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PubMed2003

Isoflurane alters energy substrate metabolism to preserve mechanical function in isolated rat hearts following prolonged no-flow hypothermic storage.

BACKGROUND: Isoflurane enhances mechanical function in hearts subject to normothermic global or regional ischemia. The authors examined the effectiveness of isoflurane in preserving mechanical function in hearts subjected to cardioplegic arrest and prolonged hypothermic no-flow storage. The role of isoflurane in altering myocardial glucose metabolism during storage and reperfusion during these conditions and the contribution of adenosine triphosphate-sensitive potassium (K(atp)) channel activation in mediating the functional and metabolic effects of isoflurane preconditioning was determined. METHODS: Isolated working rat hearts were subjected to cardioplegic arrest with St. Thomas' II solution, hypothermic no-flow storage for 8 h, and subsequent aerobic reperfusion. The consequences of isoflurane treatment were assessed during the following conditions: (1) isoflurane exposure before and during storage; (2) brief isoflurane exposure during early nonworking poststorage reperfusion; and (3) isoflurane preconditioning before storage. The selective mitochondrial and sarcolemmal K(atp) channel antagonists, 5-hydroxydecanoate and HMR 1098, respectively, were used to assess the role of K(atp) channel activation on glycogen consumption during storage in isoflurane-preconditioned hearts. RESULTS: Isoflurane enhanced recovery of mechanical function if present before and during storage. Isoflurane preconditioning was also protective. Isoflurane reduced glycogen consumption during storage under the aforementioned circumstances. Storage of isoflurane-preconditioned hearts in the presence of 5-hydroxydecanoate prevented the reduction in glycogen consumption during storage and abolished the beneficial effect of isoflurane preconditioning on recovery of mechanical function. CONCLUSIONS: Isoflurane provides additive protection of hearts subject to cardioplegic arrest and prolonged hypothermic no-flow storage and favorably alters energy substrate metabolism by modulating glycolysis during ischemia. The effects of isoflurane preconditioning on glycolysis during hypothermic no-flow storage appears to be associated with activation of mitochondrial K(atp) channels.

Adenosine Triphosphate↗
PubMed2003

Flumazenil attenuates development of tolerance to diazepam after chronic treatment of mice with either isoflurane or diazepam.

UNLABELLED: In an effort to clarify the mechanism of action of isoflurane, we studied the effect of flumazenil on mice chronically treated with isoflurane or diazepam. Mice were pretreated with diazepam, isoflurane, or saline, with and without flumazenil. After 2 wk, responses to isoflurane and diazepam were assessed, and central benzodiazepine receptor (CBR) binding characteristics were assayed. Mice pretreated with isoflurane failed the horizontal wire test at a larger isoflurane concentration (0.5%) compared with saline-pretreated mice (0.4%) (P < 0.05). These differences did not occur when flumazenil was added to the pretreatment. After the administration of diazepam, 20% of diazepam- and 11% of isoflurane-pretreated mice failed the horizontal wire test, versus 50% and 44% when flumazenil was added to either drug (P < 0.002) and 80% and 100% in the saline and saline plus flumazenil-treated mice. The increased CBR density due to flumazenil was attenuated by the coadministration of isoflurane or diazepam. Flumazenil attenuated the development of tolerance to diazepam after chronic treatment with diazepam or isoflurane and attenuated the development of tolerance to isoflurane. Isoflurane, like diazepam, attenuated the effect of flumazenil on CBR ligand binding. These findings suggest that isoflurane shares a mechanism of action with diazepam, probably via the gamma-aminobutyric acid system, most probably the CBR. IMPLICATIONS: Flumazenil attenuates the development of tolerance to isoflurane and diazepam after chronic isoflurane pretreatment. Isoflurane, like diazepam, attenuates the increase in central benzodiazepine receptor (CBR) density caused by flumazenil. These findings suggest that isoflurane and diazepam share a mechanism of action, most probably via the gamma-aminobutyric acid system and the CBR.

Anesthetics, Inhalation↗
PubMed1996

Movement associated with high cerebral concentrations of isoflurane: no evidence of seizure activity.

PURPOSE: This study examined the effect of high cerebral concentrations of isoflurane on the electroencephalogram (EEG) and motor activity while using an experimental preparation in which isoflurane can be selectively delivered to the in situ goat brain. In a previous study we found that isoflurane (> 6%), when selectively delivered to the brain, was associated with spontaneous movement. METHODS: In each of six goats, the cerebral circulation was isolated and cannulae inserted into a carotid artery and the jugular veins to permit selective delivery of isoflurane using a bubble oxygenator-roller pump system. The EEG was measured while isoflurane (1.3%, 3% and 10-12%) was delivered to the brain; isoflurane concentration in the torso during these periods was 1.3%, 0.3% and 0.3% respectively. RESULTS: The EEG was active at isoflurane 1.3% but was isoelectric with spike activity at 3% and 10-12%; EEG power decreased from 32,249 +/- 15,241 microV2 (mean +/- sd) during the control period (isoflurane = 1.3%) to 1761 +/- 2435 microV2 when cranial isoflurane = 3%, and 3346 +/- 4780 microV2 when cranial isoflurane = 10-12% (P < 0.05). When cranial isoflurane concentration was 10-12%, with the torso isoflurane concentration at 0.3%, spontaneous motor activity occurred, including stiffening, extremity and jaw movement and blinking. The EEG returned to normal when isoflurane concentration was decreased to 1.3%. CONCLUSION: The presence of spontaneous movement with concomitant high cranial concentrations of isoflurane and isoelectric EEG is unexplained, but is consistent with a facilitatory effect of isoflurane on motor activity, presumably at a subcortical level.

