bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition of Mammalian Gq Protein Function by Local Anesthetics
Authors: Hollmann Markus W. , McIntire William E. , Garrison James C. , Durieux Marcel E. 
Published: August 2004

Background
Local anesthetics have been shown to selectively inhibit functioning of Xenopus laevis Gq proteins. It is not known whether a similar interaction exists with mammalian G proteins. The goal of this study was to determine whether mammalian Gq protein is inhibited by local anesthetics.

Methods
In Xenopus oocytes, the authors replaced endogenous Gq protein with mouse Gq (expressed in Sf9 cells using baculovirus vectors). Cells endogenously expressing lysophosphatidic acid or recombinantly expressing muscarinic m3 receptors were injected with phosphorothioate DNA antisense (or sense as control) oligonucleotides against Xenopus Gq. Forty-eight hours later, oocytes were injected with purified mouse Gq (5 x 10(-8) M) or solvent as control. Two hours later, the authors injected either lidocaine, its permanently charged analog QX314 (at IC50, 50 nl), or solvent (KCl 150 mM) as control and measured Ca-activated Cl currents in response to lysophosphatidic acid or methylcholine (one tenth of EC50).

Results
Injection of anti-Gq reduced the mean response size elicited by lysophosphatidic acid to 33 +/- 7% of the corresponding control response. In contrast, responses were unchanged (131 +/- 29% of control) in cells in addition injected with mouse Gq protein. Injection of mouse Gq protein "rescued" the inhibitory effect of intracellularly injected QX314: whereas QX314 was without effect on Gq-depleted oocytes, responses to lysophosphatidic acid after QX314 injection were inhibited to 44 +/- 10% of control response in cells in addition injected with mouse Gq protein (5 x 10(-8) M). Similar results were obtained for m3 signaling and intracellularly injected lidocaine.

Conclusion
Inhibition of Gq function by local anesthetics is not restricted to Xenopus G proteins. Therefore, Gq should be considered as one additional intracellular target site for local anesthetics, especially relevant for those effects not explainable by sodium channel blockade (e.g., antiinflammatory effects).
Evidence for the Involvement of Spinal Cord α1Adrenoceptors in Nitrous Oxide–induced Antinociceptive Effects in Fischer Rats
Authors: Orii Ryo , Ohashi Yoko , Guo Tianzhi , Nelson Laura E. , Hashimoto Toshikazu , Maze Mervyn , Fujinaga Masahiko 
Published: August 2004

Background
In a previous study, the authors found that nitrous oxide (N2O) exposure induces c-Fos (an immunohistochemical marker of neuronal activation) in spinal cord gamma-aminobutyric acid-mediated (GABAergic) neurons in Fischer rats. In this study, the authors sought evidence for the involvement of alpha1 adrenoceptors in the antinociceptive effect of N2O and in activation of GABAergic neurons in the spinal cord.

Methods
Adult male Fischer rats were injected intraperitoneally with alpha1 adrenoceptor antagonist, alpha2 adrenoceptor antagonist, opioid receptor antagonist, or serotonin receptor antagonist and, 15 min later, were exposed to either air (control) or 75% N2O. In some animals, nociception was investigated with the plantar test after 30 min of exposure, while in other animals, gas exposure was continued for 90 min and the spinal cord was examined for c-Fos immunostaining. In a separate experiment, animals were exposed to the above gases alone, after which the spinal cords were examined immunohistochemically for c-Fos and alpha1 adrenoceptor by double-staining methods.

Results
The antinociceptive effect of N2O was attenuated by prazosin (an alpha1 adrenoceptor antagonist), yohimbine (an alpha2 adrenoceptor antagonist), and naloxone (an opioid receptor antagonist) but not by methysergide and tropisetron (serotonin receptor antagonists). N2O exposure induced c-Fos expression in the spinal cord, which was blocked by prazosin and naloxone but not by other drugs. N2O-induced c-Fos expression was colocalized with alpha1 adrenoceptor immunoreactivity in laminae III-IV.

Conclusions
These findings support the hypothesis that N2O activates GABAergic interneurons through alpha1 adrenoceptors to produce its antinociceptive effect.
Clonidine and Dexmedetomidine Potently Inhibit Peristalsis in the Guinea Pig Ileum In Vitro
Authors: Herbert Michael K. , Roth-Goldbrunner Susanne , Holzer Peter , Roewer Norbert 
Published: August 2004

Background
Inhibition of intestinal peristalsis is a major side effect of drugs used for anesthesia or for analgesia and sedation of patients in the intensive care unit. This in vitro study examined the effect of clonidine and dexmedetomidine on intestinal peristalsis and analyzed some of their mechanisms of action.

