bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterization of Adenosine Receptors Mediating Spinal Sensory Transmission Related to Nociceptive Information in the Rat
Authors: Nakamura Isao , Ohta Yoshihiro , Kemmotsu Osamu MD
Published: November 2003

Background

Adenosine analogs have been shown to produce antinociception after intrathecal administration. To determine the adenosine receptor subtype involved in spinal antinociception, the effects of selective agonists and an antagonist on the evoked potentials recorded from a neonatal rat spinal cord were studied. The measured potentials are a slow ventral root potential (slow VRP), which is the C-fiber-evoked excitatory response associated with nociceptive information; a monosynaptic reflex (MSR), which reflects a non-nociceptive transmission related to motor function; and a dorsal root potential (DRP), which reflects a gamma-aminobutyric acidA (GABA(A)) receptor-mediated presynaptic inhibition associated with analgesia.

Methods

The evoked potentials were recorded in response to electric stimulation of a lumbar dorsal root. Dose-response curves of agonists for these responses were obtained to determine their relative potency order. The antagonist dissociation constants (K(D) values) were estimated by Schild analysis.

Results

Adenosine agonists dose dependently inhibited the slow VRP and the MSR. However, the slow VRP was five to eight times more sensitive to them than was the MSR. The rank order of agonist potency was N6-cyclohexyladenosine (CHA) = N6-(R)-phenylisopropyladenosine (R-PIA) > 5'-N-ethylcarboxamidoadenosine (NECA) > CGS 21680 in both responses. 8-Cyclopentyltheophylline produced dose-dependent parallel shifts to the right of NECA dose-response curves for these responses. Schild analysis gave linear plots with slopes near unity. The K(D) values of CPT for the MSR and the slow VRP were estimated to be 5.5 nM and 4.3 nM, respectively. The DRP was also depressed by adenosine agonists with potency order of CHA > NECA > CGS 21680. 8-Cyclopentyltheophylline antagonized the inhibitory effects of CHA on the DRP.

Conclusions

The results indicate that adenosine agonists inhibit spinal sensory transmission related to nociception by acting at the A1 receptors. The A1 receptor also seems to be involved in transmission related to the spinal motor system. Feedback inhibition mediated by GABA(A) receptors does not contribute to this antinociceptive action.
Influence of Lidocaine on Endotoxin-induced Leukocyte-Endothelial Cell Adhesion and Macromolecular Leakage in Vivo
Authors: Schmidt Werner , Schmidt Heinfried , Bauer Harald , Gebhard Martha Maria , Martin Eike
Published: November 2003

Background

Endotoxin activates leukocyte-endothelial cell adhesion, vascular leakage, and changes in vascular micro-hemodynamics. The aim of this study was to determine whether lidocaine, which inhibits the activation of leukocytes, could attenuate microcirculatory disturbances during endotoxemia.

Methods

Thirty anesthetized male rats were randomly assigned to receive one of three treatments (n = 10 for each group): infusion of saline (control group), infusion of Escherichia coli endotoxin (LPS group: 2 mg x kg(-1) x h(-1) lipopolysaccharides) without lidocaine treatment, or infusion of endotoxin with lidocaine pretreatment 30 min before baseline measurements (lidocaine group: intravenous bolus of 2 mg/kg and continuous infusion of 2 mg x kg(-1) x h(-1)). Leukocyte adherence, erythrocyte velocity (V(RBC), and vessel diameters (Dv) were determined at baseline and at 60 and 120 min in mesenteric postcapillary venules using in vivo videomicroscopy. Macromolecular leakage was determined by measuring the extravasation of fluorescence-labeled albumin. Venular wall shear rate (tau) was calculated according to the equation tau = 8 x V(RBC) x Dv(-1).

Results

Lidocaine significantly attenuated the increase of leukocyte adherence during endotoxemia. There were no significant differences of tau within or between the groups. Macromolecular leakage exhibited the greatest increase in the LPS group. In the lidocaine group, it was significantly decreased but still increased compared with the control group.

Conclusions

These results show that lidocaine attenuates endotoxin-induced alterations in leukocyte-endothelial cell adhesion and macromolecular leakage, which suggests that lidocaine may have a therapeutic role in preventing endothelial damage in sepsis.
Halothane Attenuates Endothelium-dependent Pulmonary Vasorelaxant Response to Lemakalim, an Adenosine Triphosphate (ATP)-sensitive Potassium Channel Agonist
Authors: Seki Sumihiko , Horibe Mayumi , Murray Paul A.
Published: November 2003

Background

Lemakalim, an adenosine triphosphate (ATP)-sensitive potassium (K+(ATP)) channel agonist, causes profound pulmonary vasodilation in conscious dogs, which is attenuated during halothane anesthesia. The goal of the present study was to investigate the mechanism responsible for this attenuating effect of halothane.

Methods

Isolated canine pulmonary arterial rings were suspended for isometric tension recording in 25 ml organ baths. Rings with and without endothelium were contracted to 50% of their maximal response to phenylephrine, followed by the cumulative administration of lemakalim with or without exposure to halothane (0.5-1.5 minimum alveolar concentration [MAC] in dogs). Lemakalim dose-response curves were also generated in rings pretreated with the nitric oxide synthase inhibitor, Nw-nitro-L-arginine methyl ester (L-NAME); the cyclooxygenase inhibitor, indomethacin; or the K+(ATP) channel antagonist, glybenclamide.