Anesthetics, Inhalation↗
PubMed1997

Comparison of isoflurane and midazolam as hypnotic supplementation to moderately high-dose fentanyl during coronary artery bypass grafting: effects on systemic hemodynamics and early postoperative recovery profile.

OBJECTIVE: The aim of this study was to compare isoflurane and midazolam as hypnotic adjuncts to moderately high-dose fentanyl during coronary artery bypass grafting (CABG) with regard to perioperative hemodynamics and early postoperative recovery profile. DESIGN: Prospective open randomized clinical trial. SETTING: Single university-affiliated medical center. PARTICIPANTS: Thirty patients scheduled for elective primary CABG were randomly divided into two groups receiving either isoflurane or midazolam as adjuncts to 50 micrograms/kg of fentanyl. INTERVENTION: Anesthesia was induced with intravenous fentanyl, 10 micrograms/kg, and midazolam, 0.1 mg/kg, and maintained with either isoflurane, 0.6% or midazolam, 0.1 mg/kg/hour, in intravenous infusion. Before the sternotomy, all patients received 30 micrograms/kg of fentanyl. Midazolam and isoflurane were stopped at the start of cardiopulmonary bypass (CPB). At rewarming, all patients received fentanyl, 5 to 10 micrograms/kg, and either isoflurane, 0.6%, or midazolam, at a reduced rate of 0.05 mg/kg/h. Changes in systolic blood pressure of more than 20% from baseline were first treated with vasoactive drugs. Hypertension was corrected with ketanserin, 10 to 20 mg; hypotension with ephedrine, 5 mg. For a mean blood pressure of less than 50 mmHg during CPB phenylephrine, 0.25 to 0.5 mg, was administered. When hypotension persisted despite a vasopressor, the administration of midazolam or isoflurane was stopped. Postoperatively, the patients were mechanically ventilated overnight and sedated with intermittent doses of fentanyl, 0.15 mg, and midazolam, 5 mg. MEASUREMENTS AND MAIN RESULTS: Routine five-lead electrocardiogram (ECG) and invasive hemodynamic monitoring using a pulmonary artery catheter were performed. The mean dose of fentanyl was 3.9 mg in the midazolam group versus 3.6 mg in the isoflurane group. There were no significant perioperative differences between groups in cardiac output, filling, or pulmonary artery pressures. Systolic blood pressure from the initial incision to CPB was lower in the isoflurane group compared with the midazolam group. During this interval, ketanserin was required in nine patients from the midazolam group at a mean dose of 26 mg, compared with only one patient in the isoflurane group. During and after CPB, there was no difference in ketanserin and in vasopressive/inotropic agent requirements. Temporary cessation of midazolam was required in four patients, for a mean of 34 minutes; whereas isoflurane was stopped in 10 patients for 36 minutes, mostly in the post-CPB period. Time to awakening and to extubation in the midazolam group (217 minutes and 19.5 hours) and the isoflurane group (193 minutes and 18.2 hours) were comparable. Between intensive care unit (ICU) admission and extubation, the patients in the midazolam group received 0.89 mg of fentanyl and 36.5 mg of midazolam compared with 0.98 mg of fentanyl and 36.2 mg of midazolam in the isoflurane group. There was a tendency for a higher postoperative pulmonary shunt and more severely impaired oxygenation in the isoflurane group. CONCLUSION: Midazolam supplementation to fentanyl required more frequent antihypertensive escape during the pre-CPB period than isoflurane. However, more frequent cessation of isoflurane caused by hypotension was needed in the post-CPB period. No difference in awakening and ICU discharge was found.

Aged↗
PubMed1984

Regional distribution of brain and myocardial perfusion in swine while awake and during 1.0 and 1.5 MAC isoflurane anaesthesia produced without or with 50% nitrous oxide.

Isoflurane has been hailed as the anaesthetic of the eighties. We examined the effects of isoflurane anaesthesia on regional distribution of brain and myocardial blood flow in 11 healthy isocapnic pigs using 15 micron diameter radionuclide labelled microspheres that were injected into the left atrium. Each animal was studied during five of the following six conditions: (i) unanaesthetised (control; n = 8); (ii) 1.45% end-tidal (ET; 1.0 MAC) isoflurane anaesthesia (n = 10); (iii) 2.18% ET (1.5 MAC) isoflurane anaesthesia (n = 9); (iv) 0.95% ET isoflurane + 50% N2O anaesthesia (equivalent to 1 MAC; n = 8); (v) 1.68% ET isoflurane + 50% N2O anaesthesia (equivalent to 1.5 MAC; n = 8); and (vi) 50% N2O alone (n = 8). The order of anaesthetised steps was randomised for each pig. At every step 50 to 55 min were allowed for equilibration with isoflurane, and for N2O 35 to 40 min were allowed for equilibration. Recovery periods of 60 min each were interposed between anaesthetised steps to allow pigs to recover towards control values. Control values of blood flow in the cerebrum, cerebellum, and brain-stem were 81 +/- 5, 87 +/- 8, and 64 +/- 6 ml X min-1 X 100 g-1, respectively. During 1.45% isoflurane anaesthesia, cerebral, cerebellar and brainstem blood flows were 120%, 152%, and 145% of respective control values. With 2.18% isoflurane, perfusion in these regions of the brain was 140%, 200%, and 226% of respective control values. Substitution of 50% N2O to maintain equipotent anaesthesia markedly exaggerated the increment in cerebral blood flow, while changes in cerebellar and brain-stem blood flow were similar. Cerebral blood flow during 0.95% isoflurane + 50% N2O and 1.68% isoflurane + 50% N2O anaesthesia was 137% and 210% of the control value, respectively. Regional brain blood flow was only insignificantly altered by 50% N2O alone. It is concluded that isoflurane caused dose-dependent vasodilatation in all regions of the brain, the magnitude being greater in the cerebellum and the brain-stem. The administration of N2O with isoflurane to maintain equipotent anaesthesia exaggerated cerebral vasodilatation, especially at deeper level of anaesthesia. Myocardial blood flow in isoflurane anaesthetised pigs decreased, especially in the inner layers, in a dose-related manner. The use of 50% N2O with isoflurane permitted higher heart rate, perfusion pressure, rate-pressure product, and transmural myocardial blood flow.

