bluuebunny/crossref_metadata_2025_split huggingface dataset:
α2Adrenoceptor–mediated Presynaptic Inhibition of Primary Afferent Glutamatergic Transmission in Rat Substantia Gelatinosa Neurons
Authors: Kawasaki Yasuhiko , Kumamoto Eiichi , Furue Hidemasa , Yoshimura Megumu 
Published: November 2003

Background
Although intrathecal administration of norepinephrine is known to produce analgesia, cellular mechanisms for this action have not yet been fully understood.

Methods
The actions of norepinephrine (50 microm) on glutamatergic transmission were examined by using the whole cell patch clamp technique in substantia gelatinosa neurons of an adult rat spinal cord slice with an attached dorsal root.

Results
Norepinephrine inhibited the amplitude of monosynaptically evoked A delta-fiber and C-fiber excitatory postsynaptic currents in a reversible manner. When compared in magnitude between the A delta-fiber and C-fiber excitatory postsynaptic currents, the former inhibition (50 +/- 4%, n = 20) was significantly larger than the latter one (28 +/- 4%, n = 8). Both actions of norepinephrine were mimicked by an alpha2 adrenoceptor agonist, clonidine (10 microm), and an alpha 2A agonist, oxymetazoline (10 microm), but not by an alpha1 agonist, phenylephrine (10 microm), and a beta agonist, isoproterenol (40 microm). The inhibitory actions were antagonized by an alpha 2 antagonist, yohimbine (1 microm), all of the results of which indicate an involvement of alpha 2 adrenoceptors. Norepinephrine did not affect the amplitude of miniature excitatory postsynaptic current and of a response of substantia gelatinosa neurons to AMPA, indicating that its action on evoked excitatory postsynaptic currents is presynaptic in origin.

Conclusions
Norepinephrine inhibits A delta-fiber- and C-fiber-mediated sensory transmission to substantia gelatinosa neurons through the activation of the alpha 2 adrenoceptor (possibly alpha2A type, based on the current, published behavioral and anatomical data) existing in primary afferent terminals; this action of norepinephrine is more effective in A delta-fiber than C-fiber transmission. This could contribute to at least a part of inhibitory modulation of pain sensation in the substantia gelatinosa by intrathecally administered norepinephrine.
Vasopressin, but Not Fluid Resuscitation, Enhances Survival in a Liver Trauma Model with Uncontrolled and Otherwise Lethal Hemorrhagic Shock in Pigs
Authors: Stadlbauer Karl H. , Wagner-Berger Horst G. , Raedler Claus , Voelckel Wolfgang G. , Wenzel Volker , Krismer Anette C. , Klima Guenter , Rheinberger Klaus , Nussbaumer Walter , Pressmar Daniel , Lindner Karl H. , Königsrainer Alfred 
Published: November 2003

Background
The authors compared the effects of vasopressin fluid resuscitation on survival in a liver trauma model with uncontrolled and otherwise lethal hemorrhagic shock in pigs.

Methods
A midline laparotomy was performed on 23 domestic pigs, followed by an incision, and subsequent finger fraction across the right medial liver lobe. During hemorrhagic shock, animals were randomly assigned to receive either 0.4 U/kg vasopressin (n = 9), or fluid resuscitation (n = 7), or saline placebo (n = 7), respectively. A continuous infusion of 0.08 U x kg(-1) x min(-1) vasopressin in the vasopressin group, or normal saline was subsequently administered in the fluid resuscitation and saline placebo group, respectively. After 30 min of experimental therapy, bleeding was controlled by surgical intervention, and blood transfusion and rapid fluid infusion were subsequently performed.

Results
Maximum mean arterial blood pressure during experimental therapy in the vasopressin-treated animals was significantly higher than in the fluid resuscitation and saline placebo groups (mean +/- SD, 72 +/- 26 vs 38 +/- 16 vs 11 +/- 7 mmHg, respectively; P< 0.05). Subsequently, mean arterial blood pressure remained at approximately 40 mmHg in all vasopressin-treated animals, whereas mean arterial blood pressure in all fluid resuscitation and saline placebo pigs was close to aortic hydrostatic pressure (approximately 15 mmHg) within approximately 20 min of experimental therapy initiation. Total blood loss was significantly higher in the fluid resuscitation pigs compared with vasopressin or saline placebo after 10 min of experimental therapy (65 +/- 6 vs 42 +/- 4 vs 43 +/- 6 ml/kg, respectively; P< 0.05). Seven of seven fluid resuscitation, and seven of seven saline placebo pigs died within approximately 20 min of experimental therapy, while 8 of 9 vasopressin animals survived more than 7 days (P < 0.05).