Results

Compared with intact rings, the pulmonary vasorelaxant response to lemakalim was attenuated (P < 0.05) in endothelium-denuded rings. Halothane at 0.5 MAC had no effect on the vasorelaxant response to lemakalim. Halothane at 1 MAC attenuated (P < 0.05) the vasorelaxant response to lemakalim in intact rings, but not in endothelium-denuded rings. Halothane at 1.5 MAC attenuated (P < 0.05) the vasorelaxant response to lemakalim in both intact and endothelium-denuded rings. In endothelium-intact rings, indomethacin attenuated (P < 0.05) the vasorelaxant response to lemakalim, whereas L-NAME had no effect. Further, indomethacin, but not L-NAME, abolished the endothelium-dependent, halothane-induced attenuation of the lemakalim vasorelaxation response. Glybenclamide markedly attenuated (P < 0.05) lemakalim vasorelaxation at lemakalim doses less than 10(-6) M.

Conclusions

Lemakalim-induced pulmonary vasorelaxation involves an endothelium-dependent and vascular smooth muscle component. Further, halothane attenuates the endothelium-dependent pulmonary vasorelaxant response to lemakalim via an inhibitory effect on vasodilator metabolites of the cyclooxygenase pathway.
Nitric Oxide Produced by Inducible Nitric Oxide Synthase Delays Gastric Emptying in Lipopolysaccharide-treated Rats
Authors: Takakura Ko , Hasegawa Koichi , Goto Yukio , Muramatsu Ikunobu
Published: November 2003

Background

Endotoxin induces nitric oxide synthase (NOS), resulting in relaxation of gastric smooth muscle. The authors examined the effect of NO produced in response to lipopolysaccharide (LPS) treatment on gastric emptying in rats, and they also examined the effects of a selective inhibitor of inducible NOS (iNOS), aminoguanidine, and a suppressor of iNOS gene expression, dexamethasone.

Methods

Male Wistar rats weighing 200-250 g were used. LPS-treated rats received LPS (0.2-10 mg/kg) diluted in physiologic saline intraperitoneally. Before and at different intervals up to 8 h after administration of LPS, measurements of gastric emptying were performed in groups of 3-5 rats, by determining the amount of phenol red remaining in the stomach 20 min after intragastric instillation. In additional group of LPS (2 mg/kg)-treated rats, the gastric fundus was isolated 6 h after administration, and the tension changes in response to L-arginine, a substrate for NOS, and electrical transmural stimulation (3 Hz, 5 s) were recorded isometrically.

Results

(1) Gastric emptying was delayed by pretreatment with LPS in a dose- and time-dependent fashion (reduction from 68 +/- 12% to 22 +/- 7% with a dose of 2 mg/kg for 6 h). Aminoguanidine (50 mg/kg) or dexamethasone (5 mg/kg) partially inhibited the delay (to 39 +/- 4% or to 40 +/- 10%, respectively). (2) L-arginine (0.1 mM) produced a relaxation (28 +/- 2% reduction in active tension) in the gastric fundus strips isolated from LPS-treated rats but not from LPS-untreated rats. The relaxation was inhibited by aminoguanidine (1 mM). In contrast, the relaxation response to the electrical stimulation was not affected by aminoguanidine (0.1-1 mM).

Conclusion

The present study suggests that NO, probably produced by iNOS, is one of the factors involved in the delay of gastric emptying in the LPS-treated rats and probably in those with sepsis.
Adverse Anesthetic Outcomes Arising from Gas Delivery Equipment
Authors: Caplan Robert A. , Vistica Mary F. , Posner Karen L. , Cheney Frederick W.
Published: November 2003

Background

Anesthesia gas delivery equipment is a potentially important source of patient injury. To better define the contribution of gas delivery equipment to professional liability in anesthesia, the authors conducted an in-depth analysis of cases from the database of the American Society of Anesthesiologists Closed Claims Project.

Methods

The database of the Closed Claims Project is composed of closed US malpractice claims that have been collected in a standardized manner. All claims resulting from the use of gas delivery equipment were reviewed for recurrent patterns of injury.

Results

Gas delivery equipment was associated with 72 (2%) of 3,791 claims in the database. Death and permanent brain damage accounted for almost all adverse outcomes (n = 55, 76%). Equipment misuse was defined as fault or human error associated with the preparation, maintenance, or deployment of a medical device. Equipment failure was defined as unexpected malfunction of a medical device, despite routine maintenance and previous uneventful use. Misuse of equipment (n = 54, 75%) was three times more common than equipment failure (n = 17, 24%). Misconnects and disconnects of the breathing circuit made the largest contribution to injury (n = 25, 35%). Reviewers judged that 38 of 72 claims (53%) could have been prevented by pulse oximetry, capnography, or a combination of these two monitors. Overall, 56 of 72 gas delivery claims (78%) were deemed preventable with the use or better use of monitors. The year of occurrence for claims involving gas delivery equipment ranged from 1962 to 1991 and did not differ significantly from claims involving other adverse respiratory events.

Conclusions

Claims associated with gas delivery equipment are infrequent but severe and continue to occur in the 1990s. Educational and preventive strategies that focus on equipment misuse and breathing circuit configuration may have the greatest potential for enhancing the safety of anesthesia gas delivery equipment.
The Comparative Amnestic Effects of Midazolam, Propofol, Thiopental, and Fentanyl at Equisedative Concentrations
Authors: Veselis Robert A. , Reinsel Ruth A. , Feshchenko Vladimir A. , Wronski Marek
Published: November 2003

Background

The authors evaluated the effects of midazolam, propofol, thiopental, and fentanyl on volunteer participants' memory for words and pictures at equisedative concentrations.

Methods

Sixty-seven healthy volunteers were randomized to receive intravenous infusions of midazolam (n = 11), propofol (n = 11), thiopental (n = 10), fentanyl with ondansetron pretreatment (n = 11), ondansetron alone (n = 8), or placebo (n = 16) in a double-blind design. Three increasing and then two decreasing sedative concentrations were achieved by computer-controlled infusion in each volunteer. Measures of sedation, memory, and drug concentration were obtained at each target concentration. Drug concentrations were normalized to equisedative effects using both Emax and logistic regression methods of pharmacodynamic modeling. The serum concentrations at 50% memory effect (Cp50s) were determined using four different memory end points. The relative potencies compared with midazolam for memory impairment were determined.

