Antioxidants prevent depression of the acute hypoxic ventilatory response by subanaesthetic halothane in men.

We studied the effect of the antioxidants (AOX) ascorbic acid (2 g, I.V.) and alpha-tocopherol (200 mg, P.O.) on the depressant effect of subanaesthetic doses of halothane (0.11 % end-tidal concentration) on the acute isocapnic hypoxic ventilatory response (AHR), i.e. the ventilatory response upon inhalation of a hypoxic gas mixture for 3 min (leading to a haemoglobin saturation of 82 +/- 1.8 %) in healthy male volunteers. In the first set of protocols, two groups of eight subjects each underwent a control hypoxic study, a halothane hypoxic study and finally a halothane hypoxic study after pretreatment with AOX (study 1) or placebo (study 2). Halothane reduced the AHR by more than 50 %, from 0.79 +/- 0.31 to 0.36 +/- 0.14 l min(-1) %(-1) in study 1 and from 0.79 +/- 0.40 to 0.36 +/- 0.19 l min(-1) %(-1) in study 2, P < 0.01 for both. Pretreatment with AOX prevented this depressant effect of halothane in the subjects of study 1 (AHR returning to 0.77 +/- 0.32 l min(-1) %(-1), n.s. from control), whereas placebo (study 2) had no effect (AHR remaining depressed at 0.36 +/- 0.27 l min(-1) %(-1), P < 0.01 from control). In a second set of protocols, two separate groups of eight subjects each underwent a control hypoxic study, a sham halothane hypoxic study and finally a sham halothane hypoxic study after pretreatment with AOX (study 3) or placebo (study 4). In studies 3 and 4, sham halothane did not modify the control hypoxic response, nor did AOX (study 3) or placebo (study 4). The 95 % confidence intervals for the ratio of hypoxic sensitivities, (AOX + halothane) : halothane in study 1 and (AOX - sham halothane) : sham halothane in study 3, were [1.7, 2.6] and [1.0, 1.2], respectively. Because the antioxidants prevented the reduction of the acute hypoxic response by halothane, we suggest that this depressant effect may be caused by reactive species produced by a reductive metabolism of halothane during hypoxia or that a change in redox state of carotid body cells by the antioxidants prevented or changed the binding of halothane to its effect site. Our findings may also suggest that reactive species have an inhibiting effect on the acute hypoxic ventilatory response.

A Caenorhabditis elegans pheromone antagonizes volatile anesthetic action through a go-coupled pathway.

Volatile anesthetics (VAs) disrupt nervous system function by an ill-defined mechanism with no known specific antagonists. During the course of characterizing the response of the nematode C. elegans to VAs, we discovered that a C. elegans pheromone antagonizes the VA halothane. Acute exposure to pheromone rendered wild-type C. elegans resistant to clinical concentrations of halothane, increasing the EC(50) from 0.43 +/- 0.03 to 0.90 +/- 0.02. C. elegans mutants that disrupt the function of sensory neurons required for the action of the previously characterized dauer pheromone blocked pheromone-induced resistance (Pir) to halothane. Pheromone preparations from loss-of-function mutants of daf-22, a gene required for dauer pheromone production, lacked the halothane-resistance activity, suggesting that dauer and Pir pheromone are identical. However, the pathways for pheromone's effects on dauer formation and VA action were not identical. Not all mutations that alter dauer formation affected the Pir phenotype. Further, mutations in genes not known to be involved in dauer formation completely blocked Pir, including those altering signaling through the G proteins Goalpha and Gqalpha. A model in which sensory neurons transduce the pheromone activity through antagonistic Go and Gq pathways, modulating VA action against neurotransmitter release machinery, is proposed.

[Fatty acid-induced reversal of general anesthesia: chain length-dependence of antagonizing potencies of fatty acids].

