bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tonic Blocking Action of Meperidine on Na+and K+Channels in Amphibian Peripheral Nerves
Authors: Bräu Michael E. , Koch E. Dietlind , Vogel Werner , Hempelmann Gunter 
Published: November 2003

Background
Among opioids, meperidine (pethidine) also shows local anesthetic activity when applied locally to peripheral nerve fibers and has been used for this effect in the clinical setting for regional anesthesia. This study investigated the blocking effects of meperidine on different ion channels in peripheral nerves.

Methods
Experiments were conducted using the outside-out configuration of the patch-clamp method applied to enzymatically prepared peripheral nerve fibers of Xenopus laevis. Half-maximal inhibiting concentrations were determined for Na+ channels and different K+ channels by nonlinear least-squares fitting of concentration-inhibition curves, assuming a one-to-one reaction.

Results
Externally applied meperidine reversibly blocked all investigated channels in a concentration-dependent manner, i.e., voltage-activated Na+ channel (half-maximal inhibiting concentration, 164 microM), delayed rectifier K+ channels (half-maximal inhibiting concentration, 194 microM), the calcium-activated K+ channel (half-maximal inhibiting concentration, 161 microM), and the voltage-independent flicker K+ channel (half-maximal inhibiting concentration, 139 microM). Maximal block in high concentrations of meperidine reached 83% for delayed rectifier K+ channels and 100% for all other channels. Meperidine blocks the Na+ channel in the same concentration range as the local anesthetic agent lidocaine (half-maximal inhibiting concentration, 172 microM) but did not compete for the same binding site as evaluated by competition experiments. Low concentrations of meperidine (1 nM to 1 microM) showed no effects on Na+ channels. The blockade of Na+ and delayed rectifier K+ channels could not be antagonized by the addition of naloxone.

Conclusions
It is concluded that meperidine has a nonselective inhibitory action on Na+ and K+ channels of amphibian peripheral nerve. For tonic Na+ channel block, neither an opioid receptor nor the the local anesthetic agent binding site is the target site for meperidine block.
Spinal Cord Bioavailability of Methylprednisolone after Intravenous and Intrathecal Administration
Authors: Koszdin Kari L. , Shen Danny D. , Bernards Christopher M. 
Published: November 2003

Background
High-dose intravenously administered methylprednisolone has been shown to improve outcome after spinal cord injury. The resultant glucocorticoid-induced immunosuppression, however, results in multiple complications including sepsis, pneumonia, and wound infection. These complications could be reduced by techniques that increase the spinal bioavailability of intravenously administered methylprednisolone while simultaneously decreasing plasma bioavailability. This study aimed to characterize the spinal and plasma bioavailability of methylprednisolone after intravenous and intrathecal administration and to identify barriers to the distribution of methylprednisolone from plasma into spinal cord.

Methods
The spinal and plasma pharmacokinetics of intravenous (30-mg/kg bolus dose plus 5.4 mg x kg(-1) x h(-1)) and intrathecal (1-mg/kg bolus dose plus 1 mg x kg(-1) x h(-1)) methylprednisolone infusions were compared in pigs. In addition, wild-type mice and P-glycoprotein knockout mice were used to determine the role of P-glycoprotein in limiting spinal bioavailability of methylprednisolone.

Results
Despite the greater intravenous dose, concentrations of methylprednisolone in pig spinal cord were far higher and plasma concentrations much lower after intrathecal administration. After intraperitoneal administration in the mouse, the concentrations of methylprednisolone in muscle were not different between mice expressing P-glycoprotein (2.39 +/- 1.79 microg/g) and those lacking P-glycoprotein (2.83 +/- 0.46 microg/g). In contrast, methylprednisolone was undetectable in spinal cords of wild-type mice, whereas concentrations in spinal cords of P-glycoprotein-deficient mice were similar to those in skeletal muscle (2.83 +/- 0.27 microg/g).

Conclusions
These pig studies demonstrate that the spinal cord bioavailability of methylprednisolone is poor after intravenous administration. The studies in knockout mice suggest that this poor bioavailability results from P-glycoprotein-mediated exclusion of methylprednisolone from the spinal cord.
Comparative Contractile Effects of Halothane and Sevoflurane in Rat Aorta
Authors: Vinh Vu Huu , Enoki Taijiro , Hirata Shinichi , Toda Hiroshi , Kakuyama Masahiro , Nakamura Kumi , Fukuda Kazuhiko 
Published: November 2003

Background
Volatile anesthetic agents have been shown to have contractile effects in vascular tissues during specific conditions. This study compared contractile effects of halothane and sevoflurane in rat aorta treated with verapamil. This study also tried to elucidate the mechanism of the contraction.