Results

Equisedative concentrations were midazolam, 64.5 +/- 9.4 ng/ml; propofol, 0.7 +/- 0.2 microg/ml; thiopental, 2.9 /- 1.0 microg/ml; and fentanyl, 0.9 +/- 0.2 ng/ml. The Cp50s for 50% loss of memory for words were midazolam, 56 +/- 4 ng/ml; propofol, 0.62 +/- 0.04 microg/ml; thiopental, 4.5 +/- 0.3 microg/ml; and fentanyl, 3.2 +/- 0.4 ng/ml. Compared with midazolam, relative potencies (with 95% confidence intervals) were propofol, 0.96 (0.44-1.78); thiopental, 0.76 (0.52-0.94); and fentanyl, 0.34 (0.05-0.76). Large effects on memory were only produced by propofol and midazolam.

Conclusions

At equal sedation, propofol produces the same degree of memory impairment as midazolam. Thiopental has mild memory effects whereas fentanyl has none. Ondansetron alone has no sedative or amnesic effects.
Computer Simulation of the Effects of Alterations in Blood Flows and Body Composition on Thiopental Pharmacokinetics in Humans
Authors: Wada D. Russell , Bjorkman Sven , Ebling William F. , Harashima Hideyoshi , Harapat Sandra R. , Stanski Donald R.
Published: November 2003

Background

Understanding the influence of physiological variables on thiopental pharmacokinetics would enhance the scientific basis for the clinical usage of this anesthetic.

Methods

A physiological pharmacokinetic model for thiopental previously developed in rats was scaled to humans by substituting human values for tissue blood flows, tissue masses, and elimination clearance in place of respective rat values. The model was validated with published serum concentration data from 64 subjects. The model was simulated after intravenous thiopental administration, 250 mg, over 1 min, to predict arterial plasma concentrations under conditions of different cardiac outputs, degrees of obesity, gender, or age.

Results

The human pharmacokinetic model is characterized by a steady state volume of distribution of 2.2 l/kg, an elimination clearance of 0.22 l/min, and a terminal half-life of 9 h. Measured thiopental concentrations are predicted with an accuracy of 6 +/- 37% (SD). Greater peak arterial concentrations are predicted in subjects with a low versus a high cardiac output (3.1 and 9.4 l/min), and in subjects who are lean versus obese (56 and 135 kg). Acutely, obesity influences concentrations because it affects cardiac output. Prolonged changes are due to differences in fat mass. Changes with gender and age are relatively minor.

Conclusions

The physiological pharmacokinetic model developed in rats predicts thiopental pharmacokinetics in humans. Differences in basal cardiac output may explain much of the variability in early thiopental disposition between subjects.
Halothane and Xanthine Oxidase Increase Hepatocellular Enzyme Release and Circulating Lactate after Ischemia-Reperfusion in Rabbits
Authors: Nielsen Vance G. , Tan Sidhartha , Kirk Katharine A. , Baird Manuel S. , McCammon Andrew T. , Samuelson Paul N. , Parks Dale A.
Published: November 2003

Background

Multiple-organ injury often occurs after aortic occlusion-reperfusion. Oxidants derived from xanthine oxidase have been implicated as a source of injury after aortic occlusion-reperfusion. Halogenated anesthetics modify oxidant-mediated injury. The current study determined if halothane modifies hepatocellular enzyme release (e.g., alanine aminotransferase) and circulating lactate after aortic occlusion-reperfusion.

Methods

Rabbits were randomly assigned to one of four groups that underwent 40 min of thoracic aortic occlusion and 2 h of reperfusion: Two groups were given either halothane or fentanyl plus droperidol anesthesia and two groups were given either anesthetic and sodium tungstate (xanthine oxidase inactivator). Each of the four groups was then matched with a similarly treated group that did not undergo aortic occlusion.

Results

Halothane anesthesia was associated with significantly (P < 0.05) increased release of alanine aminotransferase (34 +/- 9 U/l at baseline and 539 +/- 370 U/l at 120 min of reperfusion; mean +/- SD) and increased plasma lactate concentrations (2.8 +/- 2.0 mM at baseline and 12.1 +/- 9.7 mM at 120 min of reperfusion) after aortic occlusion-reperfusion compared with fentanyl plus droperidol anesthesia (alanine aminotransferase, 33 +/- 12 U/l and 148 +/- 109 U/l; lactate, 3.4 +/- 2.0 mM and 3.8 +/- 1.2 mM at baseline and 120 min of reperfusion, respectively). Inactivation of xanthine oxidase significantly decreased the release of hepatocellular enzymes (P < 0.05) and decreased circulating lactate in animals anesthetized with halothane after aortic occlusion-reperfusion.

Conclusions

Halothane increased hepatocellular enzyme release and circulating lactate after aortic occlusion-reperfusion compared with fentanyl plus droperidol anesthesia. Xanthine oxidase activity inactivation also decreased hepatocellular enzyme activity release during reperfusion. These findings justify further investigations to determine if halogenated anesthetics modify tissue injury in clinical settings involving oxidant stress.
Transient Neuronal Depolarization Induces Tolerance to Subsequent Forebrain Ischemia in Rats
Authors: Taga Kiichiro , Patel Piyush M. , Drummond John C. , Cole Daniel J. , Kelly Paul J.
Published: November 2003

Background

Minor cortical injury has previously been shown to improve survival in animals subjected to ischemic insults. Although the mechanism by which an ischemia-tolerant state is achieved is not clear, transient neuronal depolarization is thought to play a central role in the development of the tolerance. One way of producing transient neuronal depolarization is by the induction of cortical spreading depression (CSD). The present study was conducted to evaluate the effect of preischemic transient depolarization, induced by CSD, on postischemic neuronal outcome in rats.