Methods
In isolated segments of the guinea pig small intestine, peristalsis was triggered by a perfusion-induced rise of the intraluminal pressure. The peristaltic pressure threshold to elicit a peristaltic wave was used to quantify drug effects on peristalsis. Vehicle (Tyrode's solution), clonidine (10 nM-100 microm), or dexmedetomidine (0.1-100 nM) were added extraserosally to the organ bath. In other series of experiments, clonidine or dexmedetomidine was administered after pretreatment with yohimbine, prazosin, apamin, naloxone, or vehicle. Clonidine was also tested after blockade of NO synthase with L-NAME and in the presence of the inactive enantiomer D-NAME.

Results
Clonidine and dexmedetomidine concentration-dependently increased peristaltic pressure threshold and inhibited peristalsis (clonidine: EC50 = 19.6 microm; dexmedetomidine: EC50 = 12.0 nM). The inhibition caused by clonidine could be prevented by pretreatment with yohimbine, naloxone, and apamin, but not by prazosin, L-NAME, or D-NAME. Inhibition caused by dexmedetomidine was prevented by yohimbine only.(50) (50)

Conclusions
The results reveal that clonidine and, much more potently, dexmedetomidine inhibit peristalsis of the guinea pig ileum. The inhibition is caused by interaction with alpha2 adrenoceptors and, in the case of clonidine, also involves activation of small conductance Ca2+ -activated potassium channels and endogenous opioidergic pathways.
Nonhalogenated Alkanes Cyclopropane and Butane Affect Neurotransmitter-gated Ion Channel and G-protein–coupled Receptors
Authors: Hara Koji , Eger Edmond I. , Laster Michael J. , Harris R. Adron 
Published: August 2004

Background
Anesthetic mechanisms of nonhalogenated alkanes cyclopropane and butane are not understood. This study was designed to look at which neurotransmitter receptors are possible targets for these anesthetics.

Methods
Effects of cyclopropane and butane on eight recombinant receptors expressed in Xenopus oocytes were examined electrophysiologically. To address molecular mechanisms of interaction with glycine and gamma-aminobutyric acid type A (GABA(A)) receptors, cyclopropane was further tested on alpha1(S267C) glycine receptor and alpha2(S270X)beta1 GABA(A) receptors that were mutated to amino acids with larger side chains.

Results
Cyclopropane (1, 2, and 5 minimum alveolar concentration [MAC]) potentiated glycine responses by 39, 62, and 161%, respectively, and butane (1 MAC) potentiated by 64% with an increase in apparent affinity for glycine, but yielded barely detectable potentiation of GABA(A) receptors. The efficacy of cyclopropane for glycine receptors was less than isoflurane and halothane. The potentiation by cyclopropane was eliminated for the alpha1(S267C) glycine receptor. Mutant GABA(A) receptors in which the corresponding amino acid was substituted with larger amino acids did not produce significant potentiation. Cyclopropane and butane inhibited nicotinic acetylcholine and N-methyl-D-aspartate receptors, potentiated G-protein-coupled inwardly rectifying potassium channels, and did not change 5-hydroxytryptamine(3A) or muscarinic(1) receptor function. Only cyclopropane markedly inhibited alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors.

Conclusions
Glycine, nicotinic acetylcholine, and N-methyl-D-aspartate receptors are sensitive to nonhalogenated alkanes, and the authors propose that glycine and N-methyl-D-aspartate receptors are good candidates for anesthetic immobility. The authors also suggest that the distinct effects on glycine and GABA(A) receptors are not due to the small volumes of these anesthetics.
Effects of Delayed Administration of Low-dose Lidocaine on Transient Focal Cerebral Ischemia in Rats
Authors: Lei Baiping , Popp Susanna , Capuano-Waters Christine , Cottrell James E. , Kass Ira S. 
Published: August 2004

Background
The authors' previous study demonstrated that a clinical antiarrhythmic dose of lidocaine, when given before ischemia, is neuroprotective in a rat model of transient focal cerebral ischemia. In this study, the authors investigated whether the administration of this dose of lidocaine, when delayed until 45 min after the onset of ischemia, also reduces ischemic brain injury.

