In vivo analysis of acute eletropharmacological effects of proton pump inhibitors using halothane-anesthetized dogs: a translational study of cardiovascular adverse events.

Long-term use of proton pump inhibitors (PPIs) is known to clinically induce hypomagnesemia, increasing the risk toward QT-interval prolongation and lethal ventricular arrhythmias, whereas PPIs can directly modulate cardiac ionic currents in the in vitro experiments. In order to fill the gap between those information, we assessed acute cardiohemodynamic and electrophysiological effects of sub- to supra-therapeutic doses (0.05, 0.5 and 5 mg/kg/10 min) of typical PPIs omeprazole, lansoprazole and rabeprazole, using halothane-anesthetized dogs (n = 6 for each drug). The low and middle doses of omeprazole and lansoprazole increased or tended to increase the heart rate, cardiac output and ventricular contraction, whereas the high dose plateaued and decreased them. Meanwhile, the low and middle doses of omeprazole and lansoprazole decreased the total peripheral vascular resistance, whereas the high dose plateaued and increased it. Rabeprazole decreased the mean blood pressure in a dose-related manner; moreover, its high dose decreased the heart rate and tended to reduce the ventricular contractility. On the other hand, omeprazole prolonged the QRS width. Omeprazole and lansoprazole tended to prolong the QT interval and QTcV, and rabeprazole mildly but significantly prolonged them in a dose-related manner. High dose of each PPI prolonged the ventricular effective refractory period. Omeprazole shortened the terminal repolarization period, whereas lansoprazole and rabeprazole hardly altered it. In effects, PPIs can exert multifarious cardiohemodynamic and electrophysiological actions in vivo, including mild QT-interval prolongation; thus, PPIs should be given with caution to patients with reduced ventricular repolarization reserve.

Modulation of Cerebral Function by Muscle Afferent Activity, with Reference to Intravenous Succinylcholine.

Cerebral Function and Muscle Afferent Activity Following Intravenous Succinylcholine in Dogs Anesthetized with Halothane: The Effects of Pretreatment with a Defasciculating Dose of Pancuronium. By WL Lanier, PA Iaizzo, and JH Milde. Anesthesiology 1989; 71:87-95. Reprinted with permission. By the mid-1980s, it was widely assumed that if the depolarizing muscle relaxant, succinylcholine, given IV, produced increases in intracranial pressure, it did so because fasciculations produced increases in intrathoracic and central venous pressures that were transferred to the brain; however, there was no direct evidence that this was true. In contrast, we explored the possibility that the succinylcholine effect on the brain was explained by the afferentation theory of cerebral arousal, which predicts that agents or maneuvers that stimulate muscle stretch receptors will tend to stimulate the brain. Our research in tracheally intubated, lightly anesthetized dogs discovered that IV succinylcholine (which does not cross the blood-brain barrier) produced a doubling of cerebral blood flow that lasted for 30 min and corresponded to activation of the electroencephalogram and increases in intracranial pressure. Later, in our Classic Paper, we were able to assess simultaneously cerebral physiology and afferent nerve traffic emanating from muscle stretch receptors (primarily muscle spindles). We affirmed that the cerebral arousal response to succinylcholine was indeed driven by muscle afferent traffic and was independent of fasciculations or increases in intrathoracic or central venous pressures. Later research in complementary models demonstrated that endogenous movement (e.g., coughing, hiccups) produced a cerebral response very similar to IV succinylcholine, apparently as a result of the same muscle afferent mechanisms, independent of intrathoracic and central venous pressures. Thus, the importance of afferentation theory as a driver of the cerebral state of arousal and cerebral physiology during anesthesia was affirmed.

Experimental analysis of the onset mechanism of TdP reported in an LQT3 patient during pharmacological treatment with serotonin-dopamine antagonists against insomnia and nocturnal delirium.

