Proliferative verrucous leukoplakia/multifocal leukoplakia in patients with and without oral submucous fibrosis.

BACKGROUND: Oral submucous fibrosis (OSF) and proliferative verrucous leukoplakia (PVL) are established as oral potentially malignant disorders. Dual pathology of the two conditions is not commonly encountered in clinical practice. This study aims to present a case series of multifocal leukoplakia in patients with and without OSF to outline the clinical behavior and challenges in the management of this high-risk group in clinical practice. MATERIAL AND METHODS: We retrospectively analyzed cases of six Indian patients (four with OSF) managed over a period of 5.5 to 13 years at the Government Dental College, Nagpur. Patient data consisting of age, gender, medical history, habits, clinical findings, and biopsy reports were recorded at the initial visit. During follow-up visits, the clinicopathological data were reassessed. When surgical intervention failed to arrest the disease or when surgery was contraindicated metronomic therapy with Folitrax 15 mg once a week and Celecoxib 100mg twice daily was initiated. RESULTS: All patients developed PVL after the initial pathology diagnosis of OSF or oral leukoplakia. Initial lesions were either homogenous or non-homogenous leukoplakia. All patients developed multiple recurrences, regional or systemic metastasis. Despite thorough interventions, the patients died of, or with the disease. CONCLUSIONS: The occurrence of two or more oral potentially malignant disorders poses challenges in patient management and possibly presents a higher risk of malignant transformation. More clinical trials are necessary to assess the benefits of metronomic therapy for patients diagnosed with aggressive PVL concurrently found with OSF.

Coming Up Short: Risks of Bias in Assessing Psychological Outcomes in Growth Hormone Therapy for Short Stature.

CONTEXT: Two often cited assumptions for treating children with GH are that short stature (SS), as an isolated physical characteristic, is associated with psychosocial morbidity and that GH treatment may increase height and improve psychological adjustment. Findings across studies regarding the psychological consequences associated with GH management of children with SS are variable and frequently contradictory. The purpose of this systematic review is to evaluate the degree to which any conclusions about the relative risks or benefits of GH treatment on psychological outcomes can be made based on the published literature. EVIDENCE ACQUISITION: Electronic databases were searched for randomized clinical trials and nonrandomized studies, published between 1958-2014, in which GH was administered for management of children with SS and psychosocial, cognitive, academic, or health-related quality of life outcomes were assessed. Methodological quality of each study was assessed using the Cochrane Collaboration's tool for assessing risk of bias. EVIDENCE SYNTHESIS: Eighty studies were evaluated. No studies were rated as having a low risk of bias, the risk of bias was unclear in seven study outcome areas, and the remaining studies were judged as having a high risk of bias. CONCLUSIONS: The high risk of bias present in the majority of the literature on GH treatment effects on psychological outcomes (in particular, lack of blinding) substantially weakens confidence in their results. This may serve to explain the variability of findings for these outcomes across studies.

Presynaptic inhibition of the release of multiple major central nervous system neurotransmitter types by the inhaled anaesthetic isoflurane.

BACKGROUND: Presynaptic effects of general anaesthetics are not well characterized. We tested the hypothesis that isoflurane exhibits transmitter-specific effects on neurotransmitter release from neurochemically and functionally distinct isolated mammalian nerve terminals. METHODS: Nerve terminals from adult male rat brain were prelabelled with [(3)H]glutamate and [(14)C]GABA (cerebral cortex), [(3)H]norepinephrine (hippocampus), [(14)C]dopamine (striatum), or [(3)H]choline (precursor of [(3)H]acetylcholine; striatum). Release evoked by depolarizing pulses of 4-aminopyridine (4AP) or elevated KCl was quantified using a closed superfusion system. RESULTS: Isoflurane at clinical concentrations (<0.7 mM; ~2 times median anaesthetic concentration) inhibited Na(+) channel-dependent 4AP-evoked release of the five neurotransmitters tested in a concentration-dependent manner. Isoflurane was a more potent inhibitor [expressed as IC(50) (SEM)] of glutamate release [0.37 (0.03) mM; P<0.05] compared with the release of GABA [0.52 (0.03) mM], norepinephrine [0.48 (0.03) mM], dopamine [0.48 (0.03) mM], or acetylcholine [0.49 (0.02) mM]. Inhibition of Na(+) channel-independent release evoked by elevated K(+) was not significant at clinical concentrations of isoflurane, with the exception of dopamine release [IC(50)=0.59 (0.03) mM]. CONCLUSIONS: Isoflurane inhibited the release of the major central nervous system neurotransmitters with selectivity for glutamate release, consistent with both widespread inhibition and nerve terminal-specific presynaptic effects. Glutamate release was most sensitive to inhibition compared with GABA, acetylcholine, dopamine, and norepinephrine release due to presynaptic specializations in ion channel expression, regulation, and/or coupling to exocytosis. Reductions in neurotransmitter release by volatile anaesthetics could contribute to altered synaptic transmission, leading to therapeutic and toxic effects involving all major neurotransmitter systems.