Anesthesia is always antagonized by high pressure in the range of 100 atm. The pressure reversal means that the volume of the macromolecule in the anesthetized state is larger than the awake state. Long-chain fatty acids tightened the structure of firefly luciferase whereas anesthetics unfolded the enzyme structure. As expected from these findings, myristate (C 14 fatty acid) at 40 microM increased the EC50 values of volatile anesthetics 250% in goldfish. This study was performed to test the hypothesis that anesthesia antagonism by fatty acid in goldfish was caused by nonspecific action on proteins. We therefore studied the chain length-dependence of the antagonizing potencies of fatty acids. The chain length of 6, 8, 10, 12, and 14 was studied. Ten goldfish were placed in a tub containing 3200 ml distilled water without (control) or with fatty acids. After 30 min of bubbling with halothane vaporized with oxygen into the tub, goldfish were electrically stimulated by constant voltage 20 V for 0.2 sec. Those did not respond to the stimuli were counted as anesthetized. All fatty acids except C 10 increased EC50 of halothane by 50-100% compared to the control (1.13% atm). However, the fatty acid concentrations required for antagonizing halothane increased as the chain length decreased, 300 microM in C 6 30-fold higher than 10 microM in C 14. Because water solubility of short-chain fatty acid is higher than long-chain fatty acid, the antagonizing potencies of fatty acids were thus determined not by their concentrations but by their thermodynamic activities (Ferguson's rule). These results suggest that fatty acid-induced anesthesia antagonism may be caused by physical and nonspecific actions on proteins.

Hepatobiliary scintigraphy for evaluating the hepatotoxic effect of halothane and the protective effect of catechin in comparison with histo-chemical analysis of liver tissue.

Halothane and its metabolites cause liver damage by decreasing liver blood flow and generating free-radical species. Catechin suppresses lipid peroxidation and increases enzyme activity, therefore it seems to be capable of protecting liver parenchyma against the direct toxic effect of halothane. The aim of this study was to investigate the role of hepatobiliary scintigraphy in detecting liver damage after halothane anaesthesia and the protective effect of catechin in comparison with histo-chemical analysis. Thirty rabbits, divided into three groups (A, controls; B, halothane; and C, catechin+halothane), were investigated. In group A no anaesthesia was administered. Group B only received halothane, while group C was pretreated with catechin and halothane anaesthesia was administered for 2 h. Dynamic scintigrams were taken for 60 min after injecting 99mTc-mebrofenin, and the time of peak uptake (TPU) and the time for half of the activity to clear from the liver (T(1/2)) were calculated. Rabbits were killed, and malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT) levels were measured in hepatic tissue. The TPU and T(1/2) values of group A is significantly lower than in groups B and C (P<0.0002 and P<0.0002, respectively, for TPU; and P<0.0002 and P<0.0003, respectively, for T(1/2)). The TPU and T(1/2) values of group B were significantly higher than in group C (P<0.0003 and P<0.0003, respectively). The hepatic MDA level of group A was significantly lower than in groups B and C (P<0.0002 and P<0.0002, respectively). SOD, GSH-Px and CAT levels of group A were significantly higher than in groups B and C (P<0.0002, P<0.0001 and P<0.003, respectively, for group A vs group B; and P<0.0005, P<0.0002 and P<0.03, respectively, for group A vs group C). The MDA level of group B was significantly higher than that in group C (P<0.0002). SOD, GSH-Px and CAT levels of group B were significantly lower than in group C (P<0.0002, P<0.0002 and P<0.003, respectively). According to these results, we suggest that catechin protects liver parenchyma against the toxic effect of halothane and its metabolites, and that, compared to invasive histo-chemical analysis, hepatobiliary scintigraphy is a useful and alternative non-invasive method for detecting the protective effect of catechin on liver parenchyma after halothane anaesthesia.