Conclusions
Vasopressin, but not fluid resuscitation or saline placebo, ensured survival with full recovery in this liver trauma model with uncontrolled and otherwise lethal hemorrhagic shock in pigs.
Morphine Enhances Pharmacological Preconditioning by Isoflurane
Authors: Ludwig Lynda M. , Patel Hemal H. , Gross Garrett J. , Kersten Judy R. , Pagel Paul S. , Warltier David C. 
Published: November 2003

Background
Adenosine triphosphate-regulated potassium channels mediate protection against myocardial infarction produced by volatile anesthetics and opioids. We tested the hypothesis that morphine enhances the protective effect of isoflurane by activating mitochondrial adenosine triphosphate-regulated potassium channels and opioid receptors.

Methods
Barbiturate-anesthetized rats (n = 131) were instrumented for measurement of hemodynamics and subjected to a 30 min coronary artery occlusion followed by 2 h of reperfusion. Myocardial infarct size was determined using triphenyltetrazolium staining. Rats were randomly assigned to receive 0.9% saline, isoflurane (0.5 and 1.0 minimum alveolar concentration [MAC]), morphine (0.1 and 0.3 mg/kg), or morphine (0.3 mg/kg) plus isoflurane (1.0 MAC). Isoflurane was administered for 30 min and discontinued 15 min before coronary occlusion. In eight additional groups of experiments, rats received 5-hydroxydecanoic acid (5-HD; 10 mg/kg) or naloxone (6 mg/kg) in the presence or absence of isoflurane, morphine, and morphine plus isoflurane.

Results
Isoflurane (1.0 MAC) and morphine (0.3 mg/kg) reduced infarct size (41 +/- 3%; n = 13 and 38 +/- 2% of the area at risk; n = 10, respectively) as compared to control experiments (59 +/- 2%; n = 10). Morphine plus isoflurane further decreased infarct size to 26 +/- 3% (n = 11). 5-HD and naloxone alone did not affect infarct size, but abolished cardioprotection produced by isoflurane, morphine, and morphine plus isoflurane.

Conclusions
Combined administration of isoflurane and morphine enhances the protection against myocardial infarction to a greater extent than either drug alone. This beneficial effect is mediated by mitochondrial adenosine triphosphate-regulated potassium channels and opioid receptors in vivo.
Gabapentin Markedly Reduces Acetic Acid–induced Visceral Nociception
Authors: Feng Yi , Cui Minglei , Willis William D. 
Published: November 2003

Background
Gabapentin has recently been used clinically as an antihyperalgesic agent to treat certain neuropathic pain states. The aim of this study is to test whether gabapentin is able to inhibit responses to peritoneal irritation-induced visceral pain and to examine the effect of gabapentin on spinal cord amino acid release.

Methods
The acetic acid-induced writhing assay was used in rats to determine the degree of antinociception. The rats received an intraperitoneal injection of acetic acid 40 min after intraperitoneal administration of vehicle or gabapentin (50, 100, or 200 mg/kg). Cerebrospinal fluid dialysate was collected by microdialysis from the spinal subarachnoid space in anesthetized rats. Acetic acid-induced release of amino acids into the dialysate, including glutamate, aspartate, serine, glutamine, and glycine, following intraperitoneal injection of acetic acid was evaluated by measurements of changes in the concentrations of these amino acids. The effects of pretreatment with saline or gabapentin (100 mg/kg intraperitoneal) on amino acid release were compared.

Results
Gabapentin reduced writhing responses in a dose-related fashion. Dialysate concentrations of glutamate, aspartate, and serine increased significantly following intraperitoneal injection of acetic acid, while glutamine and glycine concentrations were not increased significantly. When compared to saline-treated rats, animals pretreated with 100 mg/kg gabapentin showed suppression of the acetic acid-induced increases in glutamate, aspartate, and serine concentrations.

Conclusions
These data demonstrate that gabapentin effectively inhibits acetic acid-induced nociception, and the antinociceptive effect of gabapentin correlates with the suppression of noxious-evoked release of excitatory amino acids in the spinal cord.
Intrathecal Coadministration of D-APV and Morphine Is Maximally Effective in a Rat Experimental Pancreatitis Model
Authors: Lu Ying , Vera-Portocarrero Louis P. , Westlund Karin N. 
Published: November 2003

Background
Many studies have demonstrated that either glutamate -methyl-d-aspartate (NMDA) receptor antagonists or opioid receptor agonists provide antinociception. Spinal coadministration of an NMDA receptor antagonist and morphine has an additive action for control of various pain states in animal models. The current study examined spinal coadministration of low doses of NMDA receptor antagonist, D-(-)-2-Amino-5-phosphonovalerate (D-APV), and mu-opioid receptor agonist, morphine sulfate (MS), in reducing visceral nociception using an acute bradykinin induced pancreatitis model in rats.