Torsade de pointes (TdP) occurred in a long QT syndrome type 3 (LQT3) patient after switching perospirone to blonanserin. We studied how their electropharmacological effects had induced TdP in the LQT3 patient. Perospirone hydrochloride (n = 4) or blonanserin (n = 4) of 0.01, 0.1, and 1 mg/kg, i.v. was cumulatively administered to the halothane-anesthetized dogs over 10 min. The low dose of perospirone decreased total peripheral vascular resistance, but increased heart rate and cardiac output, facilitated atrioventricular conduction, and prolonged J-Tpeakc. The middle dose decreased mean blood pressure and prolonged repolarization period, in addition to those observed after the low dose. The high dose further decreased mean blood pressure with the reduction of total peripheral vascular resistance; however, it did not increase heart rate or cardiac output. It tended to delay atrioventricular conduction and further delayed repolarization with the prolongation of Tpeak-Tend, whereas J-Tpeakc returned to its baseline level. Meanwhile, each dose of blonanserin decreased total peripheral vascular resistance, but increased heart rate, cardiac output and cardiac contractility in a dose-related manner. J-Tpeakc was prolonged by each dose, but Tpeak-Tend was shortened by the middle and high doses. These results indicate that perospirone and blonanserin may cause the hypotension-induced, reflex-mediated increase of sympathetic tone, leading to the increase of inward Ca2+ current in the heart except that the high dose of perospirone reversed them. Thus, blonanserin may have more potential to produce intracellular Ca2+ overload triggering early afterdepolarization than perospirone, which might explain the onset of TdP in the LQT3 patient.

Electropharmacological effects of intracellular Ca2+ handling modulator caldaret on the heart assessed in the halothane-anesthetized dogs.

We analyzed how the enhancement of net sarcoplasmic reticulum (SR) Ca2+ uptake may affect cardiac electrophysiological properties in vivo by using caldaret which can decrease SR diastolic Ca2+ leak, enhance SR Ca2+ reuptake and inhibit reverse-mode Na+/Ca2+ exchanger. Caldaret in doses of 0.5, 5 and 50 µg/kg was intravenously administered over 10 min to the halothane-anesthetized beagle dogs (n = 5), attaining pharmacologically active plasma concentration. The low and middle doses of caldaret increased the ventricular contraction, which could be explained by its on-target pharmacological activities. The high dose enhanced the sinus automaticity followed by its suppression in addition to the increase of the total peripheral resistance, which may be unfavorable for treating diastolic heart failure. The low and middle doses enhanced the atrioventricular conduction, which may have some potential for predisposing the atria to the onset of atrial fibrillation via an induction of mitral and/or tricuspid regurgitation. The middle and high doses of caldaret prolonged the ventricular effective refractory period without altering the intraventricular conduction or repolarization period, which may prevent the onset of ventricular arrhythmias. Thus, modulation of intracellular Ca2+ handling by caldaret can induce not only inotropic effect, but also various electrophysiological actions on the in situ heart.

Analysis of proarrhythmic potential of an atypical antipsychotic drug paliperidone in the halothane-anesthetized dogs.

Fatal cases with the use of atypical antipsychotic drug paliperidone have been reported; however, there was no clinical report describing paliperidone-induced torsade de pointes. In this study we assessed its electropharmacological effects together with its proarrhythmic potential in intravenous doses of 0.03, 0.3 and 3 mg/kg using the halothane-anesthetized dogs (n = 5), which could provide approximately 2, 20 and 200 times higher peak plasma drug concentrations than its therapeutic level, respectively. Paliperidone exerted potent vasodilator effect resulting in hypotension, which may be largely explained by its α1-adrenoceptor blocking action. In vivo electrophysiological results suggest that paliperidone may inhibit human ether-à-go-go-related gene K+ channel in a dose-related manner and modestly suppress Na+ channel in the in situ heart. The high dose of paliperidone may have some potential to induce early afterdepolarization that can trigger lethal ventricular arrhythmias, whereas the low and middle doses lack such proarrhythmic possibility, indicating that at least 20 times higher plasma concentration may be considered to be safe.

Low-dose Simvastatin Increases Skeletal Muscle Sensitivity to Caffeine and Halothane.