Methods
Lidocaine was administered as an intravenous bolus (1.5 mg/kg) followed by an intravenous infusion (2 mg. kg(-1).h(-1)) for 165 min, beginning 45 min after the onset of a 90-min period of transient focal cerebral ischemia. Control animals were given the same volume of saline. Focal cerebral ischemia was induced by occluding the right middle cerebral artery using an intraluminal suture. Neurologic outcome and body weight loss were quantified 7 days later. The brain was fixed 7 days after ischemia and brain sections were stained with hematoxylin and eosin for assessment of infarct size and the number of intact neurons. In separate experiments, local cerebral blood flow and the electroencephalogram were measured during ischemia and 180 min into the reperfusion period. Infarct size was assessed after 24 h.

Results
Infarct size, at either 24 h or 7 days after ischemia, was not significantly reduced in the lidocaine group. However, the number of intact neurons was significantly increased in both the ischemic penumbra and core of the lidocaine group 7 days after ischemia, compared with the vehicle group. Rats treated with lidocaine demonstrated better neurologic outcome and less weight loss (P < 0.05). Lidocaine treatment had no significant influence on local cerebral blood flow and electroencephalogram during ischemia and reperfusion.

Conclusions
Administration of a clinical antiarrhythmic dose of lidocaine, beginning 45 min after the onset of ischemia, reduces ischemic brain injury after transient focal cerebral ischemia in the rat. This indicates that delayed administration of neuroprotective agents may reduce brain damage resulting from ischemia.
Inhibitory Effects of Isoflurane and Nonimmobilizing Halogenated Compounds on Neuronal Nicotinic Acetylcholine Receptors
Authors: Matsuura Takayuki , Kamiya Yoshinori , Itoh Hideki , Higashi Tomoko , Yamada Yoshitsugu , Andoh Tomio 
Published: August 2004

Background
Neuronal nicotinic acetylcholine receptors (nAchRs) are inhibited by low concentrations of volatile anesthetics. However, it is not clear whether this phenomenon contributes to the anesthetic effects of volatile anesthetics. Effects of a volatile anesthetic (isoflurane) and structurally related nonimmobilizers (F6: 1,2-dichlorohexafluorocyclobutane, F8: 2,3-dichlorooctafluorobutane) on the current mediated through neuronal nAchRs were studied.

Method
This study investigated neuronal nAchRs in PC12 cells and acutely dissociated rat medial habenula (MHb) neurons. Whole cell currents elicited by 30 microm nicotine were recorded in the absence and presence of the halogenated agents. The minimum alveolar concentrations (MACs) for F6 and F8 were predicted from Meyer-Overton correlation.

Results
All halogenated compounds inhibited the nicotine-induced current in a concentration-dependent manner in PC12 cells. In MHb neurons, while isoflurane and F6 significantly inhibited the nicotine-induced peak current, F8 failed to inhibit it. The peak currents in the presence of isoflurane at 1.7 MAC, of F6 at 2.4 MAC, and of F8 at 2.2 MAC were 12, 31, and 97% of control, respectively.

Conclusions
Isoflurane, F6, and F8 inhibited ganglion-type nAchRs in PC12 cells independent from their abilities to produce the anesthetic state. In MHb neurons, isoflurane and F6, which lack the immobilizing effect but has the amnesic effect, inhibited nAchRs. Native brain nicotinic receptors in MHb neurons were almost insensitive to F8, which lacks both the immobilizing and the amnesic effect. These results are consistent with the hypothesis that inhibition of nAchRs in MHb neurons is not important for the anesthetic effect but may contribute to the amnesic effect of these agents.
Investigation of Systemic Bupivacaine Toxicity using the In situ Perfused Working Heart-Brainstem Preparation of the Rat
Authors: Pickering Anthony E. , Waki Hidefumi , Headley P. Max , Paton Julian F.R. 
Published: August 2004

Background
The inadvertent systemic administration of bupivacaine has been associated with fatal cardiovascular collapse. Systemic bupivacaine may affect neural control of the cardiovascular system in addition to having toxic actions on the heart. The study tested the hypothesis that systemic bupivacaine has toxic effects on brainstem cardiorespiratory control.

Methods
The working heart-brainstem preparation (WHBP) of rat was used to examine the actions of bupivacaine administered either by arterial injection or brainstem microinjection. The WHBP is a decerebrate rostral-half of a bisected rat, which is artificially perfused with a carbogenated Ringer solution via the aorta. Phrenic nerve activity, perfusion pressure, and electrocardiographic results were recorded.