An audit of urology two-week wait referrals in a large teaching hospital in England.

INTRODUCTION: Two week wait referral guidelines have been published by the UK Department of Health for suspected urological cancers. Concordance to these guidelines is variable. Our objectives were to assess the incidence of urological malignancy and the proportion of inappropriate referrals in the two-week wait pathway. PATIENTS AND METHODS: Retrospective audit of all two-week wait referrals to the urology department over 6 months. Inappropriate referrals were those not satisfying the referral criteria, but referred under the two-week wait system. Detection rates were calculated for each referral criterion based on diagnosis obtained from histology, imaging reports and clinic letters. RESULTS: Incidence of cancer was 90 of 400 two-week wait referrals (23%). The cancer-detection rate based on reasons for referral ranged from 50 of 122 (41%) for elevated prostate-specific antigen levels to 2 of 56 (4%) for scrotal lumps; 42 (11%) referrals were inappropriate. CONCLUSIONS: The overall cancer-detection rate is acceptable. Most inappropriate referrals were for long-standing symptoms and non-specific testicular/scrotal symptoms. The testicular cancer detection rate raises questions about the two-week wait guidelines. Providing general practitioners with fast-track scrotal ultrasound and revising the guideline may reduce the disproportionately high number of patients referred with suspected testicular cancer. Other inappropriate referrals are a cause for concern as they add to the workload of the 'urgent-referral' pathway.

Histologic results 1 year after bioprosthetic repair of paraesophageal hernia in a canine model.

BACKGROUND: The use of prosthetic materials for the repair of paraesophageal hiatal hernia (PEH) may lead to esophageal stricture and perforation. High recurrence rates after primary repair have led surgeons to explore other options, including various bioprostheses. However, the long-term effects of these newer materials when placed at the esophageal hiatus are unknown. This study assessed the anatomic and histologic characteristics 1 year after PEH repair using a U-shaped configuration of commercially available small intestinal submucosa (SIS) mesh in a canine model. METHODS: Six dogs underwent laparoscopic PEH repair with SIS mesh 4 weeks after thoracoscopic creation of PEH. When the six dogs were sacrificed 12 months later, endoscopy and barium x-ray were performed, and biopsies of the esophagus and crura were obtained. RESULTS: The mean weight of the dogs 1 year after surgery was identical to their entry weight. No dog had gross dysphagia, evidence of esophageal stricture, or reherniation. At sacrifice, the biomaterial was not identifiable grossly. Biopsies of the hiatal region showed fibrosis as well as muscle fiber proliferation and regeneration. No dog had erosion of the mesh into the esophagus. CONCLUSIONS: This reproducible canine model of PEH formation and repair did not result in erosion of SIS mesh into the esophagus or in stricture formation. Native muscle ingrowth was noted 1 year after placement of the biomaterial. According to the findings, SIS may provide a scaffold for ingrowth of crural muscle and a durable repair of PEH over the long term.

The regulation of adiponectin receptors in human prostate cancer cell lines.

Obesity is a risk factor for prostate cancer, and plasma levels of the adipokine, adiponectin, are low in the former but high in the latter. Adiponectin has been shown to modulate cell proliferation and apoptosis, suggesting that adiponectin and its receptors (Adipo-R1, Adipo-R2) may provide a molecular association between obesity and prostate carcinogenesis. We show for the first time, the protein distribution of Adipo-R1 and Adipo-R2 in LNCaP and PC3 cells, and in human prostate tissue. Using real-time RT-PCR we provide novel data demonstrating the differential regulation of Adipo-R1 and Adipo-R2 mRNA expression by testosterone, 5-alpha dihydrotestosterone, beta-estradiol, tumour necrosis factor-alpha, leptin, and adiponectin in LNCaP and PC3 cells. Our findings suggest that adiponectin and its receptors may contribute to the molecular association between obesity and prostate cancer through a complex interaction with other hormones and cytokines that also play important roles in the pathophysiology of obesity and prostate cancer.

Results of laparoscopic Heller-Toupet operation for achalasia.