Objective To determine whether the myotoxic side effects of statin simvastatin affect skeletal muscle's sensitivity to caffeine and halothane.Methods Primary cultured neonate rat skeletal myotubes were treated with 0.01-5.0 µmol/L simvastatin for 48 hours. MTT was used to evaluate cellular viability. The gross morphology and microstructure of the myotubes were observed with a light and electron microscope, respectively. The intracellular calcium concentrations ([Ca2+]i) at rest and in response to caffeine and halothane were investigated by fluorescence calcium imaging. Data were analyzed by analysis of variance (ANOVA) test.Results Simvastatin (0.01-5.0 µmol/L) decreased myotube viability, changed their morphological features and microstructure, and increased the resting [Ca2+]i in a dose-dependent manner. Simvastatin did not change myotube's sensitivity to low doses of caffeine (0.625-2.5 mmol/L) or halothane (1.0-5.0 mmol/L). In response to high-dose caffeine (10.0 mmol/L, 20.0 mmol/L) and halothane (20.0 mmol/L, 40.0 mmol/L), myotubes treated with 0.01 µmol/L simvastatin showed a significant increase in sensitivity, but those treated with 1.0 µmol/L and 5.0 µmol/L simvastatin showed a significant decrease. The sarcoplasmic reticulum Ca2+ storage peaked in the myotubes treated with 0.01 µmol/L simvastatin, but it decreased when cells were treated with higher doses of simvastatin (0.1-5.0 µmol/L).Conclusions The myotoxic side effect of simvastatin was found to change the sensitivity of myotubes in response to high-dose caffeine and halothane. When dose was low, sensitivity increased mainly because of increased Ca2+ content in the sarcoplasmic reticulum, which might explain why some individuals with statin-induced myotoxic symptoms may show positive caffeine-halothane contracture test results. However, when the dose was high and the damage to the myotubes was severer, sensitivity was lower. It is here supposed that the damage itself might put individuals with statin-induced myotoxic symptoms at greater risks of presenting with rhabdomyolysis during surgery or while under anesthesia.

Electropharmacological effects of amantadine on cardiovascular system assessed with J-Tpeak and Tpeak-Tend analysis in the halothane-anesthetized beagle dogs.

Since amantadine-induced long QT syndrome has been clinically reported, we investigated its electropharmacological effects to estimate the extent of proarrhythmic risk by using the halothane-anesthetized beagle dogs (n = 4). Amantadine in doses of 0.1, 1 and 10 mg/kg was infused over 10 min with a pause of 20 min under the monitoring of multiple cardiovascular variables. J-Tpeak and Tpeak-Tend were separately measured on the lead II electrocardiogram to precisely analyze the net balance between inward and outward current modifications by amantadine. The low dose increased the ventricular contractile force, but suppressed the intraventricular conduction. The middle dose prolonged the QT interval besides enhancing the changes induced by the low dose. The high dose increased the mean blood pressure, left ventricular end-diastolic pressure and total peripheral resistance, and accelerated the atrioventricular nodal conduction, but decreased the cardiac output besides enhancing the changes induced by the middle dose. A reverse use-dependence was confirmed in the repolarization delay. Amantadine hardly affected the J-Tpeak, but prolonged the Tpeak-Tend. Amantadine can be considered to stimulate Ca(2+) channel but inhibit Na(+) and K(+) channels in the in situ heart. J-Tpeak and Tpeak-Tend analysis suggests that amantadine may possess modest risk for arrhythmia.

Emulsified halothane produces long-term epidural anesthetic effect: a study in rabbits.

