Cold-induced thermogenesis mediated by GABA in the preoptic area of anesthetized rats

Bilateral microinjections of GABA (300 mM, 100 nl) or the GABA(A) receptor agonist muscimol (100 microM, 100 nl) into the preoptic area (POA) of the hypothalamus increased the rate of whole body O(2) consumption (VO(2)) and the body core (colonic) temperature of urethane-chloralose-anesthetized, artificially ventilated rats. The most sensitive site was the dorsomedial POA at the level of the anterior commissure. The GABA-induced thermogenesis was accompanied by a tachycardic response and electromyographic (EMG) activity recorded from the femoral or neck muscles. Pretreatment with muscle relaxants / relaxant (1 mg/kg pancuronium bromide + 4 mg/kg vecuronium bromide i.v.) prevented GABA-induced EMG activity but had no significant effect on GABA-induced thermogenesis. However, pretreatment with the beta-adrenoceptor propranolol (5 mg/kg i.v.) greatly attenuated the GABA-induced increase in VO(2) and tachycardic responses. Accordingly, the GABA-induced increase in VO(2) reflected mainly nonshivering thermogenesis. On the other hand, cooling of the shaved back of the rat by contact with a plastic bag containing 28 degrees C water also elicited thermogenic, tachycardic, and EMG responses. Bilateral microinjections of the GABA(A) receptor antagonist bicuculline (500 microM, 100 nl), but not the vehicle saline, into the POA blocked these skin cooling-induced responses. These results suggest that GABA and GABA(A) receptors in the POA mediate cold information arising from the skin for eliciting cold-induced thermogenesis.

Clinical inquiries. Does quinine reduce leg cramps for young athletes?
Robertson N, Hale W, Mackler L, Poddar S.
Moses Cone Health System, Greensboro, NC, USA.

Cough and angioedema from angiotensin-converting enzyme inhibitors: new insights into mechanisms and management.

PURPOSE OF REVIEW: Angiotensin-converting enzyme inhibitors are widely prescribed for hypertension and heart failure. These drugs are commonly associated with cough, and are less commonly associated with angioedema, which may be potentially life threatening. This review describes data that extend our understanding of the mechanisms of these reactions, and provides guidance about clinical management. RECENT FINDINGS: For patients who develop angioedema from angiotensin-converting enzyme inhibitors, recent data are reassuring that the majority of such patients can tolerate angiotensin-II receptor blockers. These data support earlier conclusions that most patients with angiotensin-converting enzyme inhibitor-induced cough can tolerate angiotensin-II receptor blockers. Limited case reports suggest that in acute angioedema induced by angiotensin-converting enzyme inhibitors, patients refractory to standard treatment may benefit from the infusion of fresh frozen plasma. SUMMARY: Although data are incomplete, it appears that angiotensin-converting enzyme inhibitors cause cough and angioedema through a cascade of effects that begins with the accumulation of kinins, and then involves arachidonic acid metabolism and nitric oxide generation. Most patients who develop either cough or angioedema from angiotensin-converting enzyme inhibitors can tolerate angiotensin-II receptor blocking agents.

Benzodiazepines affect channel opening of GABA A receptors induced by either agonist binding site.
Baur R, Sigel E.
Department of Pharmacology, Friedbuehlstrasse 49, CH-3010 Bern, Switzerland.
Benzodiazepines are widely used as anxiolytics, sedatives, muscle relaxants, and anticonvulsants. They allosterically modulate GABA type A (GABA(A)) receptors by increasing the apparent affinity of the agonist GABA to elicit chloride currents. Such an increase in apparent affinity of channel gating could either be caused by an increase in affinity for GABA or by a facilitation of channel opening. In the first case, conformation of the affected sites would have to be altered. In the second case, the affected sites are not necessarily altered, because diazepam could facilitate conformational changes leading to the open channel. It is controversial as to whether benzodiazepines affect only channel opening induced by the occupation of one of the two agonist binding sites or by both. We used receptors formed by concatenated subunits to selectively destroy one of the two agonist sites by point mutation. Both of the receptors harboring only one active agonist site could be stimulated by diazepam. We therefore present evidence that binding of diazepam can affect channel opening induced by either agonist binding site.

