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M Storr

Publications and source records attributed to M Storr.

At least 19 recordsLinked to original sources
PubMed2006

STW 5 (Iberogast) and its individual herbal components modulate intestinal electrophysiology of mice.

STW 5 (Iberogast), a phytomedicine agent consisting of a fixed combination of nine individual plant extracts, is widely used in the treatment of dyspepsia and motility related disorders. Little if anything is known on the possible influence on electrophysiological properties of intestinal smooth muscle by which STW 5 causes its beneficial effects. The aim of the present study was to investigate whether herbal extracts influence electrophysiological parameters of large and small intestine. For this purpose intracellular recordings of smooth muscle cell (SMC) of the circular muscle layer of different parts of mouse intestine were performed using standard microelectrode techniques. The resting membrane potential (RMP), excitatory and inhibitory neurotransmission in proximal colon, the frequency and the amplitude of slow waves in small intestine were investigated. The RMP of SMC was -46.4+/-3.8 mV, n=11 in the colon and -59+/-1.3 mV, n=15 in small intestine. STW 5 significantly depolarized the RMP of colonic (16.6+/-2.2 mV, n=6, p<0.05) and jejunal (9.6+/-1.6 mV, n=7, p<0.05) SMC. This depolarizing effect can be mainly attributed to the constituents of chamomile flower, Angelica root and greater celandine herb. Following the electrical field stimulations (EFSs), junction potentials are influenced in a distinct manner. Excitatory junctions potentials (EJPs) of the colon were not significantly reduced (13.1+/-4.8 vs. 10.1+/-2.8 n.s., n=6) but fast (fIJP) and slow (sIJP) inhibitory junction potentials of the murine colon are reduced significantly by STW 5 (fIJP: 21.6+/-8.1 vs. 11.6+/-2.1 and sIJP: 12.1+/-3.3 vs. 6.1+/-1.3 n=6, p<0.05). The basal frequency of small intestinal slow waves was 39.5+/-1.4 min(-1) and the amplitude was 23.1+/-0.9 mV, n=15. STW 5 significantly reduced amplitude and frequency of the slow waves (11.7+/-0.8 mV; 33.5+/-3.4 min(-1), n=6, p<0.05). This effect on slow waves represents the summation of effects of the nine individual phytoextracts. Whereas Angelica root and chamomile flower completely blocked the slow wave activity, bitter candy tuft increased the frequency and amplitude, greater celandine herb reduced frequency and amplitude of the slow wave, peppermint leaf reduced frequency and left amplitude unchanged and liquorice root, caraway fruit and lemon balm leaf had no effects in basic electrophysiological properties of SMC. This study demonstrates that STW 5 causes changes in SMC RMP, excitatory and inhibitory neurotransmission and slow wave rhythmicity. These effects represent a summation effect of different constituents of this phytotherapeuticum and prove that STW 5 has characteristic effects on intestinal electrophysiology.

Animals↗
PubMed2006

CB1 and TRPV1 receptors mediate protective effects on colonic electrophysiological properties in mice.

CB1 and TRPV1 receptors modulate enteric neurotransmission and colonic inflammation. This study investigates early electrophysiological changes in distal colon of wild-type and receptor deficient mice after an inflammatory insult set by dinitrobenzene sulfonic acid (DNBS). Colitis was induced by DNBS in CB1(-/-) mice, TRPV1(-/-) mice, and their respective wild-type littermates. Electrophysiological properties consisting of membrane potentials and electrically induced inhibitory junction potentials (IJP) of circular smooth muscle cells were evaluated at different time points. Additionally a histological colitis severity score was evaluated in CB1(+/+) and CB1(-/-) mice 24 h after DNBS. Inflammation caused spontaneous atropine insensitive rhythmic action potentials in CB1(-/-) and TRPV1(-/-) mice but not in wild-type animals. This indicates that membrane stability is disturbed, which in turn indicates a lack of protective mechanisms. Focal electrical neuronal stimulation of the myenteric plexus induced IJP in the smooth muscle cells. Twenty-four hours after initiation of inflammation, the duration of the IJP is prolonged in all animals, indicating disturbances within neuromuscular interaction. In CB1(-/-) mice, it is interesting that the duration of IJP was significantly extended, as compared to CB1(+/+) mice pointing toward missing protective mechanisms in the CB1(-/-) mice. Inflammatory insults in the mouse colon induce reproducible changes in the electrophysiological properties and such changes correlate with duration of colitis. In mutants, these electrophysiological changes display different patterns, suggesting the lack of protective properties for neuromuscular interactions and membrane stability.