Efecto del isofluorano sobre la respuesta inotrópica al isoproterenol en el corazón aislado de conejo / Effect of isofluorane on the inotropic response to isoproterenol in the isolated rabbit heart

Los anestésicos volátiles provocan depresión de la función sistólica, sensibilizan al miocardio frente a la acción de las catecolaminas y también pueden alterar la respuesta miocárdica a la estimulación ß-adrenérgica, aunque con discrepancias según el agente empleado. El objetivo del presente trabajo ha sido evaluar si la presencia de isofluorano modifica la respuesta inotrópica al isoproterenol. Se utilizaron 11 corazones aislados de conejo, perfundidos según la técnica modificada de Langendorff. Fueron calculadas: la presión desarrollada ventricular izquierda (PDVI) y la máxima velocidad de ascenso de la presión en función del tiempo (+ dP/dt max). Se realizaron dos grupos experimentales: Grupo 1 (G1, n=6), donde se evaluó la respuesta a isoproterenol, en dosis de 10 elevado a -8 y 10 elevado a -7 mM; Grupo 2 (G2, n=5), isofluorano 1 vol por ciento durante 10 minutos, previo a isoproterenol 10 elevado a -8 y 10 elevado a -7 mM. En el G1: la PDVI se incrementó 128.5 ñ 2.4 y 137.1 ñ 4,4 por ciento y la + dP/dt max 169.0 ñ 14.1 y 182.6 ñ 22.2 por ciento. En el G2: el isofluorano disminuyó la PDVI 5 por ciento y la +dP/dt 8 por ciento, mientras que el isoproterenol incrementó la PDVI 157.8 ñ 4.0 (P<0.05) y 169.6 ñ 6.3 por ciento (P<0.05) y la + dP/dt max 220.19 ñ 27.6 y 262.3 ñ 27.9 por ciento (p<0.05). La presencia de isofluorano modificó la respuesta inotrópica positiva al isoproterenol en un modelo experimental con estricto control de variables y similitudes con el corazón humano. (AU)

Effects of nonimmobilizers and halothane on Caenorhabditis elegans.

We studied the effects of two nonimmobilizers, a transitional compound, and halothane on the nematode, Caenorhabditis elegans, by using reversible immobility as an end point. By themselves, the nonimmobilizers did not immobilize any of the four strains of animals tested. Toluene appears to be a transitional compound for all strains tested. The additive effects of the nonimmobilizers with halothane were also studied. Similar to results seen in studies of mice, the nonimmobilizers were antagonistic to halothane in the wild type nematode. However, the nonimmobilizers did not affect the 50% effective concentrations of halothane for two other mutant strains. For halothane, the slopes of the dose response curves were smaller in more sensitive strains compared with the wild type. As in mammals, nonimmobilizers antagonize the effects of halothane on the nematode, C. elegans. The variation in slopes in the response to halothane in different strains is consistent with multiple sites of action. These results support the use of C. elegans as a model for the study of anesthetics.

Capture and immobilisation of aardvark (Orycteropus afer) using different drug combinations.

Nine aardvarks (Orycteropus afer) were captured in the southern Free State, South Africa, for the placement of abdominal radio transmitters. Five combinations of ketamine hydrochloride with xylazine hydrochloride, midazolam or medetomidine hydrochloride were used to induce anaesthesia. In some cases the level of anaesthesia was maintained with 1.5% halothane. A mixture of ketamine hydrochloride and medetomidine hydrochloride was found to be most effective. Atipamizole reversed the affects of medetomidine hydrochloride, resulting in a smooth and full recovery within 8 minutes. The immobilisation and subsequent anaesthesia of these animals on cold winter nights resulted in hypothermia, and keeping the animals warm was essential to the success of the procedures undertaken. Reversal of the sedative medetomidine hydrochloride proved to be important, because animals that were released before they were fully conscious took refuge in their burrows so that care was impossible.

Prevention of halothane-induced hepatotoxicity by hemin pretreatment: protective role of heme oxygenase-1 induction.

