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PubMed1984

Differential effects of halothane on airway nerves and muscle.

Effects of halothane on the excitation-contraction coupling or neuro-effector transmission in the dog tracheal muscle were observed in vitro in an attempt to clarify the cellular mechanisms involved in anesthetic-induced bronchodilation. Double sucrose gap, microelectrode, and tension recording methods were used. Application of halothane evoked an initial induction of phasic contraction with no alteration in the electrical membrane properties, and secondarily a reduction in muscle tone with membrane hyperpolarization. Halothane suppressed the amplitude of the twitch contractions evoked by indirect (nerve mediated) or direct muscle stimulation, the degree of suppression being greater with the former stimulation. The threshold membrane depolarization required for the generation of tension development was increased. In the presence or absence of TEA, halothane completely suppressed the generation of an action potential or a local response in the muscle membrane, following stimulation by outward current pulses. Therefore, halothane has complex actions on Ca++ economy in the tracheal smooth muscle cell, i.e., initial release of Ca++ from the store sites followed by inactivation or a reduction in free calcium ions in the cytoplasm, and/or suppression of the influx of Ca++ across the cell membrane. Low concentrations of halothane (less than or equal to 1%) suppressed the amplitude of excitatory junction potential (EJP) without altering the membrane potential, membrane resistance, or muscle sensitivity to acetylcholine. Therefore, this anesthetic probably suppresses the release of transmitter from the nerve terminals. Halothane also suppressed the facilitation phenomena of EJP during repetitive nerve stimulation. These direct inhibitory effects of halothane on smooth muscle cells and excitatory neuro-effector transmission could account for the potent bronchodilator action of this anesthetic.

Action Potentials↗
PubMed1984

Site of selective action of halothane on the peripheral chemoreflex pathway in humans.

Halothane in humans depresses the ventilatory response to hypoxemia in a manner that suggests a selective action on one or more components of the peripheral chemoreflex arc. To test the hypothesis that this action is at the carotid bodies themselves, the authors studied the ventilatory response to subanesthetic concentrations of halothane (0.15-0.30% inspired) in six fit volunteers maintained in a steady state of isocapnic hypoxemia (PEO2 50 mmHg). Upon exposure to halothane, hypoxemia-driven ventilation decreased promptly and progressively (from 7.5 +/- 1.2 1 X min-1 X m-2 in the control state to 5.9 +/- 0.9 and 4.8 +/- 0.7 1 X min-1 X m-2 at 30 s and 60 s of inhalation respectively, means +/- SEM). The relationship of hypoxemia-driven ventilation to end-tidal halothane tensions at 30 and 60 s of halothane wash-in (PEHal 0.4 and 0.6 mmHg, respectively) approached the relationship observed in near steady states of halothane inhalation. The results are interpreted as indicating that the site of selective action is at a tissue that accumulates halothane very rapidly during the first minute of inhalation. To make possible such pharmacokinetics, that tissue would require a location having a brief circulatory transit time from the lungs, and an extremely high rate of perfusion in relation to its capacity for uptake of halothane. The only tissue of the peripheral chemoreflex pathway that can satisfy these requirements is that of the carotid bodies.

Adult↗
PubMed1985

Halothane concentration does not alter the threshold for epinephrine-induced arrhythmias in dogs.

Halothane lessens the dose of epinephrine necessary to induce ventricular arrhythmias. However, results of a previous study in dogs anesthetized at two halothane concentrations suggested, but did not confirm, that at the higher concentration (1.7%) myocardial sensitization to epinephrine was less pronounced. This study was designed to determine the myocardial sensitizing effect of halothane at four concentrations: 0.5, 1.0, 1.5, and 2%. To define the appropriate time interval between repeated epinephrine infusions, plasma epinephrine decay curves were assessed. These data indicated that at 7 min the contribution of the residual epinephrine level to the peak level was negligible. Therefore, 7 min was selected as the interval between epinephrine infusions. The arrhythmogenic dose of epinephrine (ADE) was measured at four concentrations of halothane, 0.5, 1.0, 1.5, and 2.0%. To determine the ADE at the subanesthetic concentration of halothane (0.5%), anesthesia was supplemented with etomidate. In a preliminary study, the authors confirmed that this intravenous hypnotic agent did not affect the halothane-epinephrine arrhythmogenic interaction. By analysis of variance, halothane concentration was shown to have no significant influence on the ADE (P greater than 0.05). The authors' data indicate that, over a clinically appropriate range, halothane concentration does not alter the threshold for the development of epinephrine-induced ventricular arrhythmias.