Previous studies have demonstrated that volatile anesthetics could produce local anesthesia. Emulsified isoflurane at 8% has been reported to produce epidural anesthetic effect in rabbits. This study was designed to investigate the long-term epidural anesthetic effect of emulsified halothane in rabbits. In this study, 40 healthy adult rabbits (weighting 2.0-2.5 kg) with an epidural catheter were randomly divided into 4 groups (n=10/group), receiving epidural administration of 1% lidocaine (lido group), 8% emulsified isoflurane 1ml (8% E-iso group), 8% emulsified halothane (8% E-Halo group) and 12% emulsified halothane (12% E-Halo group). After administration, sensory and motor functions as well as consciousness state were assessed until 60 minutes after sensory and motor function returned to its baseline or at least for 180 min. After epidural anesthesia, all the rabbits were continuously observed for 7 days and sacrificed for pathological evaluations. As a result, all the four study solutions produced typical epidural anesthesia. Onset times of sensory and motor function blockade were similar among the four groups (P>0.05). Duration of sensory blockade in 12% E-Halo group (83±13 min) was significantly longer than other groups: 51±12 min in 8% E-Halo group (P<0.01), 57±8 min in 8% E-iso group (P<0.01) and 47±9 min in lido group (P<0.01). Duration of sensory blockade in 8% E-iso group is longer than lido group (P<0.05). Duration of motor blockade in 12% E-Halo group (81±12 min) was also significantly longer than other groups: 40±8 min in 8% E-Halo group (P<0.01), 37±3 min in 8% E-iso group (P<0.01), 37±6 min in lido group (P<0.01). Normal consciousness was found in the rabbits from 8% E-Halo, 8% E-iso and lido groups while there were four rabbits in 12% E-Halo group (4/10) showed a light sedation. For all the rabbits, no pathological injury was found. The present study demonstrates that emulsified halothane produces reversible concentration-dependent epidural anesthesia and at 12% (v/v), emulsified halothane could produce long-term anesthesia without pathological injury.

Cardiohemodynamic and electrophysiological effects of a selective EP4 receptor agonist ONO--AE1--329 in the halothane-anesthetized dogs.

Cardiovascular effects of a highly selective prostaglandin E2 type 4 (EP4) receptor agonist ONO-AE1-329 were assessed with the halothane-anesthetized dogs (n=6). ONO-AE1-329 was intravenously infused in three escalating doses of 0.3, 1 and 3ng/kg/min for 10min with a pause of 20min between the doses. The low dose of 0.3ng/kg/min significantly increased maximum upstroke velocity of left ventricular pressure by 18% at 20min, indicating increase of ventricular contractility. The middle dose of 1ng/kg/min significantly decreased total peripheral resistance by 24% and left ventricular end-diastolic pressure by 32% at 10min, indicating dilation of arteriolar resistance vessels and venous capacitance ones, respectively; and increased cardiac output by 25% at 10min in addition to the change induced by the low dose. The high dose of 3ng/kg/min increased heart rate by 34% at 10min; decreased mean blood pressure by 14% at 10min and atrioventricular nodal conduction time by 13% at 5min; and shortened left ventricular systolic period by 8% at 10min and electromechanical coupling defined as an interval from completion of repolarization to the start of ventricular diastole by 39% at 10min in addition to the changes induced by the middle dose. No significant change was detected in a ventricular repolarization period. These results indicate that ONO-AE1-329 may possess a similar cardiovascular profile to typical phosphodiesterase 3 inhibitors as an inodilator, and suggest that EP4 receptor stimulation can become an alternative strategy for the treatment of congestive heart failure.

Repeated application of electroacupuncture ameliorates hyperglycemia in obese Zucker diabetic fatty rats.

Electroacupuncture (EA) was investigated for lowering the blood glucose (BG) in fasting male obese Zucker fatty diabetic (ZDF) rats aged 10-17 weeks. Anesthesia provided satisfactory chemical restraint to enable repeated EA. Animals in Groups 1, 2 and 3 were anesthetized on Days 1, 3, 5, 8, 10 and 12. Group 1 (n = 4) received no EA (controls), Group 2 (n = 4) EA at Zhongwan and Guanyuan acupoints, and Group 3 (n = 4) EA at both Zusanli acupoints. BG was measured at 10 and 20 minutes, and EA was applied for 30 minutes, after which BG was measured again. Group 2 had a significantly lower baseline BG at 20 minutes on Days 5, 8 and 12 and significantly less change in BG over 30 minutes on Days 3 and 5 than Group 1 (p < 0.05). Group 3 showed a significant decrease in the mean baseline BG compared to Group 1 in Week 1 (p < 0.05). Thus, repeated EA using Zhongwan and Guanyuan acupoints was effective in lowering the baseline BG and modulating the change in the BG in anesthetized animals.

Comparison of subarachnoid anesthetic effect of emulsified volatile anesthetics in rats.