Anesthesia, Inhalation↗
PubMed2006

Up-regulation of hypoxia inducible factor 1alpha by isoflurane in Hep3B cells.

BACKGROUND: The volatile anesthetic isoflurane induces hypoxia inducible factor (HIF)-1-responsive genes heme oxygenase 1, inducible nitric oxide synthase, and vascular endothelial growth factor (VEGF) expression. Little is known about the extent to which induction of HIF-1alpha is affected by isoflurane. METHODS: Hep3B cells were exposed to isoflurane at various concentrations (0.5-4%) or for different time periods (2-8 h) at 37 degrees C. HIF-1alpha gene expression and transcriptional activity, heme oxygenase 1, inducible nitric oxide synthase, and VEGF gene expression were quantified. RESULTS: Isoflurane induced a time- and concentration-dependent increase in HIF-1alpha protein but not for HIF-1alpha messenger RNA (mRNA) in Hep3B cells. The maximal increase was induced by 2% isoflurane, and the cells incubated with 2% isoflurane for 4-8 h expressed the highest protein. Similarly, HIF-1alpha transcriptional activity was higher in Hep3B cells exposed to 2% isoflurane for 16 h than that in control cells. The combination of 2% isoflurane and desferrioxamine, a hypoxia mimetic, caused a higher level of HIF-1alpha protein than that induced by 2% isoflurane alone. Reoxygenation and inhibitor of proteasome pathway MG132 did not affect the isoflurane-induced HIF-1alpha protein accumulation. Cycloheximide, an inhibitor for protein synthesis, completely abrogated the induction of HIF-1alpha protein by isoflurane. Isoflurane stimulated heme oxygenase 1, inducible nitric oxide synthase, and VEGF mRNA expression in a concentration-dependent manner, and inactivation of HIF-1alpha attenuated the induction of VEGF mRNA by isoflurane. CONCLUSION: Isoflurane can up-regulate HIF-1alpha and enhance HIF-1-responsive genes heme oxygenase 1, inducible nitric oxide synthase, and VEGF mRNA expression in Hep3B cells. The induction of HIF-1alpha by isoflurane does not involve protein degradation but depends on translation pathway.

Actins↗
PubMed1983

Systemic distribution of blood flow in swine while awake and during 1.0 and 1.5 MAC isoflurane anesthesia with or without 50% nitrous oxide.

To examine the effects of isoflurane on systemic distribution of cardiac output, organ/tissue blood flow was measured in 11 isocapnic pigs using 15-micrometer diameter radionuclide-labeled microspheres injected into the left atrium. Measurements were made on each pig during five of the following six conditions; awake (control); 1.0 MAC (1.45% end-tidal)isoflurane anesthesia; 1.5 MAC (2.18% end-tidal) isoflurane anesthesia; 0.95% end-tidal isoflurane and 50% N2O anesthesia equivalent to 1.0 MAC; 1.68% end-tidal isoflurane and 50% N2O anesthesia equivalent to 1.5 MAC; and 50% N2O administration. The order of anesthetized steps was randomized. A period of 60 min was interposed between anesthetized steps to allow pigs to recover towards control values. Mean aortic pressure decreased in a dose-related manner during isoflurane anesthesia, whereas cardiac output decreased only during 1.5 MAC isoflurane anesthesia and heart rate remained unchanged. The addition of N2O attenuated the hypotensive effects of isoflurane and cardiac output was maintained near control values because of increased heart rate. Brain blood flow increased in a dose-dependent manner with isoflurane anesthesia, but myocardial blood flow exhibited a dose-related decrease. The addition of 50% N2O to maintain the same total MAC anesthesia resulted in a larger increase in brain blood flow especially at 1.5 MAC, while myocardial blood flow was maintained near control value. Rate-pressure product and myocardial blood flow at 1.5 MAC anesthesia were higher when N2O was used with isoflurane. While blood flow and fraction of cardiac output going to the adrenal glands were unaltered during isoflurane-N2O anesthesia, blood flow increased at 1.5 MAC isoflurane anesthesia. Splenic blood flow and splenic fraction of cardiac output were increased at both MAC levels of isoflurane as well as isoflurane-N2O anesthesia whereas blood flow to the stomach, small intestine, diaphragm, skeletal muscle, and adipose tissue decreased from control values. Renal, hepatic arterial, and cutaneous blood flow remained unaltered. Fifty percent N2O in the presence of a residual end-tidal isoflurane concentration of 0.20% caused heart rate to increase from control levels, while cardiac output and mean aortic pressure were unaltered. Brain blood flow increased by 27% above control values, but perfusion in the myocardium, adrenal glands, spleen, kidneys, liver, and skin was unchanged. Stomach, small intestine, skeletal muscle, and diaphragm blood flows decreased from control values, whereas perfusion of adipose tissue increased.