Animals↗
PubMed1985

The effect of halothane on drug disposition: contribution of changes in intrinsic drug metabolizing capacity and hepatic blood flow.

Several studies have shown that halothane may influence drug disposition in animals and humans, but the mechanism remains unclear. The relative contributions of changes in metabolizing capacity and hepatic blood flow to altered drug disposition were investigated during halothane anesthesia, using propranolol as a model compound. The studies were performed on six dogs on three separate days; first, the day before anesthesia, second, during halothane (2.0 MAC) anesthesia, and third, 24 h after anesthesia. Each dog simultaneously received 40 mg unlabeled propranolol directly into the portal vein and 200 mCi of 3H-propranolol intravenously via chronically implanted catheters. Blood samples were taken every 5 min for the first hour and then every 15 min for a further 3 h for the measurement of unlabeled and 3H-propranolol concentrations. During halothane anesthesia, intraportal-intrinsic clearance was decreased by 62% (P less than 0.05) from 2,110 +/- 298 to 799 +/- 233 ml/min, while systemic clearance was decreased (P less than 0.05) from 470 +/- 33 ml/min preanesthesia to 280 +/- 38 ml/min during halothane anesthesia. The intravenous elimination half-life was increased (P less than 0.05) from 87 +/- 12 to 155 +/- 23 min during anesthesia. Although halothane anesthesia tended to lower liver plasma flow from 642 +/- 80 to 473 +/- 47 ml/min, this change was not significant. The large change in portal or intrinsic clearance indicates that halothane anesthesia markedly inhibits drug-metabolizing ability. The authors therefore conclude that the alterations in drug disposition observed during halothane anesthesia are mainly due to inhibition of drug-metabolizing capacity in the liver.

Animals↗
PubMed1986

Halothane inhibits the cholinergic-receptor-mediated influx of calcium in primary culture of bovine adrenal medulla cells.

Adrenal medulla cells are cholinoceptive cells. Stimulation of the acetylcholine receptor causes the influx of Ca to the cells, and Ca acts as the coupler of the stimulus-secretion coupling. In this study, the authors investigated the effects of halothane on the receptor-mediated influx of 45Ca using cultured bovine adrenal medulla cells. Halothane at clinical concentrations (0.5-2%) inhibited the influx of 45Ca caused by carbachol, with simultaneous inhibition of catecholamine secretion. The influx of 45Ca and the secretion of catecholamines caused by K depolarization were inhibited by a large concentration of Mg, which competes with Ca at Ca channels, but not inhibited by halothane. Inhibition of the 45Ca influx by halothane was not overcome by increase in the carbachol concentration. Inhibition of the 45Ca influx by halothane was examined in comparison with that caused by a large concentration of Mg by the application of Scatchard analysis as the function of the external Ca concentration. Halothane decreased the maximal influx of 45Ca without altering the apparent kinetic constant of Ca to Ca channels. On the contrary, a large concentration of Mg increased the apparent kinetic constant without altering the maximal influx of 45Ca. Based on these findings, the authors suggest that inhibition of the 45Ca influx by halothane was not due to the direct competitive inhibition of Ca channels, nor to the competitive antagonism of agonist-receptor interaction. As a possibility, halothane seems to inhibit the receptor-mediated activation of Ca channels through the interference of coupling between the receptor and Ca channels.

Adrenal Medulla↗
PubMed1986

Impaired systolic thickening associated with halothane in the presence of a coronary stenosis is mediated by changes in hemodynamics.