Onset and duration of rocuronium-induced neuromuscular blockade in patients with Duchenne muscular dystrophy.
Wick S, Muenster T, Schmidt J, Forst J, Schmitt HJ.
Department of Anesthesiology, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.
BACKGROUND: In patients with Duchenne muscular dystrophy (DMD) the response to nondepolarizing muscle relaxants / relaxant is scarcely documented and conflicting. The current study was conducted to determine the time to peak effect and the time for complete spontaneous recovery after a single dose of 0.6 mg/kg of rocuronium in patients with DMD. METHODS: Twenty-four patients (12 with DMD, 12 controls, aged 10-16 yr) were studied. All patients were anesthetized with propofol and fentanyl/remifentanil. Neuromuscular transmission was monitored by acceleromyography. After induction all patients received a single dose of 0.6 mg/kg of rocuronium. The complete time course of onset and spontaneous recovery were recorded RESULTS: Significant (P < 0.01) increase in the onset times to 95% neuromuscular block was observed in DMD patients (median, 203 s; range, 90-420 s) compared with controls (median, 90 s; range, 60-195 s). The time between rocuronium administration and recovery of first twitch of the train-of-four to 90% was significantly (P < 0.01) prolonged in DMD compared with controls (median, 132 min; range, 61-209 min versus 39 min; 22-55 min). The recovery index was also significantly prolonged in the DMD group compared with controls (median, 28 min, range, 15-70 min versus 8 min; 3-14 min). CONCLUSIONS: The most striking and surprising result of this study is the delayed onset of blockade in DMD after a standard dose of rocuronium. This effect should be kept in mind in situations when a rapid airway protection is necessary in DMD patients. The documented very long recovery from rocuronium-induced block emphasizes the need for careful assessment of neuromuscular function in DMD patients.


Involvement of Rho-kinase in the contractile mechanism of human ureteral smooth muscle.
Hong SK, Kwak C, Chang Jeong B, Kim BS, Kim HH.
Department of Urology, Seoul National University College of Medicine, Seoul, Korea.
AIM: Even though many agents have been implicated as modulators of ureteral contractile activity, the exact mechanisms that control human ureteral smooth muscle contractility have yet to be clearly defined. Recently, Rho-kinase has been reported to be involved in the contractile mechanism of smooth muscles in various organs. In the present study, we sought to investigate whether or not Rho-kinase is expressed in the human ureteral smooth muscle, and to study its role regarding human ureteral smooth muscle contractility. METHODS: Ureteral samples were obtained from human adult subjects undergoing radical nephrectomy. Immunohistochemistry and Western blotting were performed to determine the presence of Rho-kinase in human ureter. Functional studies were performed with human ureteral strips suspended in organ bath, and the effects of Y-27632, a specific inhibitor of Rho-kinase, on baseline tensions, spontaneous contractions, and electrical field stimulation (EFS)-induced contractions were analyzed. RESULTS: The results of immunohistochemistry and immunoblotting study indicated that Rho-kinase is present in human ureteral smooth muscle. In functional analysis, Y-27632 was shown to decrease the baseline tension. And, both spontaneous and EFS-induced contractile responses of human ureteral strips were attenuated by Y-27632 in dose-dependent manners. CONCLUSIONS: For the first time, the results of the present study indicate that Rho-kinase is present in human ureteral smooth muscle and may play an important role in the intricate mechanism of human ureteral contractility and tone. Copyright 2005 Wiley-Liss, Inc.

Contemporary diagnostic and management techniques for extraesophageal reflux disease.

