerebrate preparation allows comparison of the effects of halothane on these synaptic mechanisms with an anesthetic-free baseline state. METHODS: Two separate studies were performed in decerebrate, vagotomized, paralyzed, mechanically ventilated dogs during hypercapnic hyperoxia. In study 1, the effect of 1 minimum alveolar concentration (MAC) halothane on extracellularly recorded E neuronal activity was studied before and during complete GABA(A) receptor blockade by localized pressure ejection of bicuculline. Complete blockade of the inhibitory mechanism allowed differentiation between the effects of halothane on overall GABA(A)-mediated inhibition and on overall NMDA receptor-mediated excitation. In study 2, the effect of 1 MAC halothane on the dose response of neurons to localized picoejection of the glutamate agonist NMDA was used to estimate halothane effect on postsynaptic glutamatergic excitatory neurotransmission. RESULTS: In study 1, the spontaneous activity of 14 E neurons was depressed 38.6 +/- 20.6% (mean +/- SD) by 1 MAC halothane. Overall excitation was depressed 31.5 +/- 15.5%. The GABAergic inhibition showed a 11.7 +/- 18.3% enhancement during halothane. In study 2, the spontaneous activity of 13 E neurons was again significantly depressed by 1 MAC halothane (27.9 +/- 10.6%), but the postsynaptic response of the neurons to exogenous NMDA was not significantly depressed by halothane (3.3 +/- 38.4%). CONCLUSIONS: Together these results suggest that in our E neuron paradigm, halothane exerted its depressive effect mainly via reduction of glutamatergic presynaptic mechanisms.

Anesthetics, Inhalation↗
PubMed2005

Interaction of arousal states and low dose halothane on the acute hypercapnic ventilatory response in humans.

The purpose of this study was to examine the effect of low dose halothane on the acute ventilatory response to hypercapnia, and to assess whether arousal (due to audiovisual (AV) stimulation or pain) modulates the response to halothane. Single step increases in end-tidal Pco(2) using dynamic end-tidal forcing were performed from eucapnia (end-tidal Pco(2) held 1 mmHg (0.13 kPa) above ambient) to hypercapnia (end-tidal Pco(2) 6 mmHg (0.79 kPa) above ambient) in eight healthy volunteers, with end-tidal PO(2) held at 100 mmHg (13.2 kPa), in six protocols: 1) control conditions (darkened, quiet room, eyes closed) without halothane; 2) control conditions with 0.1 MAC halothane; 3) AV stimulation (bright room, loud television) without halothane; 4) AV stimulation with 0.1 MAC halothane; 5) pain (electrical stimulation of skin over tibia to produce visual analogue pain score 5-6/10) without halothane; 6) pain with 0.1 MAC halothane. Both AV stimulation (p = 0.014) and pain (p = 0.0003) significantly increased the baseline eucapnic minute ventilation modestly (by approximately 1.5-4 l.min(-1)). Halothane did not influence the baseline minute ventilation in any arousal state (p = 0.572), nor did it affect the hypercapnic ventilatory response in any arousal state (p = 0.208). Arousal (either AV stimulation or pain) did not affect the ventilatory response to CO(2), regardless of the presence or absence of halothane (p = 0.585). We conclude that halothane affects neither baseline minute ventilation nor the response to CO(2). Arousal can increase baseline ventilation but has no influence on the ventilatory response to CO(2).

Acoustic Stimulation↗
PubMed1988

Postganglionic sympathetic nerve activity in halothane-anaesthetized rats during controlled and spontaneous ventilation.

The aim of the study was to compare the effect of halothane anaesthesia on sympathetic nerve discharge in mechanically normoventilated and spontaneously breathing rats. Renal sympathetic nerve activity (rSNA), mean arterial pressure (MAP) and heart rate (HR) were measured in the conscious state and at the inspiratory halothane concentrations of 0.6%, 1.2% and 2.4% in one mechanically normoventilated and one spontaneously breathing group, while a third group was subjected to controlled hypoventilation at 1.2% halothane concentration. Halothane in blood was determined in two separate groups at 1.2%. In an additional group of spontaneously breathing rats, PaCO2 was analysed during consciousness and the halothane concentrations of 1.2% and 2.4%. There was a pronounced decrease in rSNA, MAP and HR at all levels of anaesthesia in the mechanically ventilated rats. However, rSNA, HR and MAP were significantly higher in the spontaneously breathing rats at increasing levels of halothane anaesthesia. Controlled hypoventilation at 1.2% halothane increased the variables significantly. In spontaneously breathing animals, PaCO2 increased significantly during the halothane exposure. The concentration of halothane in blood was significantly higher in the spontaneously breathing rats. Thus, the halothane-induced respiratory depression in the spontaneously breathing rats preserved rSNA during halothane anaesthesia, possibly via CO2-mediated chemoreceptor stimulation.