Myocardial ischemia results when halothane is administered to animals with severe coronary stenosis. This study was done to separate the effect of halothane, per se, on myocardial ischemia from indirect cardiovascular effects, primarily hypotension, that might cause ischemia by altering the oxygen supply-demand balance. Eight dogs underwent sterile surgery for implantation of sonomicrometer crystals and atrioventricular (A-V) heart block. One week later, each dog was anesthetized with morphine and chloralose. Heart rate was controlled by ventricular pacing and altered in five steps from 50 to 150 beats/min. Arterial blood pressure was controlled by blood withdrawal or phenylephrine infusion at four levels of arterial pressure (60 to 120 mmHg). Regional myocardial contraction was measured at each of the resulting 20 points as an indicator of myocardial ischemia. Twenty points were collected under each of four conditions in each animal: control, halothane (1% inspired), stenosis, halothane plus stenosis. Systolic thickening in the presence of stenosis was divided, on a point-by-point basis, by values obtained in the absence of stenosis to obviate the direct effects of blood pressure and heart rate on thickening. A separate normalization was done for data obtained in the presence of halothane. The normalized data demonstrate impaired systolic contraction at low arterial pressures and high heart rates. Multiple regression analysis failed to demonstrate a significant effect of halothane on systolic contraction once the effects of blood pressure, heart rate, and the negative inotropic effect of halothane were taken into account. Thus, the contraction failure that occurred during halothane and severe stenosis was mediated by changes in hemodynamics.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Halothane anesthetic requirements are not affected by aminophylline treatment in rats and dogs.

The authors determined the effects of aminophylline on the anesthetic requirements for halothane in rats and dogs. MAC for halothane was determined in rats (n = 24) before and after aminophylline, 100 mg X kg-1 ip, or an equal volume of saline. Because changes in central noradrenergic neurotransmission have been linked to drug-induced changes in the depth of the anesthetic state, we investigated the effect of aminophylline on the turnover of norepinephrine in discrete brain regions of halothane-anesthetized rats. To facilitate testing at steady-state aminophylline conditions and to permit frequent blood sampling, halothane MAC was determined in dogs (n = 7) before and after a therapeutic level of aminophylline (15 +/- 2 micrograms X ml-1) was obtained. Neither in the rats (1.0 vs. 1.0%) nor in the dogs (1.04 +/- 0.14 vs. 1.01 +/- 0.14%) was halothane MAC affected by aminophylline treatment. Commensurate with the lack of change of anesthetic depth, aminophylline treatment did not affect noradrenergic neurotransmission in the brain of halothane-anesthetized rats. Furthermore, the anticipated increase in circulating catecholamines following aminophylline treatment in dogs did not materialize. The authors conclude that halothane anesthetic requirements are not altered by aminophylline treatment, possibly because of the attenuation of the putative sympathomimetic effects of aminophylline by halothane.

Aminophylline↗
PubMed1987

Effect of halothane on critical levels of oxygen transport in the anesthetized newborn lamb.

A critical level of oxygen transport has been defined as the level which is required to maintain tissue oxygen uptake (VO2). If halothane reduces the susceptibility to hypoxia, it should lower the critical levels of both O2 delivery (DO2) and arterial oxygen tension (pO2). To test this hypothesis, 12 newborn lambs were anesthetized with either fentanyl and pancuronium (control group) or fentanyl, pancuronium, and 1.1% (1 MAC) halothane (halothane group). Baseline measurements of hemoglobin, cardiac output (CO), arterial and mixed-venous pO2, and saturation were obtained on FIO2 1.0, and repeated with FIO2 .21, .15, and .10. O2 delivery (CO X CaO2) and O2 consumption were calculated from measured parameters. Critical levels were selected using a system of repetitive linear regression. Halothane decreased baseline O2 consumption (12.1 +/- 0.7 to 8.4 +/- 0.4 cc X kg-1 X min-1, x +/- SEM, P less than .001, unpaired t test), but caused similar reductions in cardiac output (235 +/- 15 to 132 +/- 15 cc X kg-1 X min-1, P less than .001) and O2 delivery (29.2 +/- 2.9 to 20.2 +/- 1.6 cc X kg-1 X min-1, P less than .05). Addition of halothane decreased the critical level of O2 delivery from 17.9 to 14.3 cc X kg-1 X min-1, but had no effect on the critical level of arterial pO2 (control group, 47 mmHg halothane, 46 mmHg). Peripheral oxygen utilization was mildly reduced during halothane anesthesia, as evidenced by a decrease in oxygen extraction (control group O2 extraction rate = 0.63; halothane group O2 extraction = 0.51, P less than .05, unpaired t test).(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthesia↗
PubMed1987

Halothane inhibits calcium accumulation following myocardial ischemia and calcium paradox in guinea pig hearts.