Methods

Unilateral CSD was induced by application of KCl to the frontal cortex (CSD hemisphere) in three groups of isoflurane-anesthetized rats (CSD groups; n = 8/group). Sham animals (n = 12) did not undergo CSD. In a fifth group (n = 8), ketamine was administered during KCl application to inhibit CSD. One, three, or seven days after CSD, animals were subjected to forebrain ischemia produced by bilateral carotid artery occlusion. Injury to the striatum, hippocampus, and cortex was evaluated in hematoxylin and eosin-stained brain sections 3 days after ischemia.

Results

Preischemic CSD reduced postischemic injury in the ipsilateral cortex. The ratio of the number of injured neurons in the CSD hemisphere to that in the non-CSD hemisphere was significantly less in the groups subjected to CSD 1 day (0.51 +/- 0.33), 3 days (0.56 /- 0.22), and 7 days (0.40 +/- 0.17) before ischemia than in the sham operated group (1.11 +/- 0.47). In the ketamine group (CSD inhibition), there were no differences in the extent of injury in the two hemispheres (ratio = 0.84 +/- 0.47). Injury to the striatum and hippocampus was similar among the groups. Within each group, injury to these subcortical structures in the CSD hemisphere was not different from that in the non-CSD hemisphere.

Conclusions

The data suggest that preischemic depolarization induced by CSD results in an adaptive response that reduces the vulnerability of cortical neurons to subsequent ischemic injury (ischemic tolerance).
Functional Assessment of the Pharynx at Rest and during Swallowing in Partially Paralyzed Humans
Authors: Eriksson Lars I. , Sundman Eva , Olsson Rolf , Nilsson Lena , Witt Hanne , Ekberg Olle , Kuylenstierna Richard
Published: November 2003

Background

Functional characteristics of the pharynx and upper esophagus, including aspiration episodes, were investigated in 14 awake volunteers during various levels of partial neuromuscular block. Pharyngeal function was evaluated using videoradiography and computerized pharyngeal manometry during contrast bolus swallowing.

Methods

Measurements of pharyngeal constrictor muscle function (contraction amplitude, duration, and slope), upper esophageal sphincter muscle resting tone, muscle coordination, bolus transit time, and aspiration under fluoroscopic control (laryngeal or tracheal penetration) were made before (control measurements) and during a vecuronium-induced partial neuromuscular paralysis, at fixed intervals of mechanical adductor pollicis muscle train-of-four (TOF) fade; that is, at TOF ratios of 0.60, 0.70, 0.80, and after recovery to a TOF ratio > 0.90.

Results

Six volunteers aspirated (laryngeal penetration) at a TOF ratio < 0.90. None of them aspirated at a TOF ratio > 0.90 or during control recording. Pharyngeal constrictor muscle function was not affected at any level of paralysis. The upper esophageal sphincter resting tone was significantly reduced at TOF ratios of 0.60, 0.70, and 0.80 (P < 0.05). This was associated with reduced muscle coordination and shortened bolus transit time at a TOF ratio of 0.60.

Conclusions

Vecuronium-induced partial paralysis cause pharyngeal dysfunction and increased risk for aspiration at mechanical adductor pollicis TOF ratios < 0.90. Pharyngeal function is not normalized until an adductor pollicis TOF ratio of > 0.90 is reached. The upper esophageal sphincter muscle is more sensitive to vecuronium than is the pharyngeal constrictor muscle.
Pharyngeal Patency in Response to Advancement of the Mandible in Obese Anesthetized Persons
Authors: Isono Shiroh , Tanaka Atsuko , Tagaito Yugo , Sho Yasuhide , Nishino Takashi
Published: November 2003

Background

During anesthesia in humans, anterior displacement of the mandible is often helpful to relieve airway obstruction. However, it appears to be less useful in obese patients. The authors tested the possibility that obesity limits the effectiveness of the maneuver.

Methods

Total muscle paralysis was induced under general anesthesia in a group of obese persons (n = 9; body mass index, 32 +/- 3 kg[-2]) and in a group of nonobese persons (n = 9; body mas index, 21 +/- 2 kg[-2]). Nocturnal oximetry confirmed that none of them had sleep-disordered breathing. The cross-sectional area of the pharynx was measured endoscopically at different static airway pressures. A static pressure-area plot allowed assessment of the mechanical properties of the pharynx. The influence of mandibular advancement on airway patency was assessed by comparing the static pressure-area relation with and without the maneuver in obese and nonobese persons.

Results

Mandibular advancement increased the retroglossal area at a given pharyngeal pressure, and mandibular advancement increased the retropalatal area in nonobese but not in obese persons at a given pharyngeal pressure.

Conclusion

Mandibular advancement did not improve the retropalatal airway in obese persons.
Regulation of Mu Opioid Receptor mRNA Levels by Activation of Protein Kinase C in Human SH-SY5Y Neuroblastoma Cells
Authors: Gies Elizabeth K. , Peters Dawn M. , Gelb Carol R. , Knag Kathleen M. , Peterfreund Robert A.
Published: November 2003

Background

The mu opioid receptor (MuOR) is a member of the superfamily of G protein-coupled receptors that mediates the analgesic actions of endogenous opioid peptides and the narcotic alkaloid derivatives of morphine. Activation and translocation of protein kinase C (PKC) by N-methyl-D-aspartate receptor stimulation correlates with resistance to opioid drugs in experimental states of neuropathic pain, but the cellular mechanisms of resistance have not been identified. One possibility is that PKC activation regulates MuOR mRNA expression and thus the ability to generate functional receptors. Using a human neuroblastoma cell line, the authors tested the hypothesis that phorbol ester activation of PKC regulates MuOR mRNA levels.