Results
Systemic bupivacaine (3 microg/ml) evoked a prolonged pressor response (10.5 +/- 5 mmHg) associated with marked bradycardia (-45 +/- 22 beats/min) and prolonged the PR and QRS intervals of the electrocardiogram. The amplitude of respiratory sinus arrhythmia was attenuated (64 +/- 15%) by bupivacaine without affecting activity recorded from the phrenic nerve. Bupivacaine selectively attenuated the baroreflex gain (55 +/- 19%) but had no effect on the peripheral chemoreflex-evoked bradycardia. The bradycardia elicited by stimulation of the aortic depressor nerve was inhibited by bupivacaine, indicating baroreflex inhibition within the brainstem. Furthermore, bilateral microinjections of bupivacaine in the nucleus of the solitary tract reversibly inhibited the baroreflex.

Conclusions
These results demonstrate that arterial concentrations of bupivacaine that previously were shown to be cardiotoxic can selectively affect key cardiovascular control processes within the brainstem. Such impairment of neural cardiovascular control may contribute to the cardiovascular collapse associated with systemic bupivacaine.
Postural Stability following Ambulatory Regional Analgesia for Labor
Authors: Davies Jeremy , Fernando Roshan , McLeod Andrew , Verma Sonia , Found Philip 
Published: August 2004

Background
The safety of mobilization following low-dose regional analgesia in parturients remains controversial. Previous studies have demonstrated preserved balance function despite clinically elicited sensory deficits. The aim of this study was to use the Balance Master 6.1, a device capable of real-time analysis of ambulation, to score the performance of basic maneuvers following initiation of low-dose combined spinal-epidural analgesia in laboring women compared with pregnant and nonpregnant controls.

Methods
Using the Balance Master, balance function during the performance of several simple tasks, including walking and standing up from a sitting position, was evaluated in a prospective, controlled, observational study with 50 laboring women after combined spinal-epidural analgesia compared with 50 pregnant and 50 nonpregnant controls.

Results
Nonpregnant women scored significantly better results in 6 of the 13 measured balance function parameters compared with both the combined spinal-epidural and pregnant control groups. Compared with the nonpregnant subjects, the pregnant groups generated less force standing up from the sitting position (P < 0.0001), walked more slowly (P = 0.0067), and took shorter steps (P < 0.0001). They also took longer to step up onto and over a 20-cm-high obstacle (P < 0.0001), and they generated less force while stepping up. Initial spinal analgesia in laboring women did not significantly affect performance in comparison to the pregnant controls. Thirty-four percent of women in the combined spinal-epidural group required supplemental epidural analgesia following the initial spinal injection (n = 17) before testing; they had significantly impaired balance function in four tests compared with those receiving a spinal injection only (n = 33).

Conclusions
Being pregnant at term significantly affects balance function, although initial low-dose spinal-epidural analgesia does not impair function further. Subsequent supplemental epidural analgesia may have a detrimental effect on balance, but properly designed studies are awaited to confirm this. This study supports the practice of allowing laboring women with initial low-dose spinal-epidural analgesia to ambulate, but indicates that further studies need to be conducted on the effects of subsequent epidural supplementation.
Microinjection of an Adenosine A1Agonist into the Medial Pontine Reticular Formation Increases Tail Flick Latency to Thermal Stimulation
Authors: Tanase Diana , Baghdoyan Helen A. , Lydic Ralph 
Published: August 2004

Background
Both pain and the pharmacologic management of pain can cause the undesirable effect of sleep disruption. One goal of basic and clinical neuroscience is to facilitate rational drug development by identifying the brain regions and neurochemical modulators of sleep and pain. Adenosine is thought to be an endogenous sleep promoting substance and adenosinergic compounds can contribute to pain management. In the pontine brain stem adenosine promotes sleep but the effects of pontine adenosine on pain have not been studied. This study tested the hypothesis that an adenosine agonist would cause antinociception when microinjected into pontine reticular formation regions that regulate sleep.

Methods
The tail flick latency (TFL) test quantified the time in seconds for an animal to move its tail away from a thermal stimulus created by a beam of light. TFL measures were used to evaluate the antinociceptive effects of the adenosine A1 receptor agonist N6-p-sulfophenyladenosine (SPA). Pontine microinjection of SPA (0.1 microg/0.25 microl, 0.88 mm) was followed by TFL measures as a function of time after drug delivery and across the sleep-wake cycle.