Action Potentials↗
PubMed2006

[Perspectives of cannabinoids in gastroenterology].

In early cultures, extracts of the plant Cannabis sativa were medically used for the treatment of gastrointestinal symptoms like nausea, vomiting, diarrhoea and abdominal pain. In the United States cannabis extracts were frequently used as drugs, e. g., for the treatment of diarrhoea, until around 1920. The possibility of cannabis abuse resulted in a worldwide prohibition and thus the temporary ending of the medical use of cannabinoids. The characterisation of an endogenous cannabinoid system consisting of receptors, endogenous agonists, antagonists and degrading enzymes opens the door for a comeback of cannabinoids in medicine. The clinically proven effects in the treatment of pain, cachexia in conjunction with HIV, or malignant disease and treatment of nausea and vomiting in conjunction with chemotherapy now result in the prescription of cannabinoids as valuable medication. This review will discuss the value of cannabinoids in the treatment of nausea and vomiting, i. e., the indications for which cannabinoids are presently used in gastroenterology. Additionally, this review will discuss potential indications within gastroenterology, where results from basic research or individual observations suggest that a future use of cannabinoids in gastroenterology seems possible.

Cannabinoids↗
PubMed2005

Vanilloid receptor (TRPV1)-deficient mice show increased susceptibility to dinitrobenzene sulfonic acid induced colitis.

In the human colon, vanilloid receptor TRPV1 is overexpressed both in afferent nerve terminals and in epithelial cells during inflammation. In the past years, pharmacological experiments using TRPV1 agonists and antagonists revealed that TRPV1 receptors may play proinflammatory and protective roles in the gastrointestinal tract. Here, we applied a genetic approach to define the role of TRPV1 and analyzed the effects of dinitrobenzene sulfonic acid (DNBS)-induced colitis in TRPV1-deficient (TRPV1-/-) mice. Intrarectal infusion of DNBS induced increased inflammation in TRPV1-/- mice compared to wild-type littermates (TRPV1+/+) as evaluated by macroscopic scoring and myeloperoxidase assays. This finding indicates that TRPV1 receptors are required for the protection within sensory pathways that regulate the response following the initiation of colonic inflammation. Electrophysiological recordings from circular smooth-muscle cells, performed 8 and 24 h after DNBS treatment, revealed strong spontaneous oscillatory action potentials in TRPV1-/- but not in TRPV1+/+ colons, indicating an early TRPV1-mediated control of inflammation-induced irritation of smooth-muscle activities. These unexpected results suggest that TRPV1 receptors mediate endogenous protection against experimentally induced colonic inflammation.

Animals↗
PubMed2005

Endogenous glucagon-like peptide 1 controls endocrine pancreatic secretion and antro-pyloro-duodenal motility in humans.

BACKGROUND: Exogenous use of the intestinal hormone glucagon-like peptide 1 (GLP-1) lowers glycaemia by stimulation of insulin, inhibition of glucagon, and delay of gastric emptying. AIMS: To assess the effects of endogenous GLP-1 on endocrine pancreatic secretion and antro-pyloro-duodenal motility by utilising the GLP-1 receptor antagonist exendin(9-39)amide (ex(9-39)NH2). METHODS: Nine healthy volunteers underwent four experiments each. In two experiments with and without intravenous infusion of ex(9-39)NH2 300 pmol/kg/min, a fasting period was followed by intraduodenal glucose perfusion at 1 and 2.5 kcal/min, with the higher dose stimulating GLP-1 release. Antro-pyloro-duodenal motility was measured by perfusion manometry. To calculate the incretin effect (that is, the proportion of plasma insulin stimulated by intestinal hormones) the glycaemia observed during the luminal glucose experiments was mimicked using intravenous glucose in two further experiments. RESULTS: Ex(9-39)NH2 significantly increased glycaemia during fasting and duodenal glucose. It diminished plasma insulin during duodenal glucose and significantly reduced the incretin effect by approximately 50%. Ex(9-39)NH2 raised plasma glucagon during fasting and abolished the decrease in glucagon at the high duodenal glucose load. Ex(9-39)NH2 markedly stimulated antroduodenal contractility. At low duodenal glucose it reduced the stimulation of tonic and phasic pyloric motility. At the high duodenal glucose load it abolished pyloric stimulation. CONCLUSIONS: Endogenous GLP-1 stimulates postprandial insulin release. The pancreatic alpha cell is under the tonic inhibitory control of GLP-1 thereby suppressing postprandial glucagon. GLP-1 tonically inhibits antroduodenal motility and mediates the postprandial inhibition of antral and stimulation of pyloric motility. We therefore suggest GLP-1 as a true incretin hormone and enterogastrone in humans.