Methods

SH-SY5Y cells were maintained in a continuous monolayer culture and treated with phorbol esters or other agents before extraction of total cellular RNA. Slot-blot hybridization was used to measure the level of MuOR mRNA using 32P-labeled MuOR cDNA probes under high-stringency conditions. Autoradiograms were analyzed by scanning and densitometry.

Results

MuOR mRNA levels decreased in a dose- and time-dependent manner after tetradecanoyl phorbol acetate (TPA) was administered to activate PKC. The nadir, a level of approximately 50% of control, was at 2-8 h, followed by gradual recovery. The actions of TPA were blocked by pretreatment with the selective PKC inhibitor bisindolylmaleimide, but not by inhibition of protein synthesis with cycloheximide or anisomycin. The combination of TPA treatment and transcription inhibition with actinomycin D was associated with a transient increase in MuOR mRNA.

Conclusions

Mu opioid receptor mRNA levels are regulated by activation of PKC in a neuronal model. Protein kinase C effects which decrease MuOR mRNA levels appear largely independent of new protein synthesis, and cytotoxicity does not account for the findings. Plasticity of MuOR gene expression may contribute to variations in clinical responses to opioid analgesics in clinical states such as neuropathic pain.
Systemic Absorption and Block after Epidural Injection of Ropivacaine in Healthy Volunteers
Authors: Emanuelsson Britt-Marie K. , Persson Jan , Alm Christina , Heller Agneta , Gustafsson Lars L.
Published: November 2003

Background

For local anesthetics, the process of removal from the site of administration influences the duration of anesthesia and the risk for systemic toxicity to develop. The systemic absorption of epidural ropivacaine and the time profile of sensory and motor block were studied in healthy volunteers.

Methods

Nine persons simultaneously received 150 mg ropivacaine hydrochloride (7.5 mg/ml) epidurally and 40 mg deuterium-labeled (2H3)ropivacaine hydrochloride (0.25 mg/ml) intravenously. Peripheral arterial and venous plasma samples were collected, and assessments of sensory and motor block were made.

Results

The arterial plasma concentrations increased faster than the venous concentrations, with 50% higher maximum concentrations after both intravenous and epidural administration. The absorption was biphasic. A correlation was seen between the duration of sensory block and the slower absorption half-life; that is, the longer the half-life, the longer the duration. The extent of spread varied among the volunteers, with the median upper block level not exceeding T12. The motor block (Bromage score 1) was of slower onset (median, 0.4 h) and of shorter duration (median, 4.1 h) than the sensory block (onset, 0.2 h; duration, 6.5 h at L2 medians).

Conclusions

As much as 50% differences were seen in the arteriovenous plasma concentrations of ropivacaine during the first hour, which has implications for the interpretation of systemic toxic plasma concentrations. The absorption into the general circulation was biphasic, with a correlation between the sensory block and the slower absorption half-life. A faster onset and a longer duration of sensory compared with motor block was seen.
Myocardial Effects of Halothane and Isoflurane in Hamsters with Hypertrophic Cardiomyopathy
Authors: Vivien Benoit , Hanouz Jean-Luc , Gueugniaud Pierre-Yves , Lecarpentier Yves , Coriat Pierre , Riou Bruno
Published: November 2003

Background

The effects of halothane and isoflurane on myocardial contraction and relaxation in diseased myocardium are not completely understood.

Methods

The effects of equianesthetic concentrations of halothane and isoflurane on inotropy and lusitropy in left ventricular papillary muscles of healthy hamsters and those with genetically induced cardiomyopathy (strain BIO 14.6) were investigated in vitro (29 degrees C; pH 7.40; Ca2+ 2.5 mM; stimulation frequency, 3/min) in isotonic and isometric conditions.

Results

Halothane induced a negative inotropic effect that was greater in cardiomyopathic than in healthy hamsters (1.5 vol%, active isometric force (AF): 19 +/- 8% vs. 28 +/- 11% of control values; P < 0.05). Isoflurane induced a negative inotropic effect that was greater in cardiomyopathic than in healthy hamsters (2.0 vol%, AF: 64 +/- 13% vs. 75 +/- 11% of control values; P < 0.01). However, the negative inotropic effects of halothane and isoflurane were not different for cardiomyopathic or healthy hamsters when their concentrations were corrected for minimum alveolar concentration (MAC) values in each strain. Halothane induced a negative lusitropic effect under low load, which was more important in cardiomyopathic hamsters, suggesting a greater impairment in calcium uptake by the sarcoplasmic reticulum. In contrast, isoflurane induced a moderate positive lusitropic effect under low load in healthy but not in cardiomyopathic hamsters. Halothane and isoflurane induced no significant lusitropic effect under high load.

Conclusions

Halothane and isoflurane had greater negative inotropic effects in cardiomyopathic than in healthy hamsters. Nevertheless, no significant differences in their inotropic effects were noted when concentrations were correlated as a multiple of MAC in each strain.
Effects of Ketamine on Ventricular Conduction, Refractoriness, and Wavelength
Authors: Aya Antoine G. M. , Robert Emmanuelle , Bruelle Pascal , Lefrant Jean-Yves , Juan Jean-Marie , Peray Pascale , Eledjam Jean-Jacques , de La Coussaye Jean E.
Published: November 2003

Background

The aims of the study were to verify the effects of ketamine on ventricular conduction velocity and on the ventricular effective refractory period, to determine its effects on anisotropy and on homogeneity of refractoriness, and to use wavelength to determine whether ketamine has antiarrhythmic or arrhythmogenic properties.