Reductive metabolism of halothane in phenobarbital-pretreated rats is known to increase free radical formation that results in hepatotoxicity. It also is associated with a marked induction of microsomal heme oxygenase-1 (HO-1), suggesting that there is an alteration in heme metabolism. In this study, we examined heme metabolism in rats pretreated with phenobarbital, followed by exposure to halothane-hypoxia. In this model, there was a significant decrease in microsomal cytochrome P450 content in the liver, followed by a rapid increase in free heme concentration and a decrease in the level of mRNA for the nonspecific delta-aminolevulinate synthase. A transient but dramatic induction of HO-1 mRNA and a prolonged induction of heat shock protein 70 mRNA also occurred. The HO-1 protein was detected principally in the hepatocytes around the central vein. Serum alanine transaminase (ALT) activity, an indicator of hepatic dysfunction, increased continuously throughout the experiment. Hemin pretreatment induced hepatic HO-1 with abrogation of the halothane-induced hepatotoxicity in this model, as judged by ALT activity and normal histology. Our findings in this study thus indicate that halothane-induced hepatotoxicity is due not only to its reductive metabolite formation, but also to an increase in hepatic free heme concentration, which is a potent prooxidant; HO-1 induction is an important protective response against such changes. This is also the first study to demonstrate that hemin pretreatment, which induces HO-1 prior to exposure to halothane, effectively prevents halothane-induced hepatotoxicity.

[Intra- and intercellular Ca(2+)-signal transduction]. / Intra- en intercellulaire Ca(2+)-signaal transductie.

Calcium is one of the most universal signal-transduction elements in a large variety of cells ranging from bacteria to specialized neurons. Ca2+ acts as a second messenger controlling such processes as secretion, cell differentiation or signal transmission. In order to be able to execute their specific functions and to react in a coordinated way to stimuli, multicellular organs need a precise orchestration of cellular functions. For this purpose cells have developed different forms of intercellular communication (IC). In this study we investigated a number of mechanisms of intracellular propagation and IC using experiments with fluorescent Ca(2+)-indicators, confocal microscopy and digital imaging techniques. In ROS 17/2.8 osteoblasts, retinal pigment epithelial cells (RPE) and CPAE endothelial cells, a small mechanical deformation of the plasma membrane results in a transient increase of free cytoplasmic Ca2+ concentration ([Ca2+]i). This Ca(2+)-rise starts at the site of stimulation and propagates concentrically to neighboring cell layers. The intracellular Ca(2+)-wave in RPE and ROS cells is caused by Ca(2+)-influx followed by Ca(2+)-release from the intracellular stores and by intercellular propagation of the Ca(2+)-wave. The [Ca2+]i-transient upon mechanical stimulation of LLC-PK1 epithelial cells, C6 glioma cells and MLO-Y4 osteocytes was limited and/or variable. In CPAE cells only the intracellular release is important for evoking the Ca(2+)-transient, and is followed by IC. IC can occur via gap junctions (GJ) consisting of membrane-spanning proteins, connexins (Cx). It was demonstrated that IC and GJ in RPE and ROS cells can be reversibly blocked by gap-junction inhibitors such as heptanol or halothane. We demonstrated important differences in modulation of gap junctional communication between these cell types. While in RPE cells stimulation of PKC activity was able to inhibit IC, this was not the case in ROS cells. We screened LE-RPE cDNA via PCR using specific primers for different connexins and found no effect of high glucose solutions, which cause decreased intercellular communication, on the Cx-isoforms expressed. Cx43 is the only Cx-isoform present at the protein level for which Western blot analysis revealed the presence of different forms corresponding to different phosphorylated states. Increased phosphorylation of Cx43 was only seen after direct PKC activation by PMA, but not by indirect PKC activation by high glucose levels. The decreased communication by high glucose concentrations was however associated by a decreased expression of cellular Cx43 to about 3/4 of the level in control conditions. High glucose concentrations therefore decrease Cx43 at the protein level via a PKC effect that appears to be independent of the direct activation of PKC by phorbolesters. Mechanical stimulation did not evoke intercellular Ca(2+)-waves in LLC-PK1 epithelial cells, C6 glioma cells and MLO-Y4 osteocytes. In CPAE-endothelial cells, the contribution of gap junctions to IC following mechanical stimulation is negligible, and modulation of gap junctions via phosphorylation or high glucose solutions is absent. Perfusion experiments and pharmacological studies demonstrated that IC following mechanical stimulation of these cells occurs via release of an extracellular mediator. Our experiments provide strong evidence in favor of purinergic agonists as mediators, such as ATP but mainly ADP. In conclusion we can say that cells contain a wide spectrum of mechanisms for intra- and intercellular communication, and that widely different mechanisms can evoke the same phenomenon of intra- and intercellular Ca(2+)-waves.