Methods
An intrathecal catheter was surgically inserted into the subarachnoid space for spinal drug administration in Sprague-Dawley rats. A laparotomy was performed for ligation and cannulation of the bile-pancreatic duct. Rats were pretreated intrathecally with artificial cerebrospinal fluid (aCSF), D-APV, MS, or combined administration of D-APV and MS. These treatments were given 30 min before noxious visceral stimulation with bradykinin injected through the bile-pancreatic catheter. Spontaneous behavioral activity tests, including cage crossing, rearing, and hind limb extension, were conducted before and after bradykinin injection into the bile-pancreatic duct to assess visceral nociception.

Results
Spinal pretreatment of D-APV or low doses of MS partially reduced visceral pain behaviors in this model. Pretreatments with combinations of low doses of MS (0.05-0.5 microg) and D-APV (1 microg) were maximally effective in returning all spontaneous behavioral activities to baseline.

Conclusions
Spinal administration of combined doses of NMDA receptor antagonist, D-APV, and MS reversed three behavioral responses to induction of an acute pancreatitis model. These results suggest that in the clinical management of visceral pain, such as pancreatitis, restricted usage of glutamate antagonists might be useful as adjuvant potentiation at the onset of morphine therapy.
The Importance of Prior Stroke for the Adjusted Risk of Neurologic Injury after Cardiac Surgery for Women and Men
Authors: Hogue Charles W. , De Wet Charl J. , Schechtman Kenneth B. , Dávila-Román Victor G. 
Published: November 2003

Background
Women are at higher risk for stroke after cardiac surgery than men. Prior analysis of risk profiles for perioperative stroke that have mostly combined data from women and men may fail to identify gender-specific risks. The purpose of this study was to evaluate whether patient gender impacts adjusted risk for stroke after cardiac surgery.

Methods
Demographic and perioperative data were prospectively collected from 2,972 patients undergoing cardiac surgery. Carotid artery ultrasound examination was performed before surgery for patients aged 65 yr or older or when there was a history of transient ischemic attacks or prior stroke. Epiaortic ultrasound was performed at the time of surgery in all patients to assess for atherosclerosis of the ascending aorta.

Results
Strokes occurred after surgery in 30 women and 18 men (P < 0.0001). Based on multivariate logistic regression analysis, a history of a stroke was the strongest predictor of new stroke for both women and men. Low cardiac output syndrome, atherosclerosis of the ascending aorta, and diabetes mellitus were significantly associated with stroke for women but not for men. Analysis on the data from all patients using a gender-interaction term found that the risk for stroke associated with patient age, atherosclerosis of the aorta, diabetes, and duration of cardiopulmonary bypass was not affected by gender. The prior stroke-gender interaction, however, was significant (P = 0.017), suggesting that a prior cerebrovascular event was a more important predictor of stroke for men than women.

Conclusions
These data show that prior stroke before surgery is strongly and independently associated with susceptibility for stroke after cardiac surgery, particularly for men. Other risk factors for perioperative stroke, though, do not appear to be influenced by patient gender.
Simultaneous Assessment of Drug Interactions with Low- and High-Extraction Opioids
Authors: Ibrahim Andra E. , Feldman Jennifer , Karim Aziz , Kharasch Evan D. 
Published: November 2003

Background
Parecoxib is a parenteral cyclooxygenase-2 (COX-2) inhibitor intended for perioperative analgesia. It is an inactive prodrug hydrolyzed in vivo to the active inhibitor valdecoxib, a substrate for hepatic cytochrome P450 3A4 (CYP3A4); hence, a potential exists for metabolic interactions with other CYP3A substrates. This study determined the effects of parecoxib on the pharmacokinetics and pharmacodynamics of the CYP3A substrates fentanyl and alfentanil compared with the CYP3A inhibitor troleandomycin. Alfentanil is a low-extraction drug with a clearance that is highly susceptible to drug interactions; fentanyl is a high-extraction drug and, thus, is theoretically less vulnerable. We therefore also tested the hypothesis that the extraction ratio influences the consequence of altered hepatic metabolism of these opioids.