Adult↗
PubMed2005

[Injection of botulinum toxin for diffuse esophageal spasm].

HISTORY AND ADMISSION FINDINGS: A 67-year-old man complained of recurrent retrosternal pain for 3 - 5 minutes as the only symptom for 3 - 4 years. Only when dysphagia occurred in the course of the disease was a gastroenterologist consulted. INVESTIGATIONS: The diagnosis of diffuse esophageal spasm was confirmed by esophageal manometry and radiology. Upper gastrointestinal endoscopy revealed no further pathological findings. TREATMENT AND COURSE: 100 units of botulinum toxin were injected in 10 divided doses, into the tubular esophagus, 1 cm apart, beginning at the z-line of the gastroesophageal junction, deeply into the muscular coat of the posterior part of the esophageal wall. This achieved improvement of symptoms as well as esophageal transit time measured by scintigraphy. The symptomatic benefit has now lasted for several months. CONCLUSION: The treatment of patients with diffuse esophageal spasm with botulinum toxin is a promising therapeutic option, which can be safely performed in such patients. But this regime needs evaluation in controlled prospective clinical studies.

Aged↗
PubMed2005

Herbal extracts modulate the amplitude and frequency of slow waves in circular smooth muscle of mouse small intestine.

BACKGROUND: Herbal preparations like STW 5 (Iberogast) are widely used drugs in the treatment of dyspepsia and motility-related disorders of the gastrointestinal tract. STW 5 is a phytotherapeutic agent consisting of a fixed mixture of 9 individual plant extracts. The electrophysiological mechanisms of action of STW 5 remain obscure. AIM: The aim of the present study was to investigate whether herbal extracts influence electrophysiological parameters of the small intestine. For this purpose, the resting membrane potential (RMP) and the slow wave rhythmicity of smooth muscle cells of mouse small intestine were observed. METHODS: Intracellular recordings of smooth muscle cells of the circular muscle layer of mouse small intestine were performed using standard microelectrode techniques. After dissection of the mucosa, the small intestine was placed in an organ bath and a microelectrode was applied on a circular smooth muscle cell. The RMP and the amplitude of slow waves were measured in millivolts. RESULTS: The RMP of smooth muscle cells was -59 +/- 1.3 mV. This RMP was significantly depolarized by STW 5 (9.6 +/- 1.6 mV); the depolarizing effects can be mainly attributed to the constituents of matricariae flos, angelicae radix and chelidonii herba. The basal frequency of small intestinal slow waves was 39.5 +/- 1.4 min(-1) and the amplitude was 23.1 +/- 0.9 mV. STW 5 significantly reduced the amplitude and frequency of the slow waves (11.7 +/- 0.8 mV; 33.5 +/- 3.4 min(-1)). This effect on slow waves represents the sum of the effects of the 9 phytoextracts. Whereas angelicae radix and matricariae flos completely blocked slow wave activity, Iberis amara increased the frequency and amplitude, chelidonii herba reduced the frequency and amplitude of the slow waves, mentae piperitae folium reduced the frequency and left amplitude unchanged and liquiritae radix, carvi fructus and melissae folium had no effects. CONCLUSION: Herbal extracts cause changes in smooth muscle RMP and slow wave rhythmicity, up to reversible abolition, by blockade of large conductance Ca2+ channels and other not yet identified mechanisms. In herbal preparations like STW 5 these effects add up to a total effect and this study indicates that herbal preparations which are widely used in dyspepsia and motility-related disorders have characteristic, reproducible, reversible effects on small intestinal electrophysiology.

Animals↗
PubMed2005

[Clinically relevant breath tests in gastroenterological diagnostics--recommendations of the German Society for Neurogastroenterology and Motility as well as the German Society for Digestive and Metabolic Diseases].