5-HT2 receptor antagonist-mediated inhibition of halothane-induced contractures in skeletal muscle specimens from malignant hyperthermia susceptible patients.

Administration of 5-HT2 receptor agonists induced malignant hyperthermia (MH) in susceptible pigs. Furthermore, the 5-HT2 receptor antagonist ritanserin prevented 5-HT-induced porcine MH. It has been shown that 5-HT2 receptor agonists induce marked contractures in skeletal muscle specimens from MH susceptible (MHS) but not in specimens from normal patients. The purpose of this study was to investigate the effects of ritanserin on halothane-induced contractures in muscle specimens from MHS patients. Twenty-five patients aged 8-56 years (29.5+/-13.6) classified as MHS by the in vitro contracture test (IVCT) with halothane and caffeine according to the protocol of the European MH Group participated in this study. Muscle specimens were pretreated with ritanserin 10 micromol/l (n= 14), 20 micromol/l (n=14) and 100 micromol/l (n=12) for 10 min and subsequently halothane was added incrementally (0.11-0.22-0.44 mmol/l) to the tissue bath as described in the European MH protocol. The results of the halothane contracture test were used as control. Following administration of halothane, muscle contractures reached a maximum of 16.9+/-4.2 mN. Ritanserin led to a significant inhibition of halothane-induced contractures in MHS muscles. Following pretreatment with ritanserin, halothane-induced contracture maximum was significantly smaller with 7.5+/-3.1 mN after 10 micromol/l ritanserin, 4.9+/-1.5 mN after 20 micromol/l ritanserin and 0.5+/- 0.2 mN after 100 micromol/l ritanserin than without pretreatment. Administration of ritanserin induced at all concentrations a decrease in muscle twitch height. Increase in muscle twitch following halothane was reduced in a concentration-dependent manner by ritanserin. The presented findings indicate that 5-HT might be involved in the mechanisms of halothane-induced MH in humans. Further studies have to determine the pathophysiological role of the 5-HT system in MH, and whether ritanserin could be an alternative for treatment or prevention of halothane-induced MH.

Changes in mucociliary activity may be used to investigate the airway-irritating potency of volatile anaesthetics.

We have examined the short-term effects of three volatile anaesthetics, halothane, isoflurane and desflurane, on mucociliary activity in the rabbit maxillary sinus in vivo. Mucociliary activity was recorded photoelectrically and the signal processed by fast Fourier transformation. Administration of 1.0 MAC of halothane, isoflurane or desflurane caused a temporary increase in mucociliary activity, with mean peak responses of 47.8 (SEM 13.0)%, 44.0 (9.6)% and 45.1 (23.7)% (n = 6), respectively. The response to all three compounds was biphasic; an initial peak was observed within 2 min and a second peak at 3-8 min. The second response was not significant for halothane. In contrast, desflurane produced a significant second peak while the first was small and failed to reach significance. Halothane displayed an initial peak within 2 min which was blocked by atropine but not by the neurokinin 1 (NK1) receptor antagonist CP-99. The second peak at 3-5 min was less pronounced for halothane than for isoflurane or desflurane. The second peak was not affected by atropine pretreatment, but was blocked by pretreatment with CP-99. A combination of atropine and CP-99 pretreatment abolished the mucociliary response to halothane. Atropine pretreatment did not affect, whereas CP-99 significantly reduced, the response to desflurane. We conclude that the NK1-mediated response was most pronounced for desflurane which is considered the most airway irritating compound of the three. It is likely that the size of the NK1-mediated response reflects the airway-irritating properties of the volatile anaesthetic used.

Halothane reduces reperfusion injury after regional ischaemia in the rabbit heart in vivo.