Spinal cord is an important target of volatile anesthetics in particular for the effect of immobility. Intrathecal injection of volatile anesthetics has been found to produce subarachnoid anesthesia. The present study was designed to compare spinal anesthetic effects of emulsified volatile anesthetics, and to investigate the correlation between their spinal effects and general effect of immobility. In this study, halothane, isoflurane, enflurane and sevoflurane were emulsified by 30% Intralipid. These emulsified volatile anesthetics were intravenously and intrathecally injected, respectively. ED50 of general anesthesia and EC50 of spinal anesthesia were determined. The durations of general and spinal anesthesia were recorded. Correlation analysis was applied to evaluate the anesthetic potency of volatile anesthetics between their spinal and general effects. ED50 of general anesthesia induced by emulsified halothane, isoflurane, enflurane and sevoflurane were 0.41 ± 0.07, 0.54 ± 0.07, 0.74 ± 0.11 and 0.78 ± 0.08 mmol/kg, respectively, with significant correlation to their inhaled MAC (R(2) = 0.8620, P = 0.047). For intrathecal injection, EC50 of spinal anesthesia induced by emulsified halothane, isoflurane, enflurane and sevoflurane were 0.35, 0.27, 0.33 and 0.26 mol/L, respectively, which could be predicted by the product of inhaled MAC and olive oil/gas partition coefficients (R(2) = 0.9627, P = 0.013). In conclusion, potency and efficacy of the four emulsified volatile anesthetics in spinal anesthesia were similar and could be predicted by the product of inhaled MAC and olive oil/gas partition coefficients (MAC × olive oil/gas partition coefficients).

Genetics of residual feed intake in growing pigs: Relationships with production traits, and nitrogen and phosphorus excretion traits.

Residual feed intake (RFI) is defined as the difference between the observed ADFI and the ADFI predicted from production and maintenance requirements. The objectives of this study were to evaluate RFI as a selection criterion to improve feed efficiency and its potential to reduce N and P excretion in 4 pig breeds. Data were collected between 2000 and 2009 in French central test stations for 2 dam breeds [French Landrace (LR) and Large White (LWD)], and 2 sire breeds [Large White (LWS) and Piétrain (PP)]. Numbers of recorded pigs were 6407, 10,694, 2342, and 2448 for the LR, LWD, LWS, and PP breeds, respectively. All PP animals were genotyped for the halothane mutation. This data set was used to calculate RFI equations for each of the 4 breeds, and to estimate genetic parameters for RFI together with growth, carcass, and meat quality traits, and N and P excretion during the test period (35 to 110 kg BW). The RFI explained 20.1% in PP, 26.5% in LWS, 27.6% in LWD, and 29.5% in LR of the phenotypic variability of ADFI. The PP breed differed from the others in this respect, probably due to a lower impact of the variation of body composition on ADFI. Heritability estimates of RFI ranged from 0.21 ± 0.03 (LWD) to 0.33 ± 0.06 (PP) depending on the breed. Heritabilities of N and P excretion traits ranged from 0.29 ± 0.06 to 0.40 ± 0.06. The RFI showed positive genetic correlations with feed conversion ratio (FCR) and excretion traits, these correlations being greater in the sire breeds (from 0.57 to 0.86) than in the dam breeds (from 0.38 to 0.53). Compared with FCR, RFI had weaker genetic correlations with carcass composition, growth rate, and excretion traits. Estimates of genetic correlations between FCR and excretion traits were very close to 1 for all breeds. Finally, excretion traits were, at the genetic level, correlated positively with ADFI, negatively with growth rate and carcass leanness, whereas the halothane n mutation in PP was shown to reduce N and P excretion levels. To conclude, new selection indexes including RFI can be envisaged to efficiently disentangle the responses to selection on growth rate and body composition from those on feed efficiency, with favorable impacts on N and P excretions, particularly in sire pig breeds. However, the switch from FCR to RFI in selection indexes should not resolve the genetic antagonism between feed efficiency and meat quality.

Direct activation of sleep-promoting VLPO neurons by volatile anesthetics contributes to anesthetic hypnosis.