Methods

A high-resolution epicardial mapping system was used to study the effects of 50, 100, 150, and 200 microM racemic ketamine in 15 isolated, Langendorff-perfused rabbit hearts. Five hearts were kept intact to study the effects of ketamine on spontaneous sinus cycle length (RR) interval and its putative arrhythmogenic effects. In 10 other hearts, a thin epicardial layer was obtained by an endocardial cryoprocedure (frozen hearts) to study ventricular conduction velocity, ventricular effective refractory periods (five sites), and ventricular wavelength.

Results

Ketamine induced a concentration-dependent lengthening of the RR interval. Ketamine slowed longitudinal and transverse ventricular conduction velocity with no anisotropic change, and it prolonged the ventricular effective refractory period with no significant increase in dispersion. Ventricular longitudinal and transverse wavelengths tend to increase, but this was not statistically significant. Finally, no arrhythmia could be induced regardless of the ketamine concentration.

Conclusion

Ketamine slowed ventricular conduction and prolonged refractoriness without changing anisotropy or increasing dispersion of refractoriness. Although these effects should result in significant antiarrhythmic effects of ketamine, this should not be construed to suggest a protective effect in ischemic or other abnormal myocardium.
Lidocaine Suppresses the Anoxic Depolarization and Reduces the Increase in the Intracellular Ca sup 2+ Concentration in Gerbil Hippocampal Neurons
Authors: Liu Keyue , Adachi Naoto , Yanase Hisato , Kataoka Kiyoshi , Arai Tatsuru
Published: November 2003

Background

The movement of ions, particularly Ca2+, across the plasma membrane of neurons is regarded as an initial element of the development of ischemic neuronal damage. Because the mechanism by which lidocaine protects neurons against ischemia is unclear, the effects of lidocaine on the ischemia-induced membrane depolarization, histologic outcome, and the change in the intracellular Ca2+ concentration in the gerbil hippocampus were studied.

Methods

The changes in the direct-current potential shift in the hippocampal CA1 area produced by transient forebrain ischemia for 4 min were compared in animals given lidocaine (0.8 micromol administered intracerebroventricularly) 10 min before ischemia and those given saline. The histologic outcome was evaluated 7 days after ischemia by assessing delayed neuronal death in hippocampal CA1 pyramidal cells in these animals. In a second study, hypoxia-induced intracellular Ca2+ increases were evaluated by in vitro microfluorometry in gerbil hippocampal slices, and the effects of lidocaine (10, 50, and 100 microM) on the Ca2+ accumulation were examined. In addition, the effect of lidocaine (100 microM) drug perfusion with a Ca2+-free ischemia-like medium was investigated.

Results

The preischemic administration of lidocaine delayed the onset of the ischemia-induced membrane depolarization (anoxic depolarization) and reduced its maximal amplitude. The histologic outcome was improved by the preischemic treatment with lidocaine. The in vitro hypoxia-induced increase in the intracellular concentration of Ca2+ was suppressed by the perfusion with lidocaine-containing mediums (50 and 100 microM), regarding the initiation and the extent of the increase. The hypoxia-induced intracellular Ca2+ elevation in the Ca2+-free condition was similar to that in the Ca2+-containing condition. Perfusion with lidocaine (100 microM) inhibited this elevation in the Ca2+-free condition.

Conclusions

Lidocaine helps protect neurons from ischemia by suppressing the direct-current potential shift, by inhibiting the release of Ca2+ from the intracellular Ca2+ stores, and by inhibiting the influx from the extracellular space.
Conformational State-dependent Effects of Halothane on Cardiac Na sup + Current
Authors: Weigt Henry U. , Rehmert Georg C. , Bosnjak Zeljko J. , Kwok Wai-Meng
Published: November 2003

Background

The Na+ channel is voltage gated and characterized by three distinct states: closed, open, and inactivated. To identify the effects of halothane on the cardiac Na+ current (I(Na)) at various membrane potentials, the effects of 1.2 mM halothane at different holding potentials (V(H)) on I(Na) were examined in single, enzymatically isolated guinea pig ventricular myocytes.

Methods

The I(Na) was recorded using the whole-cell configuration of the patch-clamp technique. Currents were generated from resting V(H)s of -110, -80, or -65 mV. State-dependent block was characterized by monitoring frequency dependence, tonic block, and removal of inactivation by veratridine.

Results

Halothane produced significant (P < 0.05) V(H)-dependent depressions of peak I(Na) (mean +/- SEM): 24.4 +/- 4.1% (V(H) = -110 mV), 42.1 +/- 3.4% (V(H) = -80 mV), and 75.2 +/- 1.5% (V(H) = -65 mV). Recovery from inactivation was significantly increased when cells were held at -80 mV (control, tau = 6.0 +/- 0.3 ms; halothane, tau = 7.1 +/- 0.4 ms), but not at -110 mV. When using a V(H) of -80 mV, halothane exhibited a use-dependent block, with block of I(Na) increasing from 8.6 +/- 1.4% to 30.7 +/- 3.5% at test pulse rates of 2 and 11 Hz, respectively. Use-dependent inhibition was not apparent at V(H) of -110 mV. When inactivation of I(Na) was removed by exposure to 100 microM veratridine, no significant difference was observed in the depressant effect of halothane at both V(H)s: 26.6 +/- 4.5% (V(H) = -80 mV) and 26.4 +/- 5.6% (V(H) = -110 mV).