H (2)- and (13)C-breath tests are valuable non-invasive diagnostic tools for gastroenterological diseases. H (2)-breath tests are clinically established for the diagnosis of carbohydrate intolerance resulting from malabsorption (H (2)-breath tests with lactose, fructose, saccharose, sorbitol), of bacterial overgrowth (glucose H (2)-breath test) and for measurement of orcoceal transit time (lactulose H (2)-breath test). The (13)C-urea breath test is regarded as the "gold standard" procedure for the diagnosis of Helicobacter pylori infection. Moreover, (13)C-breath tests for measurement of gastric emptying can be considered as clinically established, meanwhile. (13)C-breath tests for the evaluation of pancreatic exocrine function or liver function can also be used clinically; however, they currently offer no substantial advantage over other diagnostic procedures. A major disadvantage of all breath tests is that they lack standardization although modifications of the test meal or solution, of the test performance and of the evaluation of data may markedly influence the results. Thus, this article presents the recommendations of the German Society of Neurogastroenterology and Motility and of the German Society of Digestive and Metabolic Diseases for clinically relevant H (2)- and (13)C-breath tests. Indications for the examinations, the procedures to be followed, the analysis of the obtained data and the conclusions to be drawn are delineated. The literature on which the recommendations are based is reviewed. However, personal experience of the authors is also taken into account since numerous questions regarding optimal test performance are not clarified by adequate studies.

Breath Tests↗
PubMed2004

[Irritable bowel syndrome: the challenge to psychosomatic and internal medical specialists to collaborate closely].

The irritable bowel syndrome is a ubiquitous disease that usually exhibits a close affinity to the group of somatoform disorders. Chronic cases in particular often suffer from psychological disturbances, and consult numerous different medical, mainly internistic-gastroenterological, treatment centers, not infrequently with no lasting success. Although the importance of gastroenterological pathophysiological aspects is beyond doubt, an early interdisciplinary diagnostic work-up--with explicit involvement of the psychosomatic-psychotherapeutic specialty--is urgently recommended. Against the background of moderate concomitant medication, a psychosomatic-psychotherapeutic treatment regimen has proven successful.

Antidepressive Agents↗
PubMed2004

Lower esophageal sphincter pressure in patients with gastroesophageal reflux diseases and posture and time patterns.

Gastroesophageal reflux disease is caused predominantly by lower esophageal sphincter insufficiency. Reports suggest that it is possible to distinguish between two main mechanisms causing reflux: low basal sphincter pressure leading to free reflux, mostly occurring at night in the supine position, and increased transient lower esophageal sphincter relaxations with normal or increased resting pressure leading to reflux during the day in an upright position. Lower esophageal sphincter pressure (LESP)-- s determined by stationary pull-through manometry--was compared to profiles of acidic reflux measured by 24-h pH monitoring in 207 patients with proven gastroesophageal reflux disease. Differences in LESP were not significant among patients with reflux predominantly during the day in an upright position and those with reflux predominantly at night in a supine position (16.1 +/- 7.4 mmHg versus 15.1 +/- 7.8 mmHg; t-test: P = 0.355). For both patterns of LESP, there was a slight negative correlation with the amount of acidic reflux (determined as a percentage of time with pH < 4). Pearson correlation coefficients were -0.196 for upright refluxers and -0.137 for bipositional/supine refluxers (P = 0.006 and P = 0.049, respectively). As there are no differences in LESP with regard to posture or time patterns of acidic reflux it seems unlikely that upright reflux is associated with increased LESP, whereas supine reflux manifests due to a hypotensive LESP. Alternatively, it may be concluded that stationary pull-through manometry is inadequate for determining the cause of gastroesophageal reflux disease and is therefore of limited use in its routine diagnosis.

Adult↗
PubMed2004

Pharmacologic management and treatment of gastroesophageal reflux disease.

Gastroesophageal reflux disease (GERD) is one of the most common diagnoses in daily practice. Diagnosis can be made on symptom evaluation, on pH-monitoring or on endoscopic findings. In contrast to commonly held opinion there is no strong evidence that lifestyle factors are a dominant factor in the pathophysiology of GERD. The various agents currently used for treatment of GERD include mucoprotective substances, antacids, H(2)-blockers and proton pump inhibitors. This article gives an overview of the pharmacological management of GERD and focuses on the differential therapy of endoscopy-negative GERD, GERD with esophagitis and maintenance therapy.

Gastroesophageal Reflux↗
PubMed2003

Cannabinoid receptor type 1 modulates excitatory and inhibitory neurotransmission in mouse colon.