In addition to having anti-ischaemic effects, halothane can protect isolated rat hearts and isolated cardiomyocytes against reperfusion injury of the "oxygen paradox" type. The aim of this study was to investigate if halothane can also protect against myocardial reperfusion injury in vivo. Twenty-two rabbits anaesthetized with alpha-chloralose underwent 30 min of occlusion of a major coronary artery and 2 h of subsequent reperfusion. Seven animals received 1 MAC of halothane for the first 15 min of reperfusion (halothane group), and eight animals served as untreated controls (controls group). In seven additional animals, the haemodynamic effects of halothane were antagonized by an i.v. infusion of noradrenaline (halothane-noradrenaline group). We measured cardiac output (CO) by an ultrasonic flow probe around the ascending aorta, left ventricular pressure (LVP) by a tip manometer and infarct size by triphenyltetrazolium staining. Baseline LVP was mean 92 (SEM 4) mm Hg and CO was 289 (16) ml min-1. During coronary occlusion, LVP was reduced to 86 (4)% of baseline and CO to 84 (4)% (similar in all groups). During halothane administration at reperfusion, LVP declined further to 55 (6)% of baseline and CO to 66 (9)% (P < 0.05 halothane group vs control group). Noradrenaline prevented the reduction in LVP (halothane-noradrenaline group 87 (5)% of baseline, control group 84 (6)% and reduction in CO (halothane-noradrenaline group 89 (5)%, control group 83 (6)%. Infarct size was 49 (6)% of the area at risk in controls and was reduced markedly by administration of halothane to 32 (3)% in the halothane group (P < 0.05) and to 30 (3)% in the halothane-noradrenaline group (P < 0.05). Treatment with halothane during the early reperfusion period after myocardial ischaemia protected the myocardium against infarction in vivo, independent of the haemodynamic effect of halothane.

Antagonism of the antinocifensive action of halothane by intrathecal administration of GABAA receptor antagonists.

BACKGROUND: The hind brain and the spinal cord, regions that contain high concentrations of gamma-aminobutyric acid (GABA) and GABA receptors, have been implicated as sites of action of inhalational anesthetics. Previous studies have established that general anesthetics potentiate the effects of gamma-aminobutyric acid at the GABAA receptor. It was therefore hypothesized that the suppression of nocifensive movements during anesthesia is due to an enhancement of GABAA receptor-mediated transmission within the spinal cord. METHODS: Rats in which an intrathecal catheter had been implanted 1 week earlier were anesthetized with halothane. Core temperature was maintained at a steady level. After MAC determination, the concentration of halothane was adjusted to that at which the rats last moved in response to tail clamping. Saline, a GABAA, a GABAB, or glycine receptor antagonist was then injected intrathecally. The latency to move in response to application of the tail clamp was redetermined 5 min later, after which the halothane concentration was increased by 0.2%. Response latencies to application of the noxious stimulus were measured at 7-min intervals during the subsequent 35 min. To determine whether these antagonists altered baseline response latencies by themselves, another experiment was conducted in which the concentration of halothane was not increased after intrathecal administration of GABAA receptor antagonists. RESULTS: Intrathecal administration of the GABAA receptor antagonists bicuculline (0.3 micrograms) or picrotoxin (0.3, 1.0 micrograms) antagonized the suppression of nocifensive movement produced by the small increase in halothane concentration. In contrast, the antinocifensive effect of the increase in halothane concentration was not attenuated by the GABAB receptor antagonist CGP 35348 or the glycine receptor antagonist strychnine. By themselves, the GABAA receptor antagonists did not alter response latency in rats anesthetized with sub-MAC concentrations of halothane. CONCLUSIONS: Intrathecal administration of bicuculline or picrotoxin, at doses that do not change the latency to pinch-evoked movement when administered alone, antagonized the suppression of noxious-evoked movement produced by halothane concentrations equal to or greater than MAC. These results suggest that enhancement of GABAA receptor-mediated transmission within the spinal cord contributes to halothane's ability to suppress nocifensive movements.

Alterations of inositol polyphosphates in skeletal muscle during porcine malignant hyperthermia.