Conclusions

The present findings indicate that the depressant action of halothane on cardiac I(Na) depends on the conformational state of the channel. As more channels are in the inactivated state, the more potent is the effect of halothane. Removal of channel inactivation by veratridine abolished the dependence of the halothane effect on V(H), but depression of the current was still evident. These results indicate a complex interaction between halothane and the various conformational states of the Na+ channel.
Modulation of Cardiac Sodium Current by α1-stimulation and Volatile Anesthetics
Authors: Weigt Henry U. , Kwok Wai-Meng , Rehmert Georg C. , Turner Lawrence A. , Bosnjak Zeljko J.
Published: November 2003

Background

Alpha1-adrenoceptor stimulation is known to produce electrophysiologic changes in cardiac tissues, which may involve modulations of the fast inward Na+ current (I(Na)). A direct prodysrhythmic alpha1-mediated interaction between catecholamines and halothane has been demonstrated, supporting the hypothesis that generation of halothane-epinephrine dysrhythmias may involve slowed conduction, leading to reentry. In this study, we examined the effects of a selective alpha1-adrenergic receptor agonist, methoxamine, on cardiac I(Na) in the absence and presence of equianesthetic concentrations of halothane and isoflurane in single ventricular myocytes from adult guinea pig hearts.

Methods

I(Na) was recorded using the standard whole-cell configuration of the patch-clamp technique. Voltage clamp protocols initiated from two different holding potentials (V(H)) were applied to examine state-dependent effects of methoxamine in the presence of anesthetics. Steady state activation and inactivation and recovery from inactivation were characterized using standard protocols.

Results

Methoxamine decreased I(Na) in a concentration- and voltage-dependent manner, being more potent at the depolarized V(H). Halothane and isoflurane interacted synergistically with methoxamine to suppress I(Na) near the physiologic cardiac resting potential of -80 mV. The effect of methoxamine with anesthetics appeared to be additive when using a V(H) of -110 mV, a potential where no Na+ channels are in the inactivated state. Methoxamine in the absence and presence of anesthetics significantly shifted the half maximal inactivation voltage in the hyperpolarizing direction but had no effect on steady-state activation.

Conclusion

The present results show that methoxamine (alpha1-adrenergic stimulation) decreases cardiac Na+ current in a concentration- and voltage-dependent manner. Further, a form of synergistic interaction between methoxamine and inhalational anesthetics, halothane and isoflurane, was observed. This interaction appears to depend on the fraction of Na+ channels in the inactivated state. (Key words: Anesthetics, volatile: halothane; isoflurane; methoxamine. Patch clamp: whole-cell configuration; sodium current; ventricular guinea pig myocytes.)
Comparison of Pre- versus Post-incision Administration of Intrathecal Bupivacaine and Intrathecal Morphine in a Rat Model of Postoperative Pain
Authors: Brennan Timothy J. , Umali Eric F. , Zahn Peter K.
Published: November 2003

Background

Preclinical studies in experimental animals suggest that preemptive analgesia may improve postoperative pain management. The beneficial effects of preemptive analgesia appear less remarkable clinically. The purpose of this study is to examine the effect of pre- and post-incision administration of intrathecal bupivacaine and intrathecal morphine in a rat model for postoperative pain.

Methods

Rats with intrathecal catheters were anesthetized with halothane, and the surgical field was prepared. A saline vehicle or the test drug was administered 15 min before an incision was made in the plantar aspect of the hindpaw or after the incision was completed. After recovery, mechanical hyperalgesia to punctate and nonpunctate stimuli was measured. Rats were tested on the day of surgery for the first 5 h and each day for 6 days.

Results

In saline vehicle-treated rats, the median withdrawal threshold decreased from 522 mN to 54 mN or less, and the response frequency to pressure from application of the plastic disc increased from 0 +/- 0% to 96 +/- 12% or greater after incision. Hyperalgesia was persistent through 2 days after surgery and then gradually returned toward preincision values over the next 4 days. Pre- or postincision administration of either intrathecal morphine or intrathecal bupivacaine reduced hyperalgesia on the day of surgery; at all subsequent times, there were no differences between the saline vehicle groups and the drug treatment groups. There were never any significant differences between pre- and postincision treatments.

Conclusions

Early reduction in pain behaviors either by pre- or postincision management had no impact on subsequent measures of hyperalgesia in this model. These results agree with a number of clinical studies and suggest that incisional pain may be initiated and maintained differently than pain in other models.
Effect of Inverse I
Authors: Zavala Elizabeth , Ferrer Miguel , Polese Guido , Masclans Joan Ramon , Planas Merce , Milic-Emili Joseph , Rodriguez-Roisin Robert , Roca Josep , Rossi Andrea
Published: November 2003

Background

It is not known whether inverse I:E ratio ventilation (IRV) offers any real benefit over conventional mechanical ventilation with positive end-expiratory pressure (CMV-PEEP) at similar levels of end-expiratory pressure.

Methods

The effects of volume-controlled and pressure-controlled IRV (VC-IRV and PC-IRV, respectively) on VA/Q inequality were compared with those of CMV-PEEP at a similar level of end-expiratory pressure and with CMV without PEEP (CMV) in eight patients in the early stages of acute respiratory distress syndrome (ARDS). Respiratory blood gases, inert gases, lung mechanics, and hemodynamics were measured 30 min after the onset of each ventilatory mode.

Results

Recruitment of nonventilated, poorly ventilated (or both) but well-perfused alveoli increased the partial pressure of oxygen (PaO2) during CMV-PEEP (+13 mmHg) and IRV-VC (+10 mmHg; P < 0.05) compared with CMV. In contrast, PC-IRV did not affect PaO2 but caused a decrease in PaCO2 (-7 mmHg; P < 0.05). The latter was due to a concomitant decrease in dead space (P < 0.01) and shift to the right of VA/Q distributions. During PC-IRV, the increase in the mean of blood flow distribution (mean Q; P < 0.01) without a change in the dispersion (log SD Q) did not result in an increase in PaO2, probably because it reflected redistribution of blood flow within well-ventilated areas.