Anesthesia, Inhalation↗
PubMed1998

Disparity of isoflurane effects on left and right ventricular afterload and hydraulic power generation in swine.

UNLABELLED: The interaction between myocardial and vascular effects of anesthetics has a potential impact on how these drugs influence performance of the heart. Most studies have focused on volatile anesthetic effects on the left ventricle (LV) and systemic circulation. Whether the right ventricle (RV) and pulmonary circulation respond in a similar fashion, however, is unclear. In the present study, we therefore examined the dose-related effects of isoflurane on LV and RV contractility and total afterload and related changes to simultaneous effects on the hydraulic power generated by each chamber. Two groups of swine were studied: one received no additional treatment before isoflurane (ISO, n = 6), and the other received hexamethonium, atropine, and propranolol to produce autonomic blockade before isoflurane administration (ISO+AB, n = 4). For each experiment, measurements were made of RV and LV regional segment lengths and pressures, along with proximal aortic and pulmonary arterial (PA) blood flow and pressure during the administration of 0, 0.5, 1.0, and 1.5 minimum alveolar anesthetic concentration (MAC) isoflurane. Contractility was assessed by calculating the regional preload recruitable stroke work slope (PRSW). Afterload was characterized in both nonpulsatile and pulsatile terms by calculating aortic input impedance magnitude (Z). From these data, total arterial resistance (R), characteristic impedance (ZC), and vascular compliance (C) were determined with reference to a three-element Windkessel model of the circulation. Additionally, steady-state (WSS), oscillatory (WOS), and total (WT) hydraulic power output of each ventricle was calculated. In the ISO group, isoflurane produced a nearly threefold greater decrease of peak systolic pressure in the LV than in the RV, yet the dose-related decrease of regional PRSW was virtually the same in both chambers. In the aorta, isoflurane produced a maximal 25% reduction in R at 1.0 MAC and doubled C without a significant change in ZC. Alternatively, PA R was increased from baseline at 1.0 and 1.5 MAC, whereas ZC was increased from all other values at 1.5 MAC. PA C was not altered by isoflurane. In ISO+AB pigs, PA ZC at baseline was higher than that evident in ISO animals but was not altered by isoflurane. In contrast, baseline aortic R was lower in ISO+AB pigs but was still modestly reduced by 1.0 MAC isoflurane. In ISO animals, WT and WSS from both ventricles demonstrated dose-related decreases, but the reductions in LV WTand WSS were greater than those for the RV at all doses. Accordingly, the power requirement per unit flow decreased for the LV but remained constant for the RV. WOS for both ventricles was also reduced by isoflurane. However, the LV WOS to WT ratio increased, which indicates that more power was lost to the system by pulsation. In contrast, reductions in RV WT and WOS were nearly parallel at all isoflurane doses, and the WOS to WT ratio was unchanged. In the ISO+AB group, isoflurane-induced alterations in LV and RV power characteristics were similar to those in the ISO group. These data indicate that, despite similar effects on biventricular contractility, isoflurane exerts qualitatively different effects on RV and LV afterload, in part via alteration in autonomic nervous activity, that influence the distribution of power output between steady-state and pulsatile components. IMPLICATIONS: In this study, we examined the effects of isoflurane on cardiac performance in swine and found that, although the drug depresses contraction of both the left and right ventricles similarly, it has different effects on forces that oppose the ejection of blood. These findings demonstrate that the two interdependent pumps that comprise the heart can be influenced differently by anesthetic drugs.

Anesthetics, General↗
PubMed1999

Isoflurane depresses motoneuron excitability by a direct spinal action: an F-wave study.

UNLABELLED: Isoflurane decreases motoneuron excitability as measured by the F wave. It is unknown how much of this effect is direct and how much occurs as the result of an indirect, supraspinal effect. Seven goats were anesthetized with isoflurane, and the carotid arteries and jugular veins were isolated to permit cranial bypass. Isoflurane was delivered to the head via a bypass-oxygenator unit and to the torso via the lungs. Evoked gastrocnemius muscle potentials were measured after supramaximal electrical stimulation of the ischiatic nerve. F- and M-wave amplitudes and F-wave latencies were determined from 20 evoked responses obtained at each of the following head/torso isoflurane concentrations: 0.8%/0.3%, 1.3%/0.3%, 3%/0.3%, 0.3/0.8%, and 1.3%/0.8%. When the torso isoflurane was 0.3%, increasing the cranial isoflurane concentration from 0.8% to 1.3% did not significantly affect the F/M amplitude ratio (from 0.188 +/- 0.166 to 0.194 +/- 0.124; P > 0.05), but the ratio decreased approximately 50% when the cranial isoflurane was 3% (to 0.088 +/- 0.078; P < 0.05). F-wave latency was not affected by changing the cranial isoflurane concentration. The F/M amplitude ratio decreased 80%-85% when isoflurane 0.8% was administered to the torso and was not measurable in five animals; at this torso concentration, changing the cranial concentration from 0.3% to 1.3% had no effect on the F/M ratio (from 0.042 +/- 0.065 to 0.030 +/- 0.041; P > 0.05). In goats, motoneuron excitability is very sensitive to the direct action of isoflurane, and supraspinal effects occur between cranial isoflurane concentrations of 1.3% and 3%. IMPLICATIONS: We studied the effect of isoflurane action in the brain on motoneuron excitability, using the F wave. We found that the F wave is very sensitive to the direct action of isoflurane and that cranial isoflurane has indirect effects between concentrations of 1.3% and 3%.