Methods
Endothelium-denuded rat thoracic aorta was used for recording of isometric tension and measurement of influx of 45Ca2+. All experiments were performed in the presence of verapamil. In recording of tension, rings were precontracted with a submaximum dose of phenylephrine, followed by exposure to halothane or sevoflurane. For measurement of influx of 45Ca2+, rat aortic strips were exposed to phenylephrine and then to additional halothane or sevoflurane. Influx of Ca2+ was estimated by incubating the strips in 45Ca2+-labeled solution for 2 min.

Results
Halothane (0.5-4.0%) induced contraction in a dose-dependent manner, whereas sevoflurane (1-4%) had no effect on tension. Influx of 45Ca2+ was strongly enhanced by halothane at 1% and 2%, but only slightly at 4%, and was not affected by 1-4% sevoflurane. SK&F 96365, a blocker of voltage-independent Ca2+ channels, abolished contraction and influx of 45Ca2+ by 1% halothane. Depletion of Ca2+ from the sarcoplasmic reticulum with ryanodine or thapsigargin reduced the contraction induced by halothane at 4% but not that at 1% and 2%.

Conclusion
Halothane is suggested to cause contraction by enhancing influx of Ca2+ via voltage-independent Ca2+ channels at concentrations up to 2% and by inducing release of Ca2+ at 4%. Sevoflurane (1-4%) is devoid of these contractile effects.
Excitatory Synaptic Transmission Mediated by NMDA Receptors Is More Sensitive to Isoflurane than Are Non-NMDA Receptor-mediated Responses
Authors: Nishikawa Koh-ichi , MacIver M. Bruce 
Published: November 2003

Background
Effects of volatile anesthetic agents on N-methyl-D-aspartate (NMDA) receptor-mediated excitatory synaptic transmission have not been well characterized. The authors compared effects produced by halothane and isoflurane on electrophysiologic properties of NMDA and non-NMDA receptor-mediated synaptic responses in slices from the rat hippocampus.

Methods
Field excitatory postsynaptic potentials (fEPSPs) in the CA1 area were recorded with extracellular electrodes after electrical stimulation of Schaffer-collateral-commissural fiber inputs. NMDA or non-NMDA receptor-mediated fEPSPs were pharmacologically isolated using selective antagonists. Clinically relevant concentrations of halothane or isoflurane were applied to slices in an artificial cerebrospinal fluid perfusate. Paired pulse facilitation was used as a measure of presynaptic effects of the anesthetic agents.

Results
Clinically relevant concentrations of halothane (1.2 vol% approximately 0.35 mM) depressed fEPSP amplitudes mediated by NMDA receptors and non-NMDA receptors to a similar degree (mean +/- SD: 63.3 +/- 14.0% of control, n = 5; 60.2 +/- 7.3% of control, n = 7, respectively). In contrast, isoflurane (1.4 vol% approximately 0.50 mM) preferentially depressed fEPSP amplitudes mediated by NMDA receptors (44.0 +/- 7.4% of control, n = 6, P < 0.001) compared with those for non-NMDA receptors (68.7 +/- 5.4% of control n = 6), indicating a selective, additional postsynaptic effect. Paired pulse facilitation of fEPSPs was increased significantly by both anesthetic agents from 1.37 +/- 0.13 to 1.91 +/- 0.25 (n = 5, P < 0.05 for halothane) and from 1.44 +/- 0.04 to 1.64 +/- 0.08 (n = 5, P < 0.01 for isoflurane), suggesting that presynaptic mechanisms are also involved in fEPSP depression produced by the anesthetic agents. Neither rise times nor decay times of fEPSPs were changed in the presence of the anesthetic agents.

Conclusions
These results indicate that fEPSPs mediated by postsynaptic NMDA receptors are more sensitive to clinically relevant concentrations of isoflurane than are non-NMDA receptor-mediated responses, but this selective effect was not observed for halothane. Both agents also appeared to depress release of glutamate from nerve terminals via presynaptic actions.
Pharmacokinetics of Rapacuronium in Infants and Children with Intravenous and Intramuscular Administration
Authors: Reynolds Lynne M. , Infosino Andrew , Brown Ronald , Hsu Jim , Fisher Dennis M. 
Published: November 2003

Background
A nondepolarizing muscle relaxant with an onset and offset profile similar to succinylcholine is desirable for pediatric anesthesia. The onset and offset of rapacuronium are rapid in children. In the current study, the authors determined its pharmacokinetic characteristics in children. In addition to administering rapacuronium by the usual intravenous route, the authors also gave rapacuronium intramuscularly to determine uptake characteristics and bioavailability.