PURPOSE OF REVIEW: To review recent advances in the diagnosis and treatment of extraesophageal reflux. RECENT FINDINGS: For most patients, the diagnosis of extraesophageal reflux relies on history and laryngoscopic exam. The reliability and reproducibility of reporting these measures may be improved with validated symptom questionnaires and standardized scoring of physical exam findings. Though dual probe pH monitoring has been the gold standard for diagnosis, it does not measure non-acid reflux events. Intraluminal impedance monitoring has the capability of measuring all esophageal reflux events (liquid, solid, gas) and may be useful in the diagnosis of non-acid reflux.Proton pump inhibitors have replaced histamine receptor antagonists as the mainstay of treatment for extraesophageal reflux. Histamine receptor antagonists are used predominantly for nocturnal acid breakthrough, or step-down therapy. Promotility and cytoprotective agents are used less commonly. Baclofen is currently being evaluated for its ability to decrease the incidence of transient lower esophageal sphincter relaxations and reduce post-prandial acid and non-acid reflux events. For individuals refractory to medical therapy, laparoscopic fundoplication techniques have proven efficacy in relieving some symptoms; the long-term benefit is not yet known. There is yet no established data on the effects of endoluminal therapies on extraesophageal reflux symptoms. SUMMARY: The diagnosis of extraesophageal reflux for most patients relies on history and laryngoscopic exam. The diagnosis can be further verified by dual probe pH and impedance monitoring. Proton pump inhibitors are the mainstay of treatment. Laparoscopic fundoplication is proven to relieve symptoms, but there is yet no data on the effects of endoluminal therapies on extraesophageal reflux symptoms.

A randomized clinical trial comparing chiropractic adjustments to muscle relaxants / relaxant for subacute low back pain.

BACKGROUND: The adult lifetime incidence for low back pain is 75% to 85% in the United States. Investigating appropriate care has proven difficult, since, in general, acute pain subsides spontaneously and chronic pain is resistant to intervention. Subacute back pain has been rarely studied. OBJECTIVE: To compare the relative efficacy of chiropractic adjustments with muscle relaxants / relaxant and placebo/sham for subacute low back pain. DESIGN: A randomized, double-blind clinical trial. METHODS: Subjects (N = 192) experiencing low back pain of 2 to 6 weeks' duration were randomly allocated to 3 groups with interventions applied over 2 weeks. Interventions were either chiropractic adjustments with placebo medicine, muscle relaxants / relaxant with sham adjustments, or placebo medicine with sham adjustments. Visual Analog Scale for Pain, Oswestry Disability Questionnaire, and Modified Zung Depression Scale were assessed at baseline, 2 weeks, and 4 weeks. Schober's flexibility test, acetaminophen usage, and Global Impression of Severity Scale (GIS), a physician's clinical impression used as a secondary outcome, were assessed at baseline and 2 weeks. RESULTS: Baseline values, except GIS, were similar for all groups. When all subjects completing the protocol were combined (N = 146), the data revealed pain, disability, depression, and GIS decreased significantly (P <.0001); lumbar flexibility did not change. Statistical differences across groups were seen for pain, a primary outcome, (chiropractic group improved more than control group) and GIS (chiropractic group improved more than other groups). No significant differences were seen for disability, depression, flexibility, or acetaminophen usage across groups. CONCLUSION: Chiropractic was more beneficial than placebo in reducing pain and more beneficial than either placebo or muscle relaxants / relaxant in reducing GIS.

Acute akinesia or akinetic crisis in Parkinson's disease.

In 22 patients with idiopathic Parkinson's disease we observed a sudden worsening of motor symptoms and severe akinesia during hospitalization because of infectious diseases, bone fractures, surgery for gastrointestinal tract diseases, and iatrogenic causes. Of these patients, 12 recovered completely, 6 had a partial recovery, and 4 died. Treatments included subcutaneous apomorphine/lisuride infusion and dantreolene (with a creatine phosphokinase level higher than 200 IU). In all patients a definite refractoriness to therapy was shown with a transient lack of response to apomorphine.

Subthalamic deep brain stimulation masking possible malignant syndrome in Parkinson disease.

Centro de Neurologia y Neurocirugia funcional, Clinica Quiron, San Sebastian, Spain.