This study was performed to test the hypothesis that halothane inhibits calcium accumulation associated with myocardial ischemia and calcium paradox. Using a Langendorff preparation in isolated guinea pig hearts, tissue 45Ca was measured after 40 and 60 min of loading with 45Ca, followed by 20 min of washout period. Myocardial ischemia was produced by a 30-min occlusion of the left anterior descending coronary artery (LAD). LAD occlusion caused an increase in 45Ca content in the anterior left ventricular muscle (ischemic area) of 215% compared to that of the posterior left ventricular muscle (normal myocardium). The increase in 45Ca content in the ischemic area was significantly less (P less than 0.05) in the presence of halothane (1%) compared to the non-halothane group. Halothane did not significantly alter 45Ca content in the non-ischemic myocardium. Myocardial injury associated with calcium paradox, which was produced by a 10-min perfusion of the heart with calcium-free Krebs solution followed by normal calcium repletion, caused a significant increase (P less than 0.05) in the 45Ca content compared to control. Addition of halothane (1%) significantly depressed (P less than 0.05) the increase in 45Ca content caused by calcium paradox. It is suggested that halothane might inhibit calcium accumulation associated with myocardial ischemia and calcium paradox under certain experimental situations. The inhibitory effect of halothane on calcium accumulation may be beneficial for the ischemic heart during halothane anesthesia.

Anesthesia↗
PubMed1987

Effect of halothane on regional cerebral blood flow and cerebral metabolic oxygen consumption in the fetal lamb in utero.

The effects of halothane on maternal and fetal hemodynamics, distribution of fetal cardiac output, regional cerebral blood flow, and fetal cerebral oxygen consumption were studied in the ewe (N = 9) using radionuclide-labeled microspheres. An adjustable uterine artery occluder was used to produce a controlled state of fetal asphyxia. Measurements were taken during three periods of study: 1) control, 2) asphyxia, and 3) asphyxia plus 15 min of 1% maternal halothane. The fetal cardiovascular response to asphyxia was acidosis, hypoxia, hypertension, bradycardia, and preservation of vital organ blood flows. There was a significant drop in maternal blood pressure when halothane was administered but uterine blood flow was maintained, 308 ml X min-1 during asphyxia versus 275 ml X min-1 with halothane. Fetal blood pressure during asphyxia plus halothane (54 mmHg) was significantly lower than that during asphyxia alone (59 mmHg), while heart rate was significantly higher: 172 beats per minute (bpm) versus 125 bpm (P less than 0.05). Despite these changes, the administration of halothane during asphyxia did not produce a reduction in vital organ flows. Cerebral blood flow was maintained: 357 +/- 37 ml X 100 g-1 X min-1 during asphyxia alone and 344 +/- 26 ml X 100 g-1 X min-1 after halothane administration (P = NS, mean +/- SEM). Cerebral oxygen delivery also was maintained: 8.3 +/- 0.8 ml X 100 g-1 X min-1 during asphyxia alone versus 9.7 +/- 1.5 ml X 100 g-1 X min-1 after halothane, compared with 11.2 +/- 1.1 ml X 100 g-1 X min-1 during the control period.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthesia, Inhalation↗
PubMed1987

Actions of halothane on the electrical activity of Purkinje fibers derived from normal and infarcted canine hearts.

