1,721,174 research outputs found
Histamine H3 receptors mediate inhibition of noradrenaline release from intestinal sympathetic nerves
Full text link1. The present study investigates whether presynaptic histamine receptors regulate noradrenaline release from intestinal sympathetic nerves. The experiments were performed on longitudinal muscle-myenteric plexus preparations of guinea-pig ileum, preincubated with [(3)H]-noradrenaline. 2. In the presence of rauwolscine, electrically-induced [(3)H]-noradrenaline release was inhibited by histamine or R-alpha-methylhistamine, whereas it was unaffected by pyridylethylamine, impromidine, pyrilamine, cimetidine, thioperamide or clobenpropit. The inhibitory effects of histamine or R-alpha-methylhistamine were antagonized by thioperamide or clobenpropit, but not by pyrilamine or cimetidine. In the absence of rauwolscine, none of these drugs modified the release of [(3)H]-noradrenaline. 3. The modulatory action of histamine was attenuated by pertussis toxin and abolished by N-ethylmaleimide. Tetraethylammonium or 4-aminopyridine enhanced the evoked tritium outflow and counteracted the inhibitory effect of histamine. However, the blocking effects of tetraethylammonium and 4-aminopyridine were no longer evident when their enhancing actions were compensated by reduction of Ca(2+) concentration in the superfusion medium. 4. Histamine-induced inhibition of tritium output was enhanced by omega-conotoxin or low Ca(2+) concentration, whereas it was not modified by nifedipine, forskolin, rolipram, phorbol myristate acetate, H7 or lavendustin A. 5. The present results indicate that presynaptic H(3) receptors, located on sympathetic nerve endings, mediate an inhibitory control on intestinal noradrenergic neurotransmission. It is suggested that these receptors are coupled to G(i)/G(o) proteins which modulate the activity of N-type Ca(2+) channels through a direct link, thus reducing the availability of extracellular Ca(2+) at the level of noradrenergic nerve terminals
Efficay and tolerability of meloxicam, a COX-2 preferential nonsteroidal anti-inflammatory drug: a review
Full text linkMeloxicam is an enolcarboxamide with preferential COX-2 inhibitory activity. In vitro studies with human tissues have confirmed the high affinity of meloxicam for COX-2, whereas COX-1 was inhibited only at the highest concentrations (ratio of 50% inhibitory concentration for COX-2 : COX-1 = 0.09 in whole blood assays).Meloxicam has a bioavailability of 89% after oral administration, is strongly bound to plasma proteins, and its half-life is 20-24 hours. It readily penetrates into synovial fluid, reaching 45-57% of plasma concentrations. Meloxicam pharmacokinetics are not significantly altered in elderly patients or in those with mild renal/hepatic impairment. The efficacy and tolerability of meloxicam in the treatment of pain and inflammation associated with rheumatic and musculoskeletal disorders has been evaluated in numerous studies comparing meloxicam 7.5-15 mg/day (up to 22.5 mg/day in ankylosing spondylitis), administered for 2 weeks to 12 months, with placebo or other nonsteroidal anti-inflammatory drugs (NSAIDs). Overall, the efficacy of meloxicam was significantly superior to that of placebo and similar to that of other NSAIDs, whereas the incidence of adverse events (especially gastrointestinal) was lower than with other NSAIDs. Intramuscular meloxicam provided faster pain relief than the oral drug in patients with rheumatoid arthritis. Meloxicam also appears to be effective in the prevention of postoperative pain, as shown in patients undergoing abdominal hysterectomy or inguinal hernia repair. Meloxicam may also have a cardioprotective role: in patients with acute coronary syndrome without ST-segment elevation, a lower incidence of cardiovascular events was observed in those who received meloxicam plus aspirin and heparin versus aspirin and heparin alone, both during coronary care stay and at 90-day follow-up. Meloxicam has demonstrated a favourable tolerability profile in large-scale comparative trials, where its gastrointestinal tolerability was superior to that of nonselective NSAIDs. In particular, meloxicam 7.5 mg/day was associated with a lower incidence of gastrointestinal adverse events compared with diclofenac (13% vs 19%; p < 0.001) or piroxicam (10.3% vs 15.4%; p < 0.001). This was confirmed by a prescription-event monitoring study that found a relatively low incidence of dyspepsia, upper gastrointestinal haemorrhage and peptic ulcer (28.3, 0.4 and 0.3 per 1000 patient-months, respectively) among first-time users of meloxicam. In conclusion, meloxicam is at least as effective as nonselective NSAIDs in the treatment of rheumatic disease or postoperative pain, but has a more favourable gastrointestinal tolerability profile. Further investigations into the potential role of meloxicam as a cardioprotective agent are warranted
L-histidine decarboxylase decreases its own transcription through downregulation of ERK activity
Full text linkA poorly defined negative feedback loop decreases transcription of theL-histidine decarboxylase (HDC) gene. To help understand this regulation, we have studied the effect of HDC protein expression on HDC gene transcription in transfected AGS-B cells. Expression of the rat HDC protein inhibited HDC promoter activity in a dose-dependent fashion. The region of the HDC promoter mediating this inhibitory effect corresponded to a previously defined gastrin and extracellular signal-related kinase (ERK)-1 response element. Overexpression of the HDC protein reduced nuclear factor binding in this region. Experiments employing specific histamine receptor agonists indicated that the inhibitory effect was not dependent on histamine production, and studies with the HDC inhibitor α-fluoromethylhistidine revealed that inhibition was unrelated to enzyme activity. Instead, an enzymatically inactive region at the amino terminal of the HDC enzyme (residues 1–271) was shown to mediate inhibition. Fluorescent chimeras containing this domain were not targeted to the nucleus, arguing against specific inhibition of the HDC transcription machinery. Instead, we found that overexpression of HDC protein decreased ERK protein levels and ERK activity and that the inhibitory effect of HDC protein could be overcome by overexpression of ERK1. These data suggest a novel feedback-inhibitory role for amino terminal sequences of the HDC protei
Genetics and pharmacogenetics of aminergic transmitter pathways in functional gastrointestinal disorders
Full text linkFunctional gastrointestinal disorders (FGIDs) are highly prevalent syndromes, without evident underlying organic causes. Their pathogenesis is multifactorial in nature, with a combination of environmental and genetic factors contributing to their clinical manifestations, for which most of current treatments are not satisfactory. It is acknowledged that amine mediators (noradrenaline, dopamine and serotonin) play pivotal regulatory actions on gut functions and visceral sensation. In addition, drugs of therapeutic interest for FGIDs act on these transmitter pathways. The present article reviews current knowledge on the impact of genetics and pharmacogenetics of aminergic pathways on FGID pathophysiology, clinical presentations, symptom severity and medical management, in an attempt of highlighting the most relevant evidence and point out issues that should be addressed in future investigations
Interplay among gut microbiota, intestinal mucosal barrier and enteric neuro-immune system: a common path to neurodegenerative diseases?