Anesthesia, Inhalation↗
PubMed2002

Sensitivity of the alpha7 nicotinic acetylcholine receptor to isoflurane may depend on receptor inactivation.

UNLABELLED: In previous studies, we demonstrated that nicotinic acetylcholine receptors (nAChRs) composed of the alpha7 subunit are unaffected by the co-application of isoflurane with agonists at concentrations up to 640 microM (two times the minimum alveolar anesthetic concentration). Modulation of alpha7-nAChR activity by isoflurane might have important behavioral ramifications because these receptors are expressed diffusely in the central and peripheral nervous systems and play pre- and postsynaptic roles in synaptic transmission. Here we have demonstrated that under some potentially physiologically relevant circumstances, the activation of alpha7 nAChRs may be inhibited by clinically relevant concentrations of isoflurane. We evaluated isoflurane inhibition of alpha7 nAChRs from chicks and humans expressed in Xenopus oocytes using two-electrode voltage clamp methodology. We determined the influence of time of preperfusion of isoflurane, agonist concentration, and membrane potential on inhibition by isoflurane. Both activation by a large concentration of agonist and isoflurane preperfusion increased inhibition. The half-maximal inhibitory concentration for isoflurane inhibition of chick alpha7 nAChR with isoflurane preperfusion and activation by 100 microM of acetylcholine was 938 +/- 26, and when activated by 1 mM of acetylcholine, it was 408 +/- 51 microM. The increase in inhibition with isoflurane preexposure and large agonist concentration raises the possibility that isoflurane interacts preferentially with a closed or closed-desensitized state of the channel. IMPLICATIONS: Nicotinic receptors expressed in the brain have been considered a possible target for the actions of isoflurane. We studied the effect of isoflurane on alpha7 type nicotinic receptors expressed in Xenopus oocytes. We find that when activated by large concentrations of acetylcholine, alpha7 nicotinic receptors are inhibited by isoflurane at concentrations near MAC.

Acetylcholine↗
PubMed1994

Does subanesthetic isoflurane affect the ventilatory response to acute isocapnic hypoxia in healthy volunteers?

BACKGROUND: Differences in results studying the effects of subanesthetic concentrations of volatile agents on the hypoxic ventilatory response may be related to the conditions under which the subjects were tested. In this study we investigated the effects of 0.1 minimum alveolar concentration (MAC) of isoflurane on the hypoxic ventilatory response without and with audiovisual stimulation. METHODS: Step decreases in arterial hemoglobin oxygen saturation from normoxia into hypoxia (arterial hemoglobin oxygen saturation 80% +/- 2%; duration of hypoxia 5 min) were performed in ten healthy subjects. We obtained four responses per subject: one without isoflurane in a darkened, quiet room; one without isoflurane with audiovisual input (music videos); one in a darkened room at 0.1 MAC isoflurane; and one at 0.1 MAC isoflurane with audiovisual input (subjects were addressed to keep their eyes open). Experiments were performed against a background of isocapnia (end-tidal carbon dioxide tension 1-1.4 mmHg above initial resting values). RESULTS: The hypoxic responses averaged 0.54 +/- 0.09 1.min-1.%-1 (without isoflurane in a darkened, quiet room), 0.27 +/- 0.06 l-min-1.%-1 (in a darkened room at 0.1 MAC isoflurane; P < 0.01), 0.56 +/- 0.131.min-1.%-1 (without isoflurane with audiovisual input), and 0.47 +/- 0.13 l.min-1.%-1 (at 0.1 MAC isoflurane with audiovisual input). Values are means +/- SE. During 0.1 MAC isoflurane administration, all subjects showed a depressed hypoxic response when not stimulated, while with stimulation two subjects had an increased response, four a decreased response and four an unchanged response compared to control. CONCLUSIONS: We observed an important effect of the study conditions on the effects that 0.1 MAC isoflurane has on the hypoxic ventilatory response. A depressant effect of subanesthetic isoflurane was found only when external stimuli to the subjects were absent. With extraneous audiovisual stimuli the effect of isoflurane on the response to hypoxia was more variable. On the average, however, the response then was not depressed by isoflurane.

Acoustic Stimulation↗
PubMed1995

Isoflurane and the pulmonary vascular pressure-flow relation at baseline and during sympathetic alpha- and beta-adrenoreceptor activation in chronically instrumented dogs.