The effects of 0.39 mM halothane (approx. 1.1 vol%) on the action potentials of proximal (false tendon) and distal (apical) left ventricular Purkinje fibers were compared in analogous in vitro preparations derived from normal dogs and animals surviving 1 day following acute myocardial infarction. In ten noninfarcted hearts, halothane reduced regional differences in repolarization by decreasing action potential duration (APD90, mean +/- SE) in proximal fibers from 300 +/- 7 to 277 +/- 6 msec (P less than or equal to 0.01) without decreasing APD90 in distal fibers (control 240 +/- 4 msec, halothane 249 +/- 5 msec). In ten infarcted hearts, halothane accentuated pathologic differences in repolarization by decreasing APD90 in the non-ischemic proximal fibers from 311 +/- 8 to 287 +/- 7 msec (P less than or equal to 0.01), while increasing APD90 in the ischemic distal fibers from 375 +/- 15 to 406 +/- 18 msec (P less than or equal to 0.01). Halothane also decreased the overshoot from 32.9 +/- 1.0 to 28.4 +/- 0.8 m V (P less than or equal to 0.01) and Vmax from 356 +/- 28 to 300 +/- 22 V/s (P less than or equal to 0.05) in ischemic fibers. In seven infarcts evaluated by extrastimulus techniques, halothane slowed the conduction of premature impulses and prolonged refractoriness, while, in five of the seven hearts, it reversibly increased the range of coupling intervals which induced probable reentrant responses. In a separate study of seven infarcts, halothane decreased the rate of spontaneous activity originating in the ischemic region. It is concluded that halothane facilitates the occurrence of re-entry while inhibiting the initiation of abnormal impulses in the in vitro canine infarction model.

Action Potentials↗
PubMed1988

Attenuation of endothelium-mediated vasodilation by halothane.

To determine whether halothane alters endothelium-mediated vasodilation of vascular smooth muscle, isolated ring preparations of rabbit aorta and canine femoral and carotid arteries were suspended for isometric tension recordings in Krebs-Ringer bicarbonate solution at 37 degrees C. Acetylcholine and bradykinin have been shown to relax these norepinephrine contracted arteries via an endothelium-dependent process. In this study, these relaxations were reversibly and significantly attenuated by 2% halothane. However, halothane did not affect relaxations caused by nitroglycerin, which, in these vessels, acts by an endothelium independent mechanism. These results suggest that halothane is not interfering with cyclic guanylate-monophosphate mediated relaxation of vascular smooth muscle, but may interfere with the synthesis, release, or transport of the endothelium-derived relaxing factor. In addition, during contractions evoked by norepinephrine, halothane caused significant decreases in tension in both the canine carotid and rabbit aortic preparations, but increased tension in the femoral artery rings. These effects were not altered by mechanical removal of the endothelium. These results suggest a direct action of halothane on the vascular smooth muscle, which can result in either an increase or decrease in tension, depending on the specific vessel. In addition to its direct vascular effect, this study suggests a new action of halothane; it interferes with endothelium-derived relaxing factor-mediated relaxation of vascular smooth muscle. This action may contribute in part to the vascular alterations seen clinically during administration of halothane.

Animals↗
PubMed1988

Comparative toxicity of halothane, isoflurane, hypoxia, and phenobarbital induction in monolayer cultures of rat hepatocytes.

Hypoxia, phenobarbital induction, and halothane anesthesia have been implicated in the pathogenesis of hepatotoxicity in the rat model. However, a controversy exists over the role of halothane in liver injury; does it act by reducing hepatic blood flow, thereby inducing hypoxia, or do its metabolites initiate the injury? These variables are difficult to separate during in vivo halothane exposure. In the present experiments, effects of halothane on hepatic perfusion were eliminated by exposing confluent monolayers of hepatocytes isolated from Fisher 344 rats livers, both with and without phenobarbital pretreatment, to 1.5% halothane or 2.0% isoflurane in 1%, 2%, or 4% (control) oxygen. Isoflurane exposure was included for a control of anesthetic effects on hepatocytes, because it is known to be metabolized minimally and probably is not associated with hepatic dysfunction. Oxygen levels were chosen to approximate those that may occur in the liver in vivo. Cell death was assayed via aspartate aminotransferase (AST) release, both immediately following a 2-h oxygen +/- anesthetic exposure and 6 h post-exposure. Per cent cell death data were analyzed using multiple regression techniques. Results obtained immediately, and 6 h after, exposure demonstrate that low oxygen levels, halothane, and phenobarbital were each highly significant factors (P less than .001) in relation to cell death, in agreement with the halothane-phenobarbital-hypoxia rat model. A toxic effect of isoflurane was not observed under identical experimental conditions. The results of the study clearly indicate that the origin of cell death in hepatocyte monolayers is multi-factorial; hypoxia, phenobarbital induction, and halothane exposure each contribute to the hepatocyte damage observed in our in vitro model.