Methods
After Institutional Review Board-approved, written, informed consent was obtained, 12 22- to 40-yr-old healthy volunteers were enrolled in the study. The protocol was a randomized, double-blinded, balanced, placebo-controlled, three-session (placebo, parecoxib, or troleandomycin pretreatment) crossover. Subjects received both alfentanil (15 microg/kg) and fentanyl (5 microg/kg; 15-min intravenous infusion) 1 h after placebo, parecoxib (40 mg intravenously every 12 h), or troleandomycin (every 6 h). Study sessions were separated by 7 or more days. Opioid concentrations in venous blood were determined by liquid chromatography-mass spectrometry. Pharmacokinetic parameters were determined by noncompartmental analysis. Opioid effects were determined by pupillometry, respiratory rate, and Visual Analog Scale scores.

Results
There were no significant differences between the placebo and parecoxib treatments in alfentanil or fentanyl plasma concentration, maximum observed plasma concentration, area under the plasma time-concentration time curve, clearance, elimination half-life, or volume of distribution. However, disposition of alfentanil, and to a lesser extent fentanyl, was significantly altered by troleandomycin. Clearances were reduced to 12% (0.64 +/- 0.25 ml. kg-1. min-1) and 61% (9.35 +/- 3.07) of control (5.53 +/- 2.16 and 15.3 +/- 5.0) for alfentanil and fentanyl (P < 0.001). Pupil diameter versus time curves were similar between placebo and parecoxib treatments but were significantly different after troleandomycin.

Conclusions
Single-dose parecoxib does not alter fentanyl or alfentanil disposition or clinical effects and does not appear to cause significant CYP3A drug interactions. CYP3A inhibition decreases alfentanil clearance more than fentanyl clearance, confirming that the extraction ratio influences the consequence of altered hepatic drug metabolism. Modified cassette, or "cocktail," dosing is useful for assessing drug interactions in humans.
Optimal Adrenergic Support in Septic Shock Due to Peritonitis
Authors: Sun Qinghua , Tu Zizhi , Lobo Suzana , Dimopoulos George , Nagy Nathalie , Rogiers Peter , De Backer Daniel , Vincent Jean-Louis 
Published: November 2003

Background
The authors evaluated optimal adrenergic support using norepinephrine, dopamine, and dobutamine in a clinically relevant model of septic shock.

Methods
Twenty-eight mature, female, anesthetized sheep (weight, 30.5 +/- 3.6 kg) underwent cecal ligation and perforation and were randomized into four groups of seven animals to be treated with norepinephrine, dopamine-norepinephrine, dobutamine-norepinephrine, or no adrenergic agent. In all groups, lactated Ringer's solution was administered to restore cardiac filling pressures to baseline. In the norepinephrine group, norepinephrine (0.5-5 microg. kg(-1). min(-1)) was titrated to maintain mean arterial pressure between 75-85 mmHg. In the dopamine-norepinephrine group, dopamine was given first, and norepinephrine was added only when mean arterial pressure remained below 75 mmHg despite the infusion of 20 microg. kg(-1). min(-1) dopamine. In the dobutamine-norepinephrine group, dobutamine was started at the same time as norepinephrine and titrated up to 20 microg. kg(-1). min(-1) to get a 15% increase in cardiac output.

Results
The dobutamine-norepinephrine group had greater cardiac output; superior mesenteric blood flow, oxygen delivery (Do(2)), and oxygen consumption ([OV0312]o(2)); and lower blood lactate concentration and partial pressure of carbon dioxide (Pco(2)) gap than the controls did. Cumulative urine output was significantly higher in the dobutamine-norepinephrine group than in the other groups. Survival time was significantly longer in the dobutamine-norepinephrine (24 +/- 4 h), dopamine- norepinephrine (24 +/- 6 h), and norepinephrine (20 +/- 1 h) groups than the control group (17 +/- 2 h; P < 0.05 vs. other groups), and significantly longer in the combined dopamine-norepinephrine and dobutamine-norepinephrine groups (24 +/- 5 h) than in the norepinephrine alone group (P < 0.05). Histologic examination of lung biopsies revealed less severe lesions in the dobutamine-norepinephrine group than in the control and norepinephrine alone groups. Anatomic alterations in the lung, liver, and small intestine were less severe in the dobutamine-norepinephrine group than in the other groups.