BACKGROUND: The extent to which isoflurane anesthesia alters systemic vascular regulation has received considerable attention. In contrast, the pulmonary vascular effects of isoflurane have not been elucidated. Our initial objective was to investigate the net effect of isoflurane on the baseline left pulmonary vascular pressure-flow (LPQ) relation compared with values measured in the conscious state. In addition, we assessed the extent to which isoflurane alters the pulmonary vascular responses to sympathetic alpha- and beta-adrenoreceptor activation. METHODS: Twelve conditioned mongrel dogs were chronically instrumented to measure the LPQ relation. LPQ plots were generated by continuously measuring the pulmonary vascular pressure gradient (pulmonary arterial pressure--left atrial pressure) and left pulmonary blood flow during gradual (approximately 1 min) inflation of a hydraulic occluder implanted around the right main pulmonary artery. LPQ plots were generated at baseline in the conscious and isoflurane-anesthetized states (n = 12). The pulmonary vascular dose-response relation to the sympathetic alpha-adrenoreceptor agonist phenylephrine also was investigated in conscious and isoflurane-anesthetized dogs (n = 6). Finally, after preconstriction with the thromboxane analogue U46619, the dose-response relation to the sympathetic beta-adrenoreceptor agonist isoproterenol was assessed in the conscious and isoflurane-anesthetized states (n = 8). RESULTS: Compared with values measured in the conscious state, isoflurane anesthesia had no net effect on the baseline LPQ relation. The magnitude of the pulmonary vasoconstrictor response to phenylephrine observed in conscious dogs was not altered during isoflurane anesthesia. In contrast, the pulmonary vasodilator response to isoproterenol was markedly potentiated (P < 0.01) during isoflurane anesthesia compared with that in the conscious state. CONCLUSIONS: These results indicate that isoflurane does not exert a net vasodilator influence on the pulmonary circulation at baseline. In contrast to the systemic circulation, the pulmonary vasoconstrictor response to sympathetic alpha-adrenoreceptor activation is maintained during isoflurane anesthesia. Surprisingly, the pulmonary vasodilator response to sympathetic beta-adrenoreceptor activation is actually potentiated during isoflurane. Thus, isoflurane anesthesia has differential effects on the canine pulmonary vascular responses to sympathetic alpha- and beta-adrenoreceptor activation.

Anesthesia, General↗
PubMed1996

Dose-dependent increases in the renal sympathetic nerve activity during rapid increase in isoflurane concentration in intact, lower airway-deafferented, and baroreceptor-deafferented rabbits.

BACKGROUND: The inhalation of high concentrations of isoflurane has been reported to increase the heart rate and the concentration of serum catecholamines. Although the precise mechanisms for the sympathetic activation of isoflurane have yet to be clearly elucidated, they are considered to possibly originate from the stimulation of airway sensory afferents, the baroreceptor reflex, or the direct stimulation of the central nervous system. To determine how these three mechanisms contribute to sympathetic augmentation, the effects of lower airway deafferentation and baroreceptor deafferentation on the isoflurane-induced changes in the renal sympathetic nerve activity (RSNA) in tracheally intubated rabbits were examined. METHODS: Twenty rabbits were given basal anesthesia. After tracheotomy and during mechanical ventilation, the changes in the heart rate, mean arterial pressure, and RSNA in response to random exposures to 1%, 2%, 3%, and 4% isoflurane were examined. The animals were assigned to one of three groups; 1, the intact group (n = 6); 2, the baroreceptor-deafferented group (n = 9), in which the sinoaortic plus vagal nerves were cut; and 3, the lower airway-deafferented group (n = 5), which underwent a bilateral vagotomy. The exposure to isoflurane was for 10 min in group 1 and 5 min in groups 2 and 3. At least 1 h was allowed for the recovery interval between exposures to isoflurane. RESULTS: The inhalation of isoflurane caused dose-dependent increases in RSNA in all three groups. RSNA during high concentrations of isoflurane began to increase at 1 min, reaching the maximum at 4 or 5 min in group 1 (2.8- and 3.8-fold at 3% and 4% isoflurane, respectively) and group 3 (2.8- and 4.5-fold at 3% and 4% isoflurane, respectively), but it reached the peak at 2 or 3 min in group 2 (1.7- and 2.4-fold at 3% and 4% isoflurane, respectively) after the initiation of inhalation, in association with early slight increases followed by decreases of mean arterial pressure in groups 1 and 2 but only gradual decreases of mean arterial pressure in group 3. The increases in RSNA in group 3 were similar to group 1, however, those in group 2 were significantly attenuated compared with group 1. CONCLUSIONS: The inhalation of isoflurane caused an increase of RSNA in intact, baroreceptor-deafferented, and lower airway-deafferented rabbits. The extent of the increases in RSNA was greater in intact and lower airway-deafferented rabbits than in baroreceptor-deafferented rabbits. Therefore, it is suggested that isoflurane may increase the efferent sympathetic nerve activity via the direct stimulation of the central nervous system and via the arterial baroreceptor reflex reflecting the reduction in arterial blood pressure. The stimulation of the vagally innervated airway may not contribute to the increase in the sympathetic nerve activity by isoflurane.

Afferent Pathways↗
PubMed1998

Improved contractility and coronary flow in isolated hearts after 1-day hypothermic preservation with isoflurane is not dependent on K(ATP) channel activation.