Animals↗
PubMed1988

Synergistic interaction of morphine and halothane in the guinea pig ileum.

The present study describes the effects of halothane on morphine activity in the myenteric plexus-longitudinal muscle preparation of the guinea pig ileum. Morphine and halothane produced a dose-related inhibition of the electrically induced muscle contractions with IC50 of 1.9 X 10(-7) and 1.7 V/V%, respectively. The effects of morphine, but not halothane, were antagonized by naloxone. The IC50 of morphine was decreased in the presence of halothane (0.8-3.0 V/V%). Hill coefficients derived from dose-response curves were less than one for morphine or halothane alone, while it was 1.4 for the combination. The pA2 values (a measure of affinity of the antagonist for the opioid receptor) for naloxone in the absence and presence of halothane (1.6%) were 9.4 and 9.1, respectively. These results indicate that 1) halothane increases the potency of morphine in the guinea pig ileum at clinically relevant concentrations, 2) the interaction between the agents is synergistic, and 3) halothane does not modify the binding of naloxone to opioid receptors, but may affect membrane or intracellular processing of the receptor signal.

Animals↗
PubMed1988

Enflurane metabolism produces covalently bound liver adducts recognized by antibodies from patients with halothane hepatitis.

The existence of a rare syndrome of "enflurane hepatitis" similar to that described for halothane and of a cross-sensitization between halothane and enflurane has been controversial, largely due to equivocal clinical case reports and a lack of a plausible molecular mechanism for the hepatotoxicity. The present study suggests a possible hypersensitivity basis for enflurane hepatitis and the apparent cross-sensitization between halothane and enflurane involving covalently bound liver microsomal adducts. Immunoblotting studies have revealed that antibodies in the sera of six patients with halothane hepatitis recognize liver microsomal antigens of Mr = 100,000, or both 100,000 and 76,000, formed in rats treated with enflurane or halothane. These antigens were not detected in microsomes from isoflurane- or sesame oil-treated rats. The recognition of these antigens could be abolished by preincubation of the sera with microsomes from halothane-treated rats. These data suggest that the difluoromethoxydifluoroacetyl halide metabolite of enflurane, as well as the trifluoroacetyl halide metabolite of halothane, covalently bind to similar hepatic proteins, and may become immunogens in susceptible patients. This mechanism may also account for the apparent cross-sensitization between halothane and enflurane anesthesia, and the development of hepatic necrosis.

Animals↗
PubMed1989

Halothane, but not isoflurane or enflurane, protects against spontaneous and epinephrine-exacerbated acute thrombus formation in stenosed dog coronary arteries.

Occlusive platelet thrombi periodically form in mechanically stenosed dog coronary arteries producing cyclical blood flow reductions occurring over 4-7 min. Cyclical coronary flow reductions are exacerbated by IV epinephrine 0.4 microgram.kg-1.min-1 for 15 min. These flow reductions can be abolished by known inhibitors of platelet function. This study assesses the effect of halothane, isoflurane, and enflurane on spontaneous- and epinephrine-exacerbated cyclical coronary flow reductions. Twenty-three open-chest dogs [1% halothane (n = 5), 0.5% halothane (n = 5), 0.25% halothane (n = 3), 1.5% isoflurane (n = 5), and 2.0% enflurane (n = 5)] with a mechanically stenosed coronary artery showed cyclical blood flow reductions. With 1.0% halothane administration, spontaneous cyclical blood flow reductions were abolished (n = 5), whereas during administration of isoflurane 1.5% (n = 5) and enflurane 2.0% (n = 5) cyclical flow reductions and myocardial ischemia continued. Subsequent administration of halothane in the isoflurane and enflurane groups showed abolition of coronary flow reductions in all animals (n = 10). In eight animals a 15-min epinephrine infusion (0.4 microgram.kg-1.min-1) was given following a control period and again following abolition of coronary flow reductions by halothane 0.5% (n = 5) and halothane 0.25% (n = 3). The magnitude of cyclical blood flow reductions (difference between initial and final coronary flow level of each flow reduction) changed from 52 +/- 11 to 61 +/- 12 ml/min (NS), and frequency increased from 0.37 to 0.57/min (P less than 0.05, n = 8) during epinephrine infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