BACKGROUND: Despite seventeen decades of continuous clinical use, the neuronal mechanisms through which volatile anesthetics act to produce unconsciousness remain obscure. One emerging possibility is that anesthetics exert their hypnotic effects by hijacking endogenous arousal circuits. A key sleep-promoting component of this circuitry is the ventrolateral preoptic nucleus (VLPO), a hypothalamic region containing both state-independent neurons and neurons that preferentially fire during natural sleep. RESULTS: Using c-Fos immunohistochemistry as a biomarker for antecedent neuronal activity, we show that isoflurane and halothane increase the number of active neurons in the VLPO, but only when mice are sedated or unconscious. Destroying VLPO neurons produces an acute resistance to isoflurane-induced hypnosis. Electrophysiological studies prove that the neurons depolarized by isoflurane belong to the subpopulation of VLPO neurons responsible for promoting natural sleep, whereas neighboring non-sleep-active VLPO neurons are unaffected by isoflurane. Finally, we show that this anesthetic-induced depolarization is not solely due to a presynaptic inhibition of wake-active neurons as previously hypothesized but rather is due to a direct postsynaptic effect on VLPO neurons themselves arising from the closing of a background potassium conductance. CONCLUSIONS: Cumulatively, this work demonstrates that anesthetics are capable of directly activating endogenous sleep-promoting networks and that such actions contribute to their hypnotic properties.

[Drug-induced liver injury]. / Il danno epatico da farmaci.

Drug-induced liver injury represents the principal cause of acute liver failure and orthotopic liver transplantation in western country. A very large number of different drugs and medicinal herbs has been associated with liver injury but just for few of them we know the process that causes liver disease. All the people which ingest a large number of drugs present a risk of developing liver injury. Diagnosis is very difficult because a specific biomarker of damage is absent and the clinical picture is common to other liver diseases. A therapeutic approach is efficacy only in few cases. When a drug-induced liver injury is suspected, cessation of the drug is the first step in their management.

Novel double and single ryanodine receptor 1 variants in two Austrian malignant hyperthermia families.

BACKGROUND: Malignant hyperthermia (MH) is a potentially lethal genetic disorder in response to volatile anesthetics and depolarizing muscle relaxants. To support the claim that a novel genetic variant causes MH, it is necessary to demonstrate that it has significant effects on the sensitivity of the ryanodine receptor (RYR1) calcium channel. In this study we focused on 2 Austrian families with strong MH disposition and new RYR1 variants. METHODS: We sequenced the entire coding region of the RYR1 from 2 Austrian MH individuals. Genotype-phenotype segregation and evolutionary conservation of the variants were considered. On a functional level, Ca(2+) release experiments with fura-2-acetoxymethyl ester were performed in cultured skeletal muscle cells derived from individuals carrying the new variants and compared with control cells from nonsusceptible individuals. Caffeine, 4-chloro-m-cresole (4-CmC), and halothane were used as specific Ca(2+) releasing agents. RESULTS: The variant p.A612P in family A segregated with an MH-susceptible phenotype and cells showed an increased sensitivity for all Ca(2+)-releasing substances tested. In family B, 2 variants (p.R2458H/p.R3348C) were identified. While p.R2458H and p.R2458H/p.R3348C segregated with an MH-susceptible diagnosis, p.R3348C alone showed an MH equivocal diagnosis. Ca(2+)-release experiments showed that exchanges of these highly conserved amino acids increased the sensitivities for the substances tested (except 4-CmC with p.R2458H and p.R3348C) when compared with the MH-negative control group. CONCLUSIONS: Our results suggest that these variants are new causative MH variants.

Comparative evaluation of halothane anaesthesia in medetomidine-butorphanol and midazolam-butorphanol premedicated water buffaloes (Bubalus bubalis).