The effects of cannabinoid receptor agonists and antagonists on smooth muscle resting membrane potentials and on membrane potentials following electrical neuronal stimulation in a myenteric neuron/smooth muscle preparation of wild-type and cannabinoid receptor type 1 (CB1)-deficient mice were investigated in vitro. Double staining for CB1 and nitric oxide synthase (neuronal) was performed to identify the myenteric CB1-expressing neurons. Focal electrical stimulation of the myenteric plexus induced a fast (f) excitatory junction potential (EJP) followed by a fast and a slow (s) inhibitory junction potential (IJP). Treatment of wild-type mice with the endogenous CB1 receptor agonist anandamide reduced EJP while not affecting fIJP and sIJP. EJP was significantly higher in CB1-deficient mice than in wild-type littermate controls, and anandamide induced no effects in CB1-deficient mice. N-arachidonoyl ethanolamide (anandamide), R-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3,-de]- 1,4-benzoxazin-6-yl]-1-naphtalenylmethanone, a synthetic CB1 receptor agonist, nearly abolished EJP and significantly reduced the fIJP in wild-type mice. N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyrazole-caroxamide (SR141716A), a CB1-specific receptor antagonist, was able to reverse the agonist effects induced in wild-type mice. SR141716A, when given alone, significantly increased EJP in wild-type mice without affecting IJP in wild-type and EJP in CB1-deficient mice. Interestingly, SR141716A reduced fIJP in CB1-deficient mice. In the mouse colon, nitrergic myenteric neurons do not express CB1, implying that CB1 is expressed in cholinergic neurons, which is in line with the functional data. Finally, excitatory and inhibitory neurotransmission in the mouse colon is modulated by activation of CB1 receptors. The significant increase in EJP in CB1-deficient mice strongly suggests a physiological involvement of CB1 in excitatory cholinergic neurotransmission.

Animals↗
PubMed2003

Endogenous CCK depresses contractile activity within the ascending myenteric reflex pathway of rat ileum.

The ascending excitatory reflex is an important part of the myenteric reflex. In order to study the ascending neural pathways, isolated segments of rat ileum were stimulated by electrical stimulation of the gut wall (20 V, 3 pulses per second, 1 ms) using platinum electrodes. The excitatory contractile response was recorded using perfused manometric side-hole tubing located 2 and 4 cm orally to the stimulation site. The contractile response to electrical stimulation was abolished by atropine (10(-6) M) or hexamethonium (10(-4) M). The excitatory response increased after administration of the cholecystokinin A (CCK(A)) receptor antagonists lorglumide (3x10(-6) M: +44.1%), devazepide (10(-8) M: +19.4%; 10(-7) M: +30.0%) and SR-27897 (10(-10) M: +21.8%, 10(-8) M: +47.0%, P<0.05, n=8). However, the CCK(B) receptor antagonist L-365,260 also caused a significant increase in the oral excitation (10(-6) M: +27.4%). sCCK-8 caused a significant reduction in the ascending response (10(-8) M: -11.5%) and induced spontaneously occurring contractions at doses ranging from 10(-10)-10(-6) M. CCK-9 significantly increased the ascending response (10(-7) M: +10.9%, P<0.05). However, caerulein (10(-10) M: -25.9%, 10(-8) M: -26.8%; P<0.01) and pentagastrin (10(-10) M: -20.2%, P<0.05; 10(-8) M: -23.7%, P<0.01; 10(-6) M: -28.3%, P<0.001) reduced the ascending contractile response significantly. These data, obtained with potent and highly specific CCK receptor antagonists, demonstrate an inhibitory role of endogenously released CCK within the ascending neural pathway. The data further suggest that exogenously applied CCK-related peptides have different effects on the myenteric reflex which might be due to excitation of the different involved neurons (short and long ascending inter- and motorneurons) in an unphysiological order. Thus in experiments investigating more complex neuronal circuits, experiments with antagonists should be regarded as more specific.

Animals↗
PubMed2002

Treatment of achalasia: the short-term response to botulinum toxin injection seems to be independent of any kind of pretreatment.