Anesthesia, Inhalation↗
PubMed2005

Nociceptive spinal withdrawal reflexes but not spinal dorsal horn wide-dynamic range neuron activities are specifically inhibited by halothane anaesthesia in spinalized rats.

The aim of the present study was to investigate the spinal cord effects and sites of action of different inhaled concentrations (0.5-2%) of the anaesthetic, halothane. Simultaneous recordings were made of 3 Hz, suprathreshold (1.5 x T) electrically evoked spinal dorsal horn (DH) wide-dynamic range (WDR) neuron responses and of single motor unit (SMU) electromyographic (EMG) responses underlying the spinal withdrawal reflex in spinalized Wistar rats. Compared with the baseline responses obtained with 0.5% halothane, the electrically evoked early responses of the DH WDR neurons as well as the SMUs were only depressed by the highest, 2% concentration of halothane. In contrast, 1.5% halothane markedly inhibited the late responses of the DH WDR neurons, whereas 1% halothane started to significantly depress the late responses of the SMUs. Likewise, wind-up of the WDR neuron late responses was inhibited by 1.5-2% halothane, whereas 1-2% halothane significantly depressed wind-up of the SMU EMG late responses. The inhibitory effects of 2% halothane on the early and the late responses of the DH WDR neurons, but not of the SMUs, were completely reversed by opioid micro-receptor antagonist naloxone (0.04 mg/kg). However, no significant effects of naloxone were found on different responses of the DH WDR neurons as well as the SMUs at 0.5-1% halothane, suggesting that different concentrations of halothane may modulate different spinal receptors. We conclude that halothane at high concentrations (1.5-2%) seems to play a predominant inhibitory role via spinal multireceptors on ventral horn (VH) motor neurons, and less on DH sensory WDR neurons, of the spinal cord.

Anesthetics, Inhalation↗
PubMed1987

Effects of halothane and other chlorinated hydrocarbons on alpha 2-adrenoceptors in the mouse cortex.

A number of general anaesthetics and organic solvents were tested for their ability to inhibit the binding of 3H-clonidine to alpha 2-adrenoceptors in mouse cerebral cortex membranes. The order of potency of the tested agents was: chloroform greater than halothane greater than trichloroethylene greater than carbon tetrachloride greater than dichloromethane. Of these agents halothane was tested further. When saturation curves of 3H-clonidine were constructed, halothane (25 mmol/l added directly to the assay) was found to induce a proportionally greater inhibition at low 3H-clonidine concentrations than at high. Computer modelling these saturation curves indicated that halothane reduced the apparent affinity of 3H-clonidine; Kd = 4.2 nmol/l in the absence of halothane and Kd = 6.0 nmol/l in its presence. Gassing the cortex membranes with 3% halothane induced a practically identical reduction in the affinity for 3H-clonidine; Kd = 4.6 nmol/l for the control versus Kd = 10.7 nmol/l for halothane. The effects of halothane was compared to that of the non-hydrolyzable GTP analog Gpp(NH)p. Gpp(NH)p in the concentration range 10(-8)-10(-3) mol/l dose-dependently reduced the binding of 1 nmol/l 3H-clonidine, the effect being essentially maximal at 10(-4) mol/l. Computer modelling of saturation curves of 3H-clonidine indicated that 0.1 mmol/l Gpp(NH)p reduced the apparent affinity of 3H-clonidine; Kd = 5.4 nmol/l in the absence of Gpp(NH)p and Kd = 9.3 nmol/l in its presence. In addition Gpp(NH)p caused some reduction in the apparent number of 3H-clonidine binding sites. The effect of halothane on 3H-clonidine binding was tested both in the absence and presence of 0.1 mmol/l 1 Gpp(NH)p. During these conditions halothane was slightly more potent in the presence of Gpp(NH)p (IC50 of halothane = 17 mmol/l) than in its absence (IC50 = 41 mmol/l).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