Conclusions

Short-term PC-IRV improved carbon dioxide clearance, but the lung became less efficient as an oxygen exchanger. Furthermore, based on mean airway and plateau pressures, the risk of barotrauma was not reduced with this type of ventilation.
Oral Transmucosal Etomidate in Volunteers
Authors: Streisand James B. , Jaarsma Ruurd L. , Gay Mason A. , Badger Mary Jane , Maland Lynn , Nordbrock Earl , Stanley Theodore H.
Published: November 2003

Background

The oral transmucosal route of delivery is now used for many drugs, including fentanyl and midazolam. Etomidate's pharmacokinetic profile and physiochemical properties suggest it may be suitable for transmucosal delivery. Transmucosal delivery might extend etomidate's use to sedation and anxiolysis. This is the first study in humans to examine the oral transmucosal administration of a novel etomidate dosage form.

Methods

Ten healthy adult volunteers consumed 12.5-mg, 25-mg, 50-mg, and 100-mg doses of oral transmucosal etomidate (OTET) on four different study days. Serum etomidate concentrations, sedation, respiratory and cardiovascular variables, taste, and side effects were determined.

Results

Five minutes after OTET administration, etomidate was detected in the venous blood. Mean peak concentrations occurred 20-30 min later and ranged from 61-174 ng/ml, related to the dose administered. Drowsiness and light sleep occurred in a dose-related manner 10-20 min after administration and lasted for 30-60 min. No episodes of SpO2 <90%, hypotension, or emesis occurred at any dose throughout the study. Nausea was rare. Two volunteers exhibited a brief episode of involuntary tremor after the 100-mg dose. The bitter taste of OTET was judged increasingly unpleasant with escalating doses.

Conclusions

Oral transmucosal etomidate produces dose-related increases in sedation and clinically significant serum concentrations with minimal side effects. The time course of these effects suggests that OTET might be useful when brief mild to moderate sedation with rapid recovery is desirable. Further development of this novel dosage form is warranted.
Lack of Effect of Intrathecally Administered N-methyl-D-aspartate Receptor Antagonists in a Rat Model for Postoperative Pain
Authors: Zahn Peter K. , Brennan Timothy J.
Published: November 2003

Background

Evidence from experiments by others indicates an important role for excitatory amino acids activating spinal n-methyl-d-aspartate (NMDA) receptors in models of persistent pain. The purpose of this study was to examine the effect of intrathecal (+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine (MK-801), a noncompetitive NMDA receptor antagonist, 2-amino-5-phosphonovaleric acid (AP5), a competitive NMDA receptor antagonist, and N-G-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, on pain behaviors in a rat model of postoperative pain.

Methods

Rats with intrathecal catheters were anesthetized and underwent a plantar incision. Withdrawal threshold to punctate stimulation applied adjacent to the wound, response frequency to application of a nonpunctate stimulus applied directly to the wound, and nonevoked pain behaviors were measured before and after intrathecal administration of MK-801 or AP5. The effect of intrathecal L-NAME on mechanical hyperalgesia was also examined.

Results

Mechanical hyperalgesia increased and was persistent after plantar incision and was not decreased by intrathecal administration of 4, 14, or 40 nmol MK-801 or 10 nmol AP5. Only the greatest dose of AP5, 30 nmol, caused a small decrease in punctate and nonpunctate hyperalgesia. Intrathecal L-NAME had no effect. Neither intrathecal MK-801 nor intrathecal AP5 affected nonevoked pain behaviors. The greatest doses caused motor deficits.

Conclusions

Unlike intrathecal and systemic morphine, intrathecal NMDA receptor antagonists did not modify pain behaviors in this rat model of postoperative pain. These data suggest that NMDA receptors do not play an important role in the maintenance of postoperative pain behaviors and that NMDA receptor antagonists, administered spinally by themselves during the postoperative period, will not be useful for the treatment of postoperative pain in humans.
Postoperative Analgesia by Intra-articular Neostigmine in Patients Undergoing Knee Arthroscopy
Authors: Yang Lin Cheng , Chen Liang-Mei , Wang Ching-Jen , Buerkle Hartmut
Published: November 2003

Background

Recently, the spinal administration of neostigmine was shown to produce a dose-dependent analgesia. However, this analgesia is limited by adverse effects. The purpose of this study was to examine the analgesic action of peripheral muscarinic receptors by administering intra-articular neostigmine after operation in patients undergoing knee arthroscopy.

Methods

Sixty patients (classified as American Society of Anesthesiologists status I or II) having arthroscopic meniscus repair during general anesthesia were randomized to receive, in a double-blind manner, after operation 125, 250, or 500 microg intra-articular neostigmine; 2 mg intra-articular morphine; or as control groups intra-articular saline or 500 microg neostigmine given subcutaneously (s.c.). Visual analog pain scores (VAS), duration of analgesia as defined by first demand for patient-controlled analgesia by morphine, and subsequent 48-h consumption of morphine were evaluated.

Results

Intra-articular (500 microg) neostigmine resulted in significant VAS reduction 1 h after injection compared with patients given intra-articular saline and with those given intra-articular morphine. Analgesia lasted longer after 500 microg intra-articular neostigmine (350 +/- 126 min) compared with intra-articular morphine (196 +/- 138 min; P < 0.05) or with the control groups (intra-articular saline, 51 +/- 11 min; s.c. neostigmine, 46 +/- 8 min; P < 0.05). The need for supplementary analgesia was significantly higher in control groups than for patients given intra-articular morphine or 500 microg intra-articular neostigmine. No significant analgesic effects were observed for the two lower doses of intra-articular neostigmine. Among all study groups, no adverse effects were observed.

Conclusions

Intra-articular injection of the acetylcholinesterase inhibitor neostigmine produced a moderate but significant analgesic effect. Several mechanisms such as the hyperpolarization of neurons, reduction in the release of pronociceptive neurotransmitters, or activation of the nitric oxide-cyclic guanosine monophosphate pathway might mediate this peripheral cholinergic antinociception by elevating endogenous acetylcholine.