BACKGROUND: It has been suggested that intrasphincteric injection of botulinum toxin (BTX) may represent an alternative therapy to balloon dilatation in achalasia. The aim of the present study was to test the effectiveness of botulinum toxin injections in achalasia patients, as assessed using lower oesophageal sphincter pressure (LOSP) and symptom scores, and to compare the response in patients with different types of pretreatment (no previous treatment, balloon dilatation, myotomy, BTX injection). METHODS: Forty patients who presented with symptomatic achalasia were treated with BTX injection (48 injections in 40 patients). Some of the patients had received prior treatment (seven with myotomy, seven with dilatation and eight with BTX). The symptoms were assessed using a global symptom score (0-10), which was evaluated before treatment, 1 week afterwards, and 1 month afterwards. Manometry was also carried out before and after treatment. Three different selections of patients were studied: all patients; untreated patients; and patients with prior BTX, dilatation, or myotomy. RESULTS: After BTX injection, there was a significant reduction in LOSP (before, 38.2+/-11.3 mmHg; 1 week after, 20.5+/-6.9 mmHg; 1 month after, 17.8+/-6.8 mmHg; P < 0.001). The global symptom score and symptom subscores (dysphagia, regurgitation, chest pain) were significantly decreased after 1 week and 1 month. When the beneficial effects following BTX injection were compared (untreated vs. pretreated), neither changes in LOSP nor beneficial effects on the symptom scores significantly differed. After 6 months, 67.7% of all treated patients were still in symptomatic remission (subgroups: previously untreated patients, 61.5%, n = 26; prior dilatation, 71.4%, n = 7; prior myotomy, 71.4%, n = 7; prior BTX, 73.9%, n = 8). CONCLUSIONS: BTX injection offers an alternative treatment for achalasia which is safe and can be performed in an outpatient setting. The initial response to BTX, in terms of symptom scores and LOSP, appears to be independent of any prior treatment. A number of patients do not adequately respond to balloon dilatation or myotomy, which are the first-line treatment modalities in achalasia patients. BTX injection can be performed in these patients, and symptomatic benefit can be expected in the same percentages as with BTX injection in untreated patients.

Adult↗
PubMed2002

Endomorphins 1 and 2 reduce relaxant non-adrenergic, non-cholinergic neurotransmission in rat gastric fundus.

It is now well established that opioids modulate cholinergic excitatory neurotransmission in the gastrointestinal tract. The aim of the present study was to characterize a possible effect of endomorphins on nonadrenergic, noncholinergic (NANC) relaxant neurotransmission in the rat gastric fundus in vitro. The drugs used in the experiments were the endogenous mu-opioid receptors (MORs) endomorphin 1 and 2 and the mu-opioid receptor antagonist CTAP (D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2). CTAP left the basal tonus and the spontaneous activity of the preparation unchanged. Electrical field stimulation (EFS) under NANC conditions at frequencies ranging from 0.5 to 16 Hz caused a frequency-dependent relaxant response on the 5-hydoxytryptamine (5-HT) (10(-7) M) precontracted smooth-muscle strip. Both endomorphin 1 and endomorphin 2 significantly reduced this relaxation in a concentration-dependent manner. Endomorphin 1 proved to be more potent in reducing the relaxant responses. The endomorphin effects were significantly reversed by the MOR antagonist CTAP. CTAP itself did not influence the EFS-induced relaxation. In summary, these data provide evidence that the endogenous MOR agonists endomorphin 1 and 2 can reduce nonadrenergic, noncholinergic neurotransmission in the rat gastric fundus smooth muscle via a pathway involving MORs. The physiological relevance of these findings remains to be established, since the data presented suggest that the endomorphins act as neuromodulators within NANC relaxant neurotransmission.

Analgesics, Opioid↗
PubMed2002

Melatonin reduces non-adrenergic, non-cholinergic relaxant neurotransmission by inhibition of nitric oxide synthase activity in the gastrointestinal tract of rodents in vitro.