Full text linkNeurological diseases, such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS) and multiple sclerosis, are often associated with functional gastrointestinal disorders. These gastrointestinal disturbances may occur at all stages of the neurodegenerative diseases, to such an extent that they are now considered an integral part of their clinical picture. Several lines of evidence support the contention that, in central neurodegenerative diseases, changes in gut microbiota and enteric neuro-immune system alterations could contribute to gastrointesinal dysfunctions as well as initiation and upward spreading of the neurologic disorder. The present review has been intended to provide a comprehensive overview of the available knowledge on the role played by enteric microbiota, mucosal immune system and enteric nervous system, considered as an integrated network, in the pathophysiology of the main neurological diseases known to be associated with intestinal disturbances. In addition, based on current human and pre-clinical evidence, our intent was to critically discuss whether changes in the dynamic interplay between gut microbiota, intestinal epithelial barrier and enteric neuro-immune system are a consequence of the central neurodegeneration or might represent the starting point of the neurodegenerative process. Special attention has been paid also to discuss whether alterations of the enteric bacterial-neuro-immune network could represent a common path driving the onset of the main neurodegenerative diseases, even though each disease displays its own distinct clinical features
Role of peripheral GABAB receptors in the regulation of pepsinogen secretion in anaesthetized rats
Full text linkThe purpose of the present study was to investigate the role played by GABAB receptors in the regulation of gastric basal pepsinogen secretion in anaesthetized rats. Following parenteral administration, the GABAB receptor agonists (-)-baclofen and 3-aminopropylphosphinic acid (3-APPA) caused a dose-dependent increase in basal pepsinogen secretion which was associated with a parallel increment in acid output. The gastric stimulant effects induced by both agonists were not affected by intracerebroventricular injection of the GABAB receptor antagonists 2-hydroxy-saclofen, 3-aminopropyl(diethoxymethyl)phosphinic acid (CGP 35348) or phaclofen, whereas the excitatory actions were antagonized by intravenously administered 2-hydroxy-saclofen or CGP 35348, but not phaclofen. In addition, the (-)-baclofen-induced increases in both pepsinogen and acid output, were fully prevented by omeprazole or cimetidine, partly reduced by atropine and unaffected by pretreatment with capsaicin. When tested on rats undergoing bilateral cervical vagotomy, both (-)-baclofen and 3-APPA were still able to stimulate the basal pepsinogen and acid secretions, although at a lesser extent than in animals with intact vagus nerves. The stimulant actions elicited by (-)-baclofen in vagotomized rats were antagonized by 2-hydroxy-saclofen or CGP 35348, but not phaclofen. Moreover, these gastric excitatory effects were prevented by cimetidine or compound 48/80, while being unaffected by atropine. The present results show that peripheral GABAB receptors mediate an excitatory effect on gastric pepsinogen secretion which totally depends on an increase in acid output. It is also suggested that both vagal cholinergic and extravagal pathways, probably histaminergic in nature, take part in these GABAB receptor-mediated gastric stimulant actions
Somatostatin modulates both cyclooxygenase-2 expression and proliferation in human colon cancer cells
No full textPharmacological modulation of adenosine receptor pathways and inflammatory disorders: the way towards novel therapeutics?
Full text linkAbstract non previsto dalla rivista per questo tipo di articol
A holistic view of adenosine pathways in the control of intestinal neuromuscular functions: the enteric purinome concept
Full text linkAdenosine is involved in the modulation of enteric neuromuscular functions, operating a fine tuning of smooth muscle contractility, peristaltic reflex and transit. In this issue of the BJP, Zizzo et al. report novel findings on the expression of adenosine receptors in mouse duodenum, extending our knowledge of their involvement in the control of spontaneous and neurogenic intestinal motility. In this study, particular attention was paid to the differential activation of adenosine receptors, as a result of their interplay with regulatory systems, modulating the availability of endogenous adenosine in a compartmentalised manner. This evidence will contribute to the holistic evaluation of the role played by adenosine in the regulation of intestinal motility, in accordance with the novel concept of the enteric 'purinome'. This commentary discusses the role of the 'purinome' in the modulation of enteric neuromuscular activity, pointing out its involvement in the intestinal neuroplasticity associated with bowel dysmotility
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