Conclusions
In this prolonged septic shock model, association of norepinephrine with either dopamine or dobutamine resulted in the longest survival and the least severe pulmonary lesions. The combination of dobutamine with norepinephrine was associated with a better myocardial performance, greater Do(2) and [OV0312]o(2), lower blood lactate concentration and Pco(2) gap, and less anatomic injury.
Halothane Depresses Glutamatergic Neurotransmission to Brain Stem Inspiratory Premotor Neurons in a Decerebrate Dog Model
Authors: Stucke Astrid G. , Zuperku Edward J. , Tonkovic-Capin Viseslav , Tonkovic-Capin Mislav , Hopp Francis A. , Kampine John P. , Stuth Eckehard A. E. 
Published: November 2003

Background
Inspiratory bulbospinal neurons in the caudal ventral medulla are premotor neurons that drive phrenic motoneurons and ultimately the diaphragm. Excitatory drive to these neurons is mediated by N-methyl-d-aspartate (NMDA) receptors and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptors and modulated by an inhibitory gamma-aminobutyric acid(A) (GABA(A))ergic input. The authors investigated the effect of halothane on these synaptic mechanisms in decerebrate dogs.

Methods
Studies were performed in decerebrate, vagotomized, paralyzed, and mechanically ventilated dogs during hypercapnic hyperoxia. The effect of 1 minimum alveolar concentration (MAC) halothane on extracellularly recorded neuronal activity was measured during localized picoejection of the GABA(A) receptor blocker bicuculline and the glutamate agonists AMPA and NMDA. Complete blockade of the GABA(A)ergic mechanism by bicuculline allowed differentiation between the effects of halothane on overall GABA(A)ergic inhibition and on overall glutamatergic excitation. The neuronal responses to exogenous AMPA and NMDA were used to estimate the anesthetic effect on postsynaptic glutamatergic neurotransmission.

Results
Halothane, 1 MAC, depressed the spontaneous activity of 21 inspiratory neurons by 20.6 +/- 18.0% (mean +/- SD; P = 0.012). Overall glutamatergic excitation was depressed 15.4 +/- 20.2% (P = 0.001), while overall GABA(A)ergic inhibition did not change. The postsynaptic responses to exogenous AMPA and NMDA were also depressed by 18.6 +/- 35.7% (P = 0.03) and 22.2 +/- 26.2% (P = 0.004), respectively.

Conclusion
Halothane, 1 MAC, depressed the activity of inspiratory premotor neurons by a reduction of glutamatergic excitation. Overall inhibitory drive did not change. The postsynaptic AMPA and NMDA receptor response was significantly reduced. These findings contrast with studies in expiratory premotor neurons in which overall inhibition was significantly increased by halothane and there was no reduction in the postsynaptic glutamate receptor response.
Mitochondrial Adenosine Triphosphate–regulated Potassium Channel Opening Acts as a Trigger for Isoflurane-induced Preconditioning by Generating Reactive Oxygen Species
Authors: Tanaka Katsuya , Weihrauch Dorothee , Ludwig Lynda M. , Kersten Judy R. , Pagel Paul S. , Warltier David C. 
Published: November 2003

Background
Whether the opening of mitochondrial adenosine triphosphate-regulated potassium (K(ATP)) channels is a trigger or an end effector of anesthetic-induced preconditioning is unknown. We tested the hypothesis that the opening of mitochondrial K(ATP) channels triggers isoflurane-induced preconditioning by generating reactive oxygen species (ROS) in vivo.

Methods
Pentobarbital-anesthetized rabbits were subjected to a 30-min coronary artery occlusion followed by 3 h reperfusion. Rabbits were randomly assigned to receive a vehicle (0.9% saline) or the selective mitochondrial K(ATP) channel blocker 5-hydroxydecanoate (5-HD) alone 10 min before or immediately after a 30-min exposure to 1.0 minimum alveolar concentration (MAC) isoflurane. In another series of experiments, the fluorescent probe dihydroethidium was used to assess superoxide anion production during administration of 5-HD or the ROS scavengers N-acetylcysteine or N-2-mercaptopropionyl glycine (2-MPG) in the presence or absence of 1.0 MAC isoflurane. Myocardial infarct size and superoxide anion production were measured using triphenyltetrazolium staining and confocal fluorescence microscopy, respectively.

Results
Isoflurane (P < 0.05) decreased infarct size to 19 +/- 3% (mean +/- SEM) of the left ventricular area at risk as compared to the control (38 +/- 4%). 5-HD administered before but not after isoflurane abolished this beneficial effect (37 +/- 4% as compared to 24 +/- 3%). 5-HD alone had no effect on infarct size (42 +/- 3%). Isoflurane increased fluorescence intensity. Pretreatment with N-acetylcysteine, 2-MPG, or 5-HD before isoflurane abolished increases in fluorescence, but administration of 5-HD after isoflurane only partially attenuated increases in fluorescence produced by the volatile anesthetic agent.

Conclusions
The results indicate that mitochondrial K(ATP) channel opening acts as a trigger for isoflurane-induced preconditioning by generating ROS in vivo.