BACKGROUND: Isoflurane protects against reperfusion injury in isolated hearts when given before, during, and initially after hypoxia or ischemia and aids in preconditioning hearts if given before ischemia. The aims of the current study were to determine if isoflurane is cardioprotective during 1-day, severe hypothermic perfusion and if a mechanism of protection is K(ATP) channel activation. METHODS: Guinea pig hearts (n = 60) were isolated, perfused with Kreb's solution initially at 37 degrees C, and assigned to either a nontreated warm, time control group or one of five cold-treated groups: drug-free cold control, 1.3% isoflurane, 1.3% isoflurane plus glibenclamide (4 microM), 2.6% isoflurane, or 2.6% isoflurane plus glibenclamide. Isoflurane and glibenclamide were given 20 min before hypothermia, during low-flow hypothermia (3.8 degrees C) for 22 h, and for 30 min after rewarming to 37 degrees C. Heart rate, left ventricular pressure, %O2 extraction, and coronary flow were measured continuously, and responses to epinephrine, adenosine, 5-hydroxytryptamine, and nitroprusside were examined before and after hypothermia. RESULTS: Each group had similar initial left ventricular pressures, coronary flows, and responses to adenosine, 5-hydroxytryptamine, and nitroprusside. Before hypothermia, isoflurane with or without glibenclamide increased coronary flow while decreasing left ventricular pressure and %O2 extraction. After hypothermia, left ventricular pressure and coronary flow were reduced in all cold groups but least reduced in isoflurane-treated groups. During normothermic perfusion after isoflurane and glibenclamide, left ventricular pressure, coronary flow, %O2 extraction, and flow responses to adenosine, 5-hydroxytryptamine, and nitroprusside were similarly improved in isoflurane and isoflurane-plus-glibenclamide groups over the cold control group but not to levels observed in the warm-time control group. CONCLUSION: Isoflurane, like halothane, given before, during, and initially after hypothermia markedly improved but did not restore cardiac perfusion and function. Protective effects of isoflurane were not concentration dependent and not inhibited by the K(ATP) channel blocker glibenclamide. Volatile anesthetics have novel cardioprotective effects when given during long-term severe hypothermia.

Adenosine Triphosphate↗
PubMed1999

Mechanisms of isoflurane-induced myocardial preconditioning in rabbits.

BACKGROUND: Isoflurane has cardioprotective effects that mimic the ischemic preconditioning phenomenon. Because adenosine triphosphate-sensitive potassium channels and adenosine receptors are implicated in ischemic preconditioning, the authors wanted to determine whether the preconditioning effect of isoflurane is mediated through these pathways. METHODS: Myocardial infarct size was measured in seven groups of propofol-anesthetized rabbits, each subjected to 30 min of anterolateral coronary occlusion followed by 3 h of reperfusion. Groups differed only in the pretreatments given, and controls received no pretreatment. An ischemia-preconditioned group was pretreated with 5 min of coronary occlusion and 15 min of reperfusion. An isoflurane-preconditioned group was pretreated with 15 min end-tidal isoflurane, 1.1%, and then 15 min of washout. An isoflurane-plus-glyburide group was administered 0.33 mg/kg glyburide intravenously before isoflurane pretreatment. An isoflurane plus 8-(p-sulfophenyl)-theophylline (SPT) group received 7.5 mg/kg SPT intravenously before isoflurane. Additional groups were administered identical doses of glyburide or SPT, but they were not pretreated with isoflurane. Infarct size and area at risk were defined by staining. Data were analyzed by analysis of variance or covariance. RESULTS: Infarct size, expressed as a percentage of the area at risk (IS:AR) was 30.2+/-11% (SD) in controls. Ischemic preconditioning and isoflurane preexposure reduced myocardial infarct size significantly, to 8.3+/-5% and 13.4+/-8.2% (P<0.05), respectively. Both glyburide and SPT pretreatment eliminated the preconditioning-like effect of isoflurane (IS:AR = 30.0+/-9.1% and 29.2+/-12.6%, respectively; P = not significant). Neither glyburide nor SPF alone increased infarct size (IS:AR = 33.9+/-7.6% and 31.8+/-12.7%, respectively; P = not significant). CONCLUSIONS: Glyburide and SPT abolished the preconditioning-like effects of isoflurane but did not increase infarct size when administered in the absence of isoflurane. Isoflurane-induced preconditioning and ischemia-induced preconditioning share similar mechanisms, which include activation of adenosine triphosphate-sensitive potassium channels and adenosine receptors.

Anesthetics, Inhalation↗
PubMed2000

Prevention of isoflurane-induced preconditioning by 5-hydroxydecanoate and gadolinium: possible involvement of mitochondrial adenosine triphosphate-sensitive potassium and stretch-activated channels.

BACKGROUND: Both mitochondrial adenosine triphosphate-sensitive potassium (MKATP) channels (selectively blocked by 5-hydroxydecanoate) and stretch-activated channels (blocked by gadolinium) have been involved in the mechanism of ischemic preconditioning. Isoflurane can reproduce the protection afforded by ischemic preconditioning. We sought to determine whether isoflurane-induced preconditioning may involve MKATP and stretch-activated channels. METHODS: Anesthetized open-chest rabbits underwent 30 min of coronary occlusion followed by 3 h of reperfusion. Before this, rabbits were randomized into one of six groups and underwent a treatment period consisting of either no intervention for 40 min (control group; n = 9) or 15 min of isoflurane inhalation (1.1% end tidal) followed by a 15-min washout period (isoflurane group; n = 9). The two groups received an intravenous bolus dose of either 5-hydroxydecanoate (5 mg/kg) or gadolinium (40 micromol/kg) before coronary occlusion and reperfusion (5-hydroxydecanoate, n = 9; gadolinium, n = 7). Two additional groups received 5-hydroxydecanoate or gadolinium before isoflurane exposure (isoflurane-5-hydroxydecanoate, n = 10; isoflurane-gadolinium, n = 8). Area at risk and infarct size were assessed by blue dye injection and tetrazolium chloride staining. RESULTS: Area at risk was comparable among the six groups (29 +/- 7, 30 +/- 5, 27 +/- 6, 35 +/- 7, 31 +/- 7, and 27 +/- 4% of the left ventricle in the control, isoflurane, isoflurane-5-hydroxydecanoate, 5-hydroxydecanoate, isoflurane-gadolinium, and gadolinium groups, respectively). Infarct size averaged 60 +/- 20% (SD) in untreated controls versus 54 +/- 27 and 65 +/- 15% of the risk zone in 5-hydroxydecanoate- and gadolinium-treated controls (P = nonsignificant). In contrast, infarct size in the isoflurane group was significantly reduced to 26 +/- 11% of the risk zone (P < 0.05 vs.control). Both 5-hydroxydecanoate and gadolinium prevented this attenuation: infarct size averaged 68 +/- 23 and 56 +/- 21% of risk zone in the isoflurane-5-hydroxydecanoate and isoflurane-gadolinium groups, respectively (P = nonsignificant vs.control). CONCLUSION: 5-Hydroxydecanoate and gadolinium inhibited pharmacologic preconditioning by isoflurane. This result suggests that MKATP channels and mechanogated channels are probably involved in this protective mechanism.