Methods
Forty unpremedicated patients aged 2 months to 3 yr were anesthetized with halothane, 0.82-1.0% end-tidal concentration. When anesthetic conditions were stable, rapacuronium was injected either into a peripheral vein (2 mg/kg for infants, 3 mg/kg for children) or a deltoid muscle (2.8 mg/kg for infants, 4.8 mg/kg for children). Four venous plasma samples were obtained from each subject 2-240 min after rapacuronium administration. A mixed-effects population pharmacokinetic analysis was applied to these values to determine bioavailability, absorption rate constant, and time to peak plasma concentration with intramuscular administration.

Results
Plasma clearance was 4.77 ml x kg(-1) x min(-1) + 8.48 ml/min. Intramuscular bioavailability averaged 56%. Absorption from the intramuscular depot had two rate constants: 0.0491 min(-1) (72.4% of absorbed drug) and 0.0110 min(-1) (27.6% of the absorbed drug). Simulation indicated that plasma concentration peaks 4.0 and 5.0 min after intramuscular rapacuronium in infants and children, respectively, and that, at 30 min, less than 25% of the administered dose remains to be absorbed from the intramuscular depot.

Conclusions
In infants and children, rapacuronium's clearance and steady state distribution volume are less than in adults. After intramuscular administration, bioavailability is 56%, and plasma rapacuronium concentrations peak within 4 or 5 min.
Risk of Surgery and Anesthesia for Ischemic Stroke
Authors: Wong Gilbert Y. , Warner David O. , Schroeder Darrell R. , Offord Kenneth P. , Warner Mark A. , Maxson Pamela M. , Whisnant Jack P. 
Published: November 2003

Background
The goal of this study was to determine if the combination of surgery and anesthesia is an independent risk factor for the development of incident (first-time) ischemic stroke.

Methods
All residents of Rochester, MN, with incident ischemic stroke from 1960 through 1984 (1,455 cases and 1,455 age- and gender-matched controls) were used to identify risk factors associated with ischemic stroke. Cases and controls undergoing surgery involving general anesthesia or central neuroaxis blockade before their stroke/index date of diagnosis were identified. A conditional logistic regression model was used to estimate the odds ratio of surgery and anesthesia for ischemic stroke while adjusting for other known risk factors.

Results
There were 59 cases and 17 controls having surgery within 30 days before their stroke/index date. After adjusting for previously identified risk factors, surgery within 30 days before the stroke/index date (perioperative period) was found to be an independent risk factor for stroke (P<0.001; odds ratio, 3.9; 95% confidence interval, 2.1-7.4). In an analysis that excluded matched pairs where the case and/or control underwent surgery considered "high risk" for stroke (cardiac, neurologic, or vascular procedures), "non-high-risk surgery" was also found to be an independent risk factor for perioperative stroke (P = 0.002; odds ratio, 2.9; 95% confidence interval, 1.5-5.7).

Conclusion
Our results suggest that there is an increased risk of ischemic stroke in the 30 days after surgery and anesthesia. This risk remains elevated even after excluding surgeries (cardiac, neurologic, and vascular surgeries) considered to be high risk for ischemic stroke.
Norepinephrine Facilitates Inhibitory Transmission in Substantia Gelatinosa of Adult Rat Spinal Cord (Part 1)
Authors: Baba Hiroshi , Shimoji Koki , Yoshimura Megumu 
Published: November 2003

Background
The activation of descending norepinephrine-containing fibers from the brain stem inhibits nociceptive transmission at the spinal level. How these descending noradrenergic pathways exert the analgesic effect is not understood fully. Membrane hyperpolarization of substantia gelatinosa (Rexed lamina II) neurons by the activation of alpha2 receptors may account for depression of pain transmission. In addition, it is possible that norepinephrine affects transmitter release in the substantia gelatinosa.

Methods
Adult male Sprague-Dawley rats (9-10 weeks of age, 250-300 g) were used in this study. Transverse spinal cord slices were cut from the isolated lumbar cord. The blind whole-cell patch-clamp technique was used to record from neurons. The effects of norepinephrine on the frequency and amplitude of miniature excitatory and inhibitory postsynaptic currents were evaluated.

Results
In the majority of substantia gelatinosa neurons tested, norepinephrine (10-100 microM) dose-dependently increased the frequency of gamma-aminobutyric acid (GABA)ergic and glycinergic miniature inhibitory postsynaptic currents; miniature excitatory postsynaptic currents were unaffected. This augmentation was mimicked by an alpha1-receptor agonist, phenylephrine (10-60 microM), and inhibited by alpha1-receptor antagonists prazosin (0.5 microM) and 2-(2,6-dimethoxyphenoxyethyl) amino-methyl-1,4-benzodioxane (0.5 microM). Neither postsynaptic responsiveness to exogenously applied GABA and glycine nor the kinetics of GABAergic and glycinergic inhibitory postsynaptic currents were affected by norepinephrine.