Malignant hyperthermia (MH) may result from increased intracellular calcium concentrations. Increased 1,4,5-IP3 concentrations could mediate this increase in Ca2+. In this study we measured inositol polyphosphates in selectively bred MH susceptible (MHS) and MH non-susceptible (MHN) swine. MH crisis was induced by halothane challenge, and dantrolene was administered in order to measure inositol polyphosphates after MH reversal. Muscle biopsies of skeletal muscles of the hind limbs were obtained in random order and inositol polyphosphates determined by high pressure liquid chromatography using a metal dye detection method. Inositol polyphosphates were determined in three groups: (1) MHS vs MHN basal, (2) during MH crisis induced by halothane and (3) following treatment with dantrolene after halothane challenge. Clinical variables (P(_)VO2, P(-)VCO2, PE'CO2 and pH) indicated that MH was readily induced in MHS swine. Basal concentrations of all inositol polyphosphates were higher in MHS swine compared with MHN swine. After halothane challenge, 1,3,4-IP3, 1,3,4,6-IP4 and 1,3,4,5-IP4 concentrations increased in MHS animals compared with the respective baseline values, whereas no changes in MHN animals could be detected. Dantrolene administration decreased inositol polyphosphate concentrations in MHS swine. MHN swine showed no changes in inositol polyphosphates after dantrolene. These findings indicate that inositol polyphosphates may be involved in metabolic changes after triggering and treatment of MH.

Echocardiographic evaluation of vagolytic effects of atropine sulfate during pediatric halothane anesthesia.

The aims of this study were to define the antagonistic effects of atropine sulfate to halothane-induced cardiovascular depression in children, and to clarify whether or not a larger dose of atropine is more effective in attenuating the cardiovascular depression. Thirty-four children aged 1-12 years who had undergone minor surgery, free from cardiac or pulmonary disease, were assigned at random to two groups. M-mode echocardiographic evaluation of left ventricular function in each patient was performed at three points (before induction, point A; after induction, point B; and following administration of atropine, point C). Results were compared between points A and B, B and C and C and A, and between the two study groups with different doses of atropine (0.01 mg/kg vs 0.02 mg/kg). Heart rate (HR), mean blood pressure (MBP) and left ventricular shortening fraction (LVSF) decreased, and left ventricular end-diastolic dimension (LVEDD) were increased significantly by halothane induction. Although HR and MBP recovered following atropine, LVSF and LVEDD remained unchanged. There were no differences found between the values after vagolysis in both study groups, except for HR and mean velocity of circumferential fiber shortening (mVcf). Heart rate increased above that of pre-induction, even following the smaller dose of atropine. The myocardial depression cannot be necessarily attenuated by vagolysis regardless of the dosage of atropine. The smaller dose (i.e. 0.01 mg/kg) seems to be sufficient only to antagonize the bradycardia and hypotension during halothane anesthesia in children.

Reversal of volatile anesthetic-induced depression of myocardial contractility by extracellular calcium also enhances left ventricular diastolic function.

BACKGROUND: Volatile anesthetics depress global left ventricular function by altering intracellular calcium (Ca2+) homeostasis at several sites within the myocyte. Although extracellular Ca2+ partially reverses the negative inotropic effects of volatile anesthetics, the actions of extracellular Ca2+ on anesthetic-induced diastolic dysfunction are unexplored. This investigation examined and compared the direct effects of extracellular Ca2+ on left ventricular systolic and diastolic function in conscious and anesthetized dogs. METHODS: Experiments were conducted in the presence of pharmacologic blockade of the autonomic nervous system because autonomic nervous activity may significantly influence the hemodynamic actions of anesthetics and Ca2+ in vivo. Three groups comprised a total of 27 experiments conducted using nine dogs chronically instrumented for measurement of aortic and left ventricular pressure, left ventricular dP/dt, subendocardial segment length, and cardiac output. Myocardial contractility was evaluated using the preload recruitable stroke work relationship slope (Mw). Diastolic function was assessed using a time constant of isovolumic relaxation (tau), a regional chamber stiffness constant (Kp), and maximum segment lengthening velocity during rapid ventricular filling (dL/dtE) and atrial systole (dL/dtA). On 3 separate days, a CaCl2 infusion at 1.25, 2.5, or 5 mg.kg-1 x min-1 was administered. Hemodynamics and ventricular pressure-length loops were recorded after a 20-min equilibration at each dose in the conscious state or during halothane or isoflurane anesthesia. RESULTS: In conscious dogs, CaCl2 produced a significant (P < .05) and dose-dependent increase in contractility as evaluated by Mw. In the presence of halothane anesthesia, CaCl2 increased contractility (Mw of 26 +/- 5 mmHg to 78 +/- 10 mmHg during the high dose of CaCl2), enhanced isovolumic relaxation (tau of 57.9 +/- 4.2 ms to 41.1 +/- 1.9 ms during the high dose of CaCl2), improved rapid ventricular filling (dL/dtE of 11.8 +/- 1.4 mm/s to 20.2 +/- 1.6 mm/s during the high dose of CaCl2), and reduced regional chamber stiffness (Kp of 0.70 +/- 0.18 mm-1 to 0.38 +/- 0.04 mm-1 during the high dose of CaCl2). Similar findings were observed when CaCl2 was administered to dogs anesthetized with isoflurane. CONCLUSIONS: Although CaCl2 produced positive inotropic effects in both the conscious and anesthetized states, CaCl2 did not alter diastolic function in conscious dogs. In contrast, CaCl2 reversed halothane- and isoflurane-induced negative lusitropic actions. The results of the present investigation suggest that improvement of left ventricular performance by CaCl2 during volatile anesthesia may be related to actions in diastole as well as systole.