Results
Compared with saline (control), pontine administration of the adenosine agonist significantly increased latency to tail withdrawal (P < 0.0001). The increase in antinociceptive behavior evoked by the adenosine agonist SPA was blocked by pretreatment with the adenosine A1 receptor antagonist 8-cyclopentyl-1, 3-dipropylxanthine (DPCPX, 0.75 ng/0.25 microl, 10 microm).

Conclusions
These preclinical data encourage additional research on the cellular mechanisms by which adenosine in the pontine reticular formation contributes to the supraspinal modulation of pain.
Missed Opportunities in Addressing Drinking Behavior in Medical and Mental Health Services
Authors: Weisner Constance , Matzger Helen 
Published: August 2004

Background: Epidemiological and clinical literature point to the importance of screening for alcohol problems in medical and psychiatric settings. However, little is known about which problem drinkers seek help from those services or about the characteristics of those who have their drinking addressed.Methods: We interviewed a probability sample of adult dependent and problem drinkers in the general population (n= 672) and consecutive admissions to chemical dependency programs in a northern California county (n= 926). We reinterviewed them 1 year later and measured medical and mental health visits and whether their drinking was addressed during the visit.Results: Almost two‐thirds of problem drinkers had a medical visit, and approximately one‐third had a mental health visit, yet drinking was not often discussed, especially during medical visits. Many of those more likely to have a visit were not more likely to have their drinking addressed. Women and individuals older than 40 years had more medical and mental health visits [odds ratio (OR), 1.71; p < 0.001 and OR, 1.55; p < 0.001, respectively, for women; OR, 1.57; p < 0.05 and OR, 1.64; p < 0.05, respectively, for age ≥40 years], but were not more likely to have their drinking addressed in either setting, and women were less likely than men to have their drinking addressed in mental health settings (OR, 0.62; p < 0.05). Those with higher alcohol severity and those who had attended chemical dependency treatment during the previous year were more likely to have their drinking addressed in each setting. Insurance status predicted medical, but not mental health, visits and was not related to having drinking addressed in either setting.Conclusions: Drinking behavior was not routinely addressed by medical and mental health practitioners for dependent and problem‐drinking men and women who presented in public and private medical and mental health settings.
Cardiac Overexpression of Alcohol Dehydrogenase Exacerbates Cardiac Contractile Dysfunction, Lipid Peroxidation, and Protein Damage After Chronic Ethanol Ingestion
Authors: Hintz Kadon K. , Relling David P. , Saari Jack T. , Borgerding Anthony J. , Duan Jinhong , Ren Bonnie H. , Kato Kosai , Epstein Paul N. , Ren Jun 
Published: August 2004

Background: Alcoholic cardiomyopathy is manifested as ventricular dysfunction, although its specific toxic mechanism remains obscure. This study was designed to examine the impact of enhanced acetaldehyde exposure on cardiac function via cardiac‐specific overexpression of alcohol dehydrogenase (ADH) after alcohol intake.Methods: ADH transgenic and wild‐type FVB mice were placed on a 4% alcohol or control diet for 8 weeks. Mechanical and intracellular Ca2+ properties were evaluated in cardiac myocytes. Levels of acetaldehyde, lipid peroxidation, and protein carbonyl formation were determined.Results: FVB and ADH mice consuming ethanol exhibited elevated blood ethanol/acetaldehyde, cardiac acetaldehyde, and cardiac hypertrophy compared with non‐ethanol‐consuming mice. However, the levels of cardiac acetaldehyde and hypertrophy were significantly greater in ADH ethanol‐fed mice than FVB ethanol‐fed mice. ADH transgene itself did not affect mechanical and intracellular Ca2+ properties with the exception of reduced resting intracellular Ca2+ and Ca2+ re‐sequestration at low pace frequency. Myocytes from ethanol‐fed mice showed significantly depressed peak shortening, velocity of shortening/relengthening, rise of intracellular Ca2+ transients, and sarco(endo)plasmic reticulum Ca2+ load associated with similar duration of shortening/relengthening compared with myocytes from control mice. Strikingly, the ethanol‐induced mechanical and intracellular Ca2+ defects were exacerbated in ADH myocytes compared with the FVB group except velocity of shortening/relengthening. The lipid peroxidation end products malondialdehyde and protein carbonyl formation were significantly elevated in both livers and hearts after chronic ethanol consumption, with the cardiac lipid and protein damage being exaggerated by ADH transgene.Conclusion: These data suggest that increased cardiac acetaldehyde exposure due to ADH transgene may play an important role in cardiac contractile dysfunctions associated with lipid and protein damage after alcohol intake.