Conclusion
These results suggest that norepinephrine enhances inhibitory synaptic transmission in the substantia gelatinosa through activation of presynaptic alpha1 receptors, thus providing a mechanism underlying the clinical use of alpha1 agonists with local anesthetics in spinal anesthesia.
Norepinephrine Facilitates Inhibitory Transmission in Substantia Gelatinosa of Adult Rat Spinal Cord (Part 2)
Authors: Baba Hiroshi , Goldstein Peter A. , Okamoto Manabu , Kohno Tatsuro , Ataka Toyofumi , Yoshimura Megumu , Shimoji Koki 
Published: November 2003

Background
It has been reported previously that norepinephrine, when applied to the spinal cord dorsal horn, excites a subpopulation of dorsal horn neurons, presumably inhibitory interneurons. In the current study, the authors tested whether norepinephrine could activate inhibitory interneurons, specifically those that are "GABAergic."

Methods
A transverse slice was obtained from a segment of the lumbar spinal cord isolated from adult male Sprague-Dawley rats. Whole-cell patch-clamp recordings were made from substantia gelatinosa neurons using the blind patch-clamp technique. The effects of norepinephrine on spontaneous GABAergic inhibitory postsynaptic currents were studied.

Results
In the majority of substantia gelatinosa neurons tested, norepinephrine (10-60 microM) significantly increased both the frequency and the amplitude of GABAergic inhibitory postsynaptic currents. These increases were blocked by tetrodotoxin (1 microM). The effects of norepinephrine were mimicked by the alpha1-receptor agonist phenylephrine (10-80 microM) and inhibited by the alpha1-receptor-antagonist WB-4101 (0.5 microM). Primary-afferent-evoked polysynaptic excitatory postsynaptic potentials or excitatory postsynaptic currents in wide-dynamic-range neurons of the deep dorsal horn were also attenuated by phenylephrine (40 microM).

Conclusion
The observations suggest that GABAergic interneurons possess somatodendritic alpha1 receptors, and activation of these receptors excites inhibitory interneurons. The alpha1 actions reported herein may contribute to the analgesic action of intrathecally administered phenylephrine.
Synergistic Effect between Intrathecal Non-NMDA Antagonist and Gabapentin on Allodynia Induced by Spinal Nerve Ligation in Rats
Authors: Chen Shao-Rui , Eisenach James C. , McCaslin Patrick P. , Pan Hui-Lin 
Published: November 2003

Background
Glutamate and non-N-methyl-D-aspartate (NMDA) receptors have been implicated in the development of neuroplasticity in the spinal cord in neuropathic pain. The spinal cord has been identified as one of the sites of the analgesic action of gabapentin. In the current study, the authors determined the antiallodynic effect of intrathecal 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) in a rat model of neuropathic pain. Also tested was a hypothesis that intrathecal injection of CNQX and gabapentin produces a synergistic effect on allodynia in neuropathic rats.

Methods
Allodynia was produced in rats by ligation of the left L5 and L6 spinal nerves. Allodynia was determined by application of von Frey filaments to the left hind paw. Through an implanted intrathecal catheter, 10-100 microg gabapentin or 0.5-8 microg CNQX disodium (a water-soluble formulation of CNQX) was injected in conscious rats. Isobolographic analysis was performed comparing the interaction of intrathecal gabapentin and CNQX using the ED50 dose ratio of 15:1.

Results
Intrathecal treatment with gabapentin or CNQX produced a dose-dependent increase in the withdrawal threshold to mechanical stimulation. The ED50 for gabapentin and CNQX was 45.9+/-4.65 and 3.4+/-0.22 microg, respectively. Intrathecal injection of a combination of CNQX and gabapentin produced a strong synergistic antiallodynic effect in neuropathic rats.