The action of halothane on spontaneous contractile waves and stimulated contractions in isolated rat and dog heart cells.

The cell length of single, isolated rat and dog heart cells was monitored during exposure to halothane-containing solution to define the cellular mechanism of halothane's negative inotropic effect. Spontaneous contractile waves, which reflect spontaneous Ca release from the sarcoplasmic reticulum (SR) in resting rat heart cells, exhibited a significant increase in frequency and a decrease in amplitude in the presence of halothane 0.27 mM (0.9 vol%) and 0.55 mM (1.7 vol%). Electrically stimulated dog and rat heart cells abruptly exposed to halothane (0.47-0.55 mM or 1.5-1.7 vol%) revealed a transient increase in twitch amplitude (significantly different from control). Twitch amplitude then declined to values significantly below control as halothane exposure continued. This decrease in twitch reached 42 +/- 13% (mean +/- SD) of control in rat cells and 50 +/- 14% in dog cells beating at 60 beats per min. In dog cells the magnitude of the transient increase in twitch amplitude was greater at faster beating rates compared with lower rates in the same cells (P less than 0.01) and the transient increase was insensitive to verapamil. Halothane 0.55 mM (1.7 vol%) also significantly accelerated the rate of decline in the twitch amplitude of successive beats in rat cells stimulated after a rest interval (negative staircase). The findings regarding spontaneous contractile waves indicate a direct effect of halothane at the SR in resting cells, occurring independently of any changes in the slow inward current. The halothane-induced changes in beating cells can be explained by an enhancement of Ca release from the SR with an eventual reduction of SR Ca stores.

Animals↗
PubMed1990

The effect of halothane on norepinephrine responsiveness in rabbit small mesenteric veins.

The effect of halothane on the response of small isolated mesenteric capacitance veins to exogenous norepinephrine and electrically induced endogenous norepinephrine release was studied. The role of extra- and intracellular Ca2+ in norepinephrine-induced contractions was also examined. Two-millimeter-long segments from the second-order branch of the mesenteric vein were stretched to twice their resting diameter, and the generated tension was measured with a force transducer. Dose-dependent effects of norepinephrine on generated tension were examined before and after exposure to 0.75 and 1.5% halothane. (These concentrations produced perfusate halothane concentrations of 0.31 and 0.49 mM respectively.) Norepinephrine produced an increase in the basal vessel tension along with a superimposed rhythmic oscillation in tension. Although the magnitude of the tension increase was not affected by either concentration of halothane, the amplitude of the oscillations was reduced. Ryanodine (a blocker of Ca2+ release from the sarcoplasmic reticulum), like halothane, decreased the amplitude of the oscillations, but did not affect overall tension development. In the Ca2(+)-free medium the contractile response to norepinephrine was greatly attenuated as compared to control, whereas the oscillatory behavior was completely abolished. Norepinephrine release was examined indirectly by measuring the increase in tension during electric field stimulation. Response to endogenously released norepinephrine was significantly decreased by exposure to halothane 1.5% (0.49 mM) and blocked by pretreating the vessel with phentolamine. At concentrations used clinically, halothane did not affect overall developed tension in response to exogenously applied norepinephrine. However, 1.5% (0.49 mM) halothane decreased both sarcoplasmic-reticulum-dependent oscillations in tension and electrically induced release of endogenous norepinephrine.

Animals↗