Six clinically healthy male water buffaloes (Bubalus bubalis) 2-3 years of age and weighing 290-325 kg were used for 2 different treatments (H1 and H2). The animals of group H1 were premedicated with medetomidine (2.5 g/kg,i.v.) and butorphanol (0.05 mg/kg, i.v.), while in group H2 midazolam (0.25 mg/kg) and butorphanol (0.05 mg/kg) were used intravenously. Induction of anaesthesia was achieved by 5% thiopental sodium in H1 (3.85 +/- 0.63 mg/kg) and H2 (6.96 +/- 0.45 mg/kg) groups. The anaesthesia was maintained with halothane in 100 % oxygen through a large animal anaesthetic machine. Better analgesia and sedation with a significantly lower dose of thiopental for induction and significantly higher values of sternal recumbency time and standing time were recorded in group H1 than in group H2, whereas no significant (P > 0.05) difference for the halothane concentration was observed between groups H1 and H2. Significant decrease in heart rate was observed in group H1 whereas it significantly increased in group H2. In both groups, RR decreased during the preanaesthetic period, which increased significantly (P < 0.01) after halothane administration. In both groups a significant (P < 0.01) fallin RT was recorded from 20 min to the end of observation period. A significant (P < 0.05) fall in MAP was observed in group H1 from 15 min until the end, while in group H2 MAP increased nonsignificantly (P > 0.05) after premedication and a significant (P < 0.05) occurredafter thiopental administration. In both groups a significant (P < 0.01) increase in CVP and a significant (P < 0.01) decrease in SpO2 were observed after premedication which persisted up to 120 min. ECG changes included significant (P < 0.01) decrease and increase in QRS amplitudes in groups H1 and H2 respectively, a significant (P < 0.05) increase in PR interval was recorded at 15 min in group H1, a significant (P < 0.05) decrease in PR interval in group H2, a significant (P < 0.05) decrease in T wave amplitude in group H1, and a significant (P < 0.01) increase in duration of T wave in group H1 . It is concluded that both combinations can be used safely in buffaloes for surgery of 2 h duration but better sedation, analgesia and muscular relaxation and more dose sparing effect on anaesthetics and shorter recovery times were observed in group H1.

Electroacupuncture analgesia, stress responses, and variations in sensitivity in rats anesthetized with different sub-MAC anesthetics.

The use of anesthetics to stabilize animals for the purpose of electroacupuncture (EA) analgesic studies can be problematic because of the interference of differential physiological responses to EA and pain. In this study, EA-induced physiological profiles were surveyed under a sub-minimal alveolar concentration (sub-MAC) of two different anesthetics in a previously proposed minimal stress model. First, to select an adequate concentration, compliance with EA and tail-flick stimulation was evaluated under various concentrations of halothane and isoflurane. Second, using the chosen concentrations, low- (4-Hz) and high-frequency (100-Hz) EA were conducted on the right hind limb. The EA effects of the two gases were compared by tail-flick latency (TFL), hemodynamic variables, and individual variations in analgesic sensitivity. The optimal concentrations for halothane and isoflurane were 0.5% and 0.75%, respectively. TFLs were stable under these anesthetic levels, but rats under 0.75% isoflurane had better compliance than those under 0.5% halothane. EA inhibited TFLs with distinct analgesic patterns when comparing high- and low-frequency EA, but TFL suppression did not differ between the two gases. Heart rate and blood pressure showed temporal and differential responses to low- vs. high-frequency EA, but were comparable between groups under the two anesthetics. The ratios of EA non-responders in the isoflurane and halothane groups were 32.4% and 26.7%, respectively, without statistical difference. We concluded that sub-MAC halothane and isoflurane provide optimal conditions for the study of EA-induced analgesia in rats. In this model, 0.75% isoflurane appears to be a better choice than 0.5% halothane in terms of EA compliance.

Prefeeding with omega-3 fatty acids suppresses inflammation following hemorrhagic shock.