Adenosine Triphosphate↗
PubMed2002

Isoflurane hyperalgesia is modulated by nicotinic inhibition.

BACKGROUND: The inhaled anesthetic isoflurane inhibits neuronal nicotinic acetylcholine receptors (nAChRs) at concentrations lower than those used for anesthesia. Isoflurane produces biphasic nociceptive responses, with both hyperalgesia and analgesia within this concentration range. Because nicotinic agonists act as analgesics, the authors hypothesized that inhibition of nicotinic transmission by isoflurane causes hyperalgesia. METHODS: The authors studied female mice at 6-8 weeks of age. They measured hind paw withdrawal latency at isoflurane concentrations from 0 to 0.98 vol% after the animals had received a nicotinic agonist (nicotine), a nicotinic antagonist (mecamylamine or chlorisondamine), or saline intraperitoneally. In addition, the authors tested the interactions between mecamylamine and isoflurane and nicotine and isoflurane in heterologously expressed alpha(4)beta(2) nAChRs. RESULTS: Female mice had significant hyperalgesia from isoflurane. Nicotine administration prevented isoflurane-induced hyperalgesia without altering the antinociception produced by higher isoflurane concentrations. Mecamylamine treatment caused a biphasic nociceptive response similar to that caused by isoflurane. Mecamylamine and isoflurane had an additive effect, both at heterologously expressed alpha(4)beta(2) nAChRs and on the production of hyperalgesia in vivo. Mecamylamine thus potentiated hyperalgesia but did not affect analgesia. CONCLUSIONS: Since hyperalgesia occurs in vivo at isoflurane doses that antagonize nAChRs in vitro, is prevented by a nicotinic agonist, and is mimicked and potentiated by nicotinic antagonists, the authors conclude that isoflurane inhibition of nAChRs activation is involved in the pathway that causes hyperalgesia. At subanesthetic doses, isoflurane can either enhance pain responses (produce hyperalgesia) or be analgesic (antinociceptive). In rats, low volatile anesthetic concentrations (0.1-0.2 minimum alveolar concentration [MAC]) elicit hyperalgesia, while 0.4-0.6 MAC elicits antinociception.

Animals↗
PubMed2004

Combination of isoflurane and caspase inhibition reduces cerebral injury in rats subjected to focal cerebral ischemia.

BACKGROUND: Recent data indicate that the neuroprotective efficacy of isoflurane is not sustained. Delayed neuronal death, mediated in part by apoptosis, contributes to the gradual increase in the size of the infarction. These data suggest that isoflurane may not be able to inhibit delayed neuronal death. The prevention of apoptosis by a caspase inhibitor might provide neuroprotection in addition to that provided by isoflurane. The current study was conducted to determine whether isoflurane-mediated neuroprotection can be made more durable with the administration of z-VAD-fmk, a nonspecific caspase inhibitor. METHODS: Fasted Wister rats were allocated to awake-zVAD, awake-vehicle, isoflurane-zVAD, or isoflurane-vehicle groups (n = 16/group). Animals were subjected to focal ischemia for 60 min by filament occlusion of the middle cerebral artery. In the awake groups, isoflurane was discontinued after occlusion of the middle cerebral artery. In the isoflurane groups, isoflurane anesthesia was maintained at 1.5 minimum alveolar concentration during occlusion of the middle cerebral artery. Before and after ischemia, daily injections of z-VAD-fmk or vehicle were administered into the lateral cerebral ventricle for 14 days. Neurologic assessment was performed 14 days after ischemia. The volume of cerebral infarction and the number of intact neurons in the periinfarct cortex were determined by image analysis of hematoxylin and eosin-stained coronal brain sections. RESULTS: Infarction volume was less in the isoflurane-zVAD group (23 +/- 11 mm, mean +/- SD) than in isoflurane-vehicle, awake-vehicle, and awake-zVAD groups (82 +/- 31, 86 +/- 31, and 59 +/- 25 mm, respectively; P < 0.05). In comparison with the awake-vehicle and isoflurane-vehicle groups, the administration of z-VAD-fmk significantly decreased infarction volume (P < 0.05). The infarction volume between the awake-vehicle and isoflurane-vehicle groups was not different. The number of intact neurons within the periinfarct cortex was significantly less in the awake-vehicle group than in the other three groups (P < 0.05). The isoflurane-zVAD group demonstrated better neurologic function than the awake-vehicle group (P < 0.05). CONCLUSION: These findings are consistent with the premise that ongoing delayed neuronal death, in part mediated by apoptosis, contributes to the progression of cerebral infarction during the recovery period, and its inhibition can provide sustained neuroprotection.

Amino Acid Chloromethyl Ketones↗