Conclusions
This study shows that intrathecal administration of CNQX exhibits an antiallodynic effect in this rat model of neuropathic pain. Furthermore, CNQX and gabapentin, when combined intrathecally, produce a potent synergistic antiallodynic effect on neuropathic pain in spinal nerve-ligated rats.
Xenon Does Not Alter Cardiac Function or Major Cation Currents in Isolated Guinea Pig Hearts or Myocytes
Authors: Stowe David F. , Rehmert Georg C. , Kwok Wai-Meng , Weigt Henry U. , Georgieff Michael , Bosnjak Zeljko J. 
Published: November 2003

Background
The noble gas xenon (Xe) has been used as an inhalational anesthetic agent in clinical trials with little or no physiologic side effects. Like nitrous oxide, Xe is believed to exert minimal unwanted cardiovascular effects, and like nitrous oxide, the vapor concentration to achieve 1 minimum alveolar concentration (MAC) for Xe in humans is high, i.e., 70-80%. In the current study, concentrations of up to 80% Xe were examined for possible myocardial effects in isolated, erythrocyte-perfused guinea pig hearts and for possible effects on altering major cation currents in isolated guinea pig cardiomyocytes.

Methods
Isolated guinea pigs hearts were perfused at 70 mm Hg via the Langendorff technique initially with a salt solution at 37 degrees C. Hearts were then perfused with fresh filtered (40-microm pore) and washed canine erythrocytes diluted in the salt solution equilibrated with 20% O2 in nitrogen (control), with 20% O2, 40% Xe, and 40% N2, (0.5 MAC), or with 20% O2 and 80% Xe (1 MAC), respectively. Hearts were perfused with 80% Xe for 15 min, and bradykinin was injected into the blood perfusate to test endothelium-dependent vasodilatory responses. Using the whole-cell patch-clamp technique, 80% Xe was tested for effects on the cardiac ion currents, the Na+, the L-type Ca2+, and the inward-rectifier K+ channel, in guinea pig myocytes suffused with a salt solution equilibrated with the same combinations of Xe, oxygen, and nitrogen as above.

Results
In isolated hearts, heart rate, atrioventricular conduction time, left ventricular pressure, coronary flow, oxygen extraction, oxygen consumption, cardiac efficiency, and flow responses to bradykinin were not significantly (repeated measures analysis of variance, P>0.05) altered by 40% or 80% Xe compared with controls. In isolated cardiomyocytes, the amplitudes of the Na+, the L-type Ca2+, and the inward-rectifier K+ channel over a range of voltages also were not altered by 80% Xe compared with controls.

Conclusions
Unlike hydrocarbon-based gaseous anesthetics, Xe does not significantly alter any measured electrical, mechanical, or metabolic factors, or the nitric oxide-dependent flow response in isolated hearts, at least partly because Xe does not alter the major cation currents as shown here for cardiac myocytes. The authors' results indicate that Xe, at approximately 1 MAC for humans, has no physiologically important effects on the guinea pig heart.
Midazolam Selectively Potentiates the A2A- but not A1-receptor– mediated Effects of Adenosine
Authors: Seubert Christoph N. , Morey Timothy E. , Martynyuk Anatoly E. , Cucchiara Roy F. , Dennis Donn M. 
Published: November 2003

Background
Inhibition of adenosine metabolism offers a unique approach to harness the cardioprotective properties of adenosine in a site- and event-specific manner. Benzodiazepines inhibit adenosine metabolism by blocking nucleoside transporter. Therefore, the authors studied the binding affinities of structurally different benzodiazepines to nucleoside transporter and benzodiazepine-induced potentiation of A1-adenosine (negative dromotropy) and A2A-adenosine (coronary vasodilation) receptor-mediated effects.

Methods
In membranes from porcine striatum and guinea pig ventricle, competition binding assays to displace [3H]nitrobenzylmercaptopurine riboside ([3H]NBMPR) from nucleoside transporter were performed using alprazolam, chlorodiazepoxide, diazepam, flurazepam, and midazolam. The augmentation by the most potent benzodiazepine of A1- and A2A-adenosine receptor-mediated responses, elicited by exogenous administration of adenosine or brief periods of global hypoxia, was subsequently studied in guinea pig Langendorff-perfused hearts.

Results
All benzodiazepines completely displaced [3H]NBMPR in a concentration-dependent manner with Hill coefficients not significantly different from unity in both striatal and ventricular membranes. Midazolam was the most potent inhibitor of nucleoside transporter (ventricle:pKi = 5.22+/-0.41, Ki = 6 microM). In isolated hearts, midazolam (5, 10, 20 microM) significantly augmented coronary flow in a concentration-dependent manner in the presence of adenosine (30 nM), an effect reversed by ZM 241385, a selective A2A-receptor antagonist. In contrast, midazolam did not increase the effect of adenosine (30 nM) on atrioventricular conduction. Similarly, midazolam potentiated A2A- but not A1-receptor-mediated effects of endogenous adenosine released during hypoxia.

Conclusions
Structurally distinct benzodiazepines inhibit nucleoside transporter to different degrees. Midazolam selectively augments A2A- but not A1-receptor-mediated effects of adenosine by inhibiting nucleoside transporter.