BACKGROUND: Hemorrhagic shock followed by resuscitation stimulates an inflammatory response. This study tests the hypothesis that prefeeding with fish oil rich in ω-3 fatty acids (FAs) will attenuate that response. METHODS: Male Sprague-Dawley rats (n = 60; 350 ± 30 g) were randomly but unequally assigned to 3 groups: sham (n = 12), control (n = 24), and fish oil (n = 24). In the fish oil group, rat chow was supplemented with fish oil (600 mg/kg/d, 25% ω-3 FA). Control and sham group diets were supplemented with corn oil. Under fluothane, hemorrhagic shock was induced, and arterial pressure was maintained at 25 to 30 mm Hg for 30 minutes. Resuscitation was carried out by giving 21 mL/kg lactated Ringer's solution and returning shed blood to the animal. Half of each group was killed at 30 minutes and at 4 hours postresuscitation. Liver samples were assayed for indicators of inflammation and heat shock protein 25 (Hsp25). Lung edema was measured. RESULTS: All animals survived. At 30 minutes postresuscitation, expression of mRNA for inducible nitric oxide synthase (iNOS) was significantly elevated in the control group but normal in the fish oil group. At 4 hours, expression of mRNA for Hsp25 was significantly increased in the fish oil group. Lung edema index was significantly lower in the fish oil group than in either sham or control groups. CONCLUSIONS: Fish oil prefeeding in a rodent model of hemorrhagic shock was associated with increased liver mRNA expression of Hsp25, reduced liver mRNA expression of iNOS, and decreased lung edema. These findings support the validity of the study hypothesis.

ECoG studies of valproate, carbamazepine and halothane in frontal-lobe epilepsy induced by head injury in the rat.

The use of electrocorticography (ECoG) with etiologically realistic epilepsy models promises to facilitate the discovery of better anti-epileptic drugs (AEDs). However, this novel approach is labor intensive, and must be optimized. To this end, we employed rostral parasagittal fluid percussion injury (rpFPI) in the adolescent rat, which closely replicates human contusive closed head injury and results in posttraumatic epilepsy (PTE). We systematically examined variables affecting the power to detect anti-epileptic effects by ECoG and used a non-parametric bootstrap strategy to test several different statistics, study designs, statistical tests, and impact of non-responders. We found that logarithmically transformed data acquired in repeated-measures experiments provided the greatest statistical power to detect decreases in seizure frequencies of preclinical interest with just 8 subjects and with up to approximately 40% non-responders. We then used this optimized design to study the anti-epileptic effects of acute exposure to halothane, and chronic (1 week) exposures to carbamazepine (CBZ) and valproate (VPA) 1 month post-injury. While CBZ was ineffective in all animals, VPA induced, during treatment, a progressive decrease in seizure frequency in animals primarily suffering from non-spreading neocortical seizures, but was ineffective in animals with a high frequency of spreading seizures. Halothane powerfully blocked all seizure activity. The data show that rpFPI and chronic ECoG can conveniently be employed for the evaluation of AEDs, suggest that VPA may be more effective than CBZ to treat some forms of PTE, and support the theory that pharmacoresistance may depend on the severity of epilepsy. The data also demonstrate the utility of chronic exposures to experimental drugs in preclinical studies and highlight the need for greater attention to etiology in clinical studies of AEDs.

Intramuscular injection of malignant hyperthermia trigger agents induces hypermetabolism in susceptible and nonsusceptible individuals.

BACKGROUND AND OBJECTIVE: A new minimally invasive metabolic test for the diagnosis of susceptibility for malignant hyperthermia measuring intramuscular p(CO(2)) and lactate following local application of caffeine and halothane in humans was recently proposed. The present study tested the hypothesis that a more simplified test protocol allows a differentiation between malignant hyperthermia susceptible (MHS) and malignant hyperthermia nonsusceptible (MHN) and control individuals. METHODS: With approval of the local ethics committee and informed consent, microdialysis and p(CO(2)) probes with attached microtubing were placed into the lateral vastus muscle of six MHS, seven MHN and seven control individuals. Following equilibration, boluses of 500 microl caffeine 80 mmol l(-1) and halothane 10 vol% dissolved in soybean oil were injected locally. p(CO(2)) and lactate were measured spectrophotometrically. RESULTS: The maximal rate of p(CO(2)) increase was significantly higher in MHS than in MHN and control individuals following application of halothane and caffeine, respectively. Intramuscular caffeine injection leads to a significantly higher increase of local lactate levels in MHS than in MHN and control individuals, whereas halothane increased local lactate levels in all investigated groups. Haemodynamic and systemic metabolic parameters did not differ between the investigated groups. CONCLUSION: Local caffeine and halothane injection increased intramuscular metabolism in MHS individuals significantly more than in the two other groups. In contrast to previous investigations, direct injection of the concentrations of halothane described here increased lactate and p(CO(2)) even in MHN skeletal muscle.