The aim of the present study was to investigate the effects of melatonin on non-adrenergic, non-cholinergic (NANC) relaxant neurotransmission in the gastrointestinal tract, which is mainly mediated by nitrergic and peptidergic mechanisms. Melatonin (10(-7)-10(-3) M) had no effect on the basal tonus of the rat gastric fundus smooth muscle. Relaxant responses following electrical stimulation(40 V; 0.5 ms pulse duration; 10 s stimulation duration) under NANC conditions on a 5-hydroxytryptamine (5-HT, 10(-7) M) contraction plateau were elicited at frequencies in the range of 0.5-16 Hz. Melatonin significantly reduced these inhibitory NANC responses (16 Hz without melatonin: -103 +/- 6.3%; melatonin 10(-5) M: -80.4 +/- 7.5%; melatonin 10(-4) M: -39.1 +/- 17.1%). Intracellular recording was carried out in a mouse colonic preparation. Electrical neural stimulation of the mouse colonic neurons caused biphasic intracellular hyperpolarization in smooth-muscle cells. The initial fast component is apamin-sensitive, and the following slow component is dependent on nitrergic mechanisms, as it is abolished in the presence of NG-nitro-L-arginine (L-NNA). Melatonin significantly reduced the nitric oxide-dependent slow component of neurally transmitted hyperpolarization, whereas the initial fast component was left unchanged. In a synaptosomal preparation of the enteric nervous system of rat intestine, enzymatic nitric oxide synthase (NOS) activity was significantly reduced by melatonin at concentrations ranging from 10(-7) to 10(-4) M (basal preparation including cofactors: 61.2 +/- 9.4 fmol/mg; melatonin 10(-4) M: 39.2 +/- 6.9 fmol/mg). Reverse transcriptase-polymerase chain reaction (RT-PCR) studies were conducted to investigate the melatonin receptors (mt(1), MT(2) and MT(3)) present in the esophagus, stomach and ileum of the rat. The presence of mt1 mRNA expression alone, but not of mRNA expression for MT(2) or MT(3), was demonstrated in the tissues. In conclusion, this study demonstrates that melatonin reduces the functional inhibitory NANC response. It shows that this effect may be the result of a reduction of the nitrergic component of the smooth-muscle inhibitory junction potential (IJP) and related to direct inhibition of NOS activity in enteric synaptosomes. The presence of mt1 receptor transcripts adds supportive evidence for a possible physiological role of melatonin within the enteric nervous system.

Adrenergic Agents↗
PubMed2002

Okadaic acid inhibits relaxant neural transmission in rat gastric fundus in vitro.

The aim of the present study was to characterize the influence of the phosphatase type 1 and 2A inhibitor okadaic acid on non-adrenergic, non-cholinergic (NANC) neurotransmission in the rat gastric fundus. Okadaic acid (10-6 M), an inhibitor of protein phosphatases 1 and 2A, did not show any influence on the basal tonus or on a contraction plateau induced by 5-HT (10-7 M) within 30 min of observation. When okadaic acid (10-6 M) was applied 10 min prior to 5-HT (10-7 M), the contraction plateau of serotonin was unchanged. To investigate the inhibitory neurotransmission, the muscle strips were pre-contracted using 5-HT (10-7 M), and inhibitory stimuli were applied at the contraction plateau, which was stable over 30 min. The inhibitory effects of vasoactive intestinal peptide (VIP), nitric oxide (NO) and electrical field stimulation (EFS, 40 V, 0.5 ms, frequencies ranging from 0.5 to 16 Hz) were examined. When okadaic acid (10-6 M) was applied prior to EFS-induced NANC relaxation, significant attenuation of the inhibitory response was demonstrated (16 Hz: control: -92.4 +/- 1.9%; okadaic acid 10-7 M: -60.7 +/- 6.1%; okadaic acid 10-6 M: -25.3 +/- 3.4%; n=11; P < 0.01). By contrast, neither the concentration-dependent inhibitory actions of VIP (10-11-10-8 M) (VIP 10-8 M: -100%; VIP 10-8 M + okadaic acid 10-6 M: -89.9 +/- 8.3%; n=8; n.s) nor that of diethylamine nitric oxide (DEA-NO) (3 x 10-7-10-4 M) (DEA-NO 10-4 M: -95.3 +/- 8.4%; DEA-NO 10-4 M + okadaic acid 10-7 M: -98.3 +/- 6.3%; DEA-NO 10-4 M + okadaic acid 10-6 M: 96.5 +/- 7.6%; n=9; n.s.) on 5-HT induced contraction were altered by pre-incubation with okadaic acid (10-6 M). This is the first report that supports the concept that protein phosphatases 1 and 2A may contribute to the regulation of rat gastric fundus motility. The protein phosphatase inhibitor okadaic acid significantly reduces electrically induced inhibitory NANC responses, while leaving direct muscular effects of the inhibitory NANC neurotransmitters VIP and NO unaffected - suggesting a neural site of action. The potential roles of protein phosphatases on NANC neurotransmission remain to be clarified in detail, as this might offer a new pathway for modulating smooth-muscle function.

Animals↗