Effect of calcium channel agonist (BAY K8644) on volatile anesthetic-mediated depression in neonatal rabbit papillary muscle.

Heart muscle is dependent on the entry of calcium from the extracellular fluid to support contraction, and neonatal hearts are particularly sensitive to reductions in transsarcolemmal entry of calcium. Accordingly, this study evaluated the ability of the calcium channel agonist BAY K8644 to prevent or reverse the myocardial depressant effects of halothane or isoflurane in right ventricular papillary muscles from neonatal rabbits. The ability of BAY K8644 to reverse reductions in force (F) and dF/dt (halothane and isoflurane) or prevent reduction (halothane) was studied. Halothane decreased F to 24 +/- 2% of baseline values (p = 0.001). The addition of BAY K8644 reversed F to only 54 +/- 3% of baseline (p = 0.001 vs. baseline and p = 0.002 vs. halothane alone). Isoflurane decreased F to 20 +/- 2% of baseline (p = 0.001) with a return to 45 +/- 4% of baseline with the addition of BAY K8644 (p = 0.0001 vs. baseline and p = 0.0025 vs. isoflurane alone). With BAY K8644 in the bath prior to the addition of halothane, halothane decreased F to 38 +/- 4% of baseline (p = 0.001). dF/dt mirrored changes in F in all studies. These data show that a calcium channel agonist is only partially effective in modulating volatile anesthetic-induced depression in neonatal rabbit ventricular papillary muscle.

Flumazenil does not antagonize halothane, thiamylal or propofol anaesthesia in rats.

We have studied the effects of flumazenil on sleep time and EEG in rats anaesthetized with 1.5% halothane, propofol 20 mg kg-1, thiamylal 30 mg kg-1, or combinations of diazepam 5 mg kg-1 and anaesthetic agents. We also studied the effects of flumazenil 0.3, 3 and 30 mg kg-1 on behaviour and EEG. Flumazenil 0.3 and 3 mg kg-1 alone had no effect on behaviour or EEG, but flumazenil 30 mg kg-1 had depressive effects similar to those of diazepam on behaviour and EEG. Flumazenil 0.3, 3 and 30 mg kg-1 i.v., antagonized the effects of diazepam 10 mg kg-1 i.v. on behaviour and EEG. Flumazenil had no antagonistic effect on sleep time induced by anaesthetic agents, but flumazenil 30 mg kg-1 potentiated propofol-induced anaesthesia. Flumazenil did not affect anaesthesia-induced EEG changes. Diazepam 5 mg kg-1 potentiated anaesthesia. Flumazenil antagonism of diazepam potentiation varied with anaesthetic agent: flumazenil 0.3 mg kg-1 antagonized diazepam action in halothane anaesthesia, but 30 mg kg-1 was required in propofol anaesthesia; this large dose was insufficient in thiamylal anaesthesia.