BACKGROUND: Laparoscopic myotomy has become the preferred treatment for achalasia. Controversy persists on the need for fundoplication and/or its type; when used, most series have utilized the Dor fundoplication. We report a large series of laparoscopic Heller-Toupet procedures. METHODS: All patients operated for achalasia were entered into a prospective database. Pre and postoperative esophageal symptoms, satisfaction scores, and SF-36 variables were compared. Surgical failures were defined as recurrent or persistent dysphagia leading to secondary treatment. Data are expressed as mean +/- S.D. RESULTS: One hundred consecutive cases were analyzed (61 men, 39 women, age 47 +/- 17 yr). Heller-Toupet was performed in 94, whereas six patients had a Dor fundoplication because of mucosal perforation (three) or technical difficulties performing a posterior wrap (three). Operative time was 148 +/- 21 min. There were 13 intraoperative adverse events managed laparoscopically, and no conversions. Minor postoperative complications were noted in two cases, whereas there were no major complications or deaths. Mean hospital stay was 1.2 +/- 0.5 days, (range 1-4). Follow-up was complete in 92% at 26 +/- 17 months. Failures leading to further treatment occurred in 4%. All symptom scores were significantly improved (p < 0.0001). Solid dysphagia score went from 6.4 to 1.0 postoperatively; regurgitation score went from 4.5 to 0.2 (combined frequency and severity, range 0-8). Postoperative global esophageal symptoms scale revealed improvement in 97%, and all domains of the SF-36 were improved. CONCLUSIONS: Although the best surgical approach to achalasia is yet to be determined, laparoscopic Heller-Toupet operation in experienced hands is a safe and effective procedure with low rates of morbidity and failure and high patient satisfaction.

Influence of spastic motor disorders of the esophageal body on outcomes from laparoscopic antireflux surgery.

BACKGROUND: The clinical outcomes of laparoscopic antireflux surgery (LARS) in patients with the spectrum of nonspecific spastic esophageal motor disorders (NSSDs) are not known. METHODS: From a prospective database of patients undergoing LARS between 1997 and 2000, those with preoperative manometry at our institution and follow-up at ?6 months were identified. RESULTS: Of the 121 patients, 35 had NSSDs. There were no differences in symptoms between groups preoperatively, but in the immediate postoperative period NSSD patients had more symptoms than nonspastic patients. At 18-month mean follow-up, NSSD patients reported significantly more heartburn (22% vs 7%), waterbrash (14% vs 4%), and medication usage (17% vs 5%) than nonspastic patients (p <0.05 for each). Despite this difference, nearly all patients reported subjective improvement postoperatively, and the degree of improvement was similar between groups. CONCLUSIONS: Patients with NSSDs are more likely to have esophageal symptoms following LARS than subjects without these abnormalities. However, these patients still experience significant improvement in preoperative symptoms.

Symptomatic outcomes of laparoscopic antireflux surgery in patients eligible for endoluminal therapies.

BACKGROUND: This study compared clinical outcomes after laparoscopic antireflux surgery (LARS) in patients with gastroesophageal reflux disease (GERD) who would be eligible for endoluminal therapies (ET) with those in patients who would be excluded from ET. METHODS: From 1995 to the present, 459 patients who underwent LARS were analyzed prospectively. Of these, 117 patients (25%) without preoperative dysphagia, stricture, esophagitis worse than grade 2 or hiatal hernia larger than 2 cm were considered potential candidates for ET (group 1). By these criteria, 342 patients (75%) were not eligible for ET (group 2). Medication use and GERD symptoms were evaluated and compared between the two groups. RESULTS: Perioperative outcomes including duration of operation, morbidity, length of hospital stay and return to work were similar in the two groups. Although LARS significantly reduced medication use and GERD symptoms in both groups during a mean follow-up period longer than 2 years, there were no outcome differences between groups 1 and 2. The reported improvement in esophageal symptoms and overall satisfaction was 90% or more in both groups. CONCLUSIONS: The findings show that LARS is an effective treatment option in patients with GERD whether they are candidates for ET or not. In patients with uncomplicated GERD who currently meet inclusion criteria for ET, LARS provides excellent symptom relief and marked reduction in medication use during a mean follow-up period longer than 2 years.

Endothelial dysfunction accompanies a pro-oxidant, pro-diabetic challenge in the insulin resistant, obese Zucker rat in vivo.

We have recently made the novel observation that a pro-oxidant challenge with hydroquinone in combination with buthionine sulfoximine (each at 50 mg/kg i.p. daily for 7 days) provokes the onset of type II diabetes mellitus in a model of insulin resistance, the obese Zucker rat. Since endothelial dysfunction in oxidant stress may aggravate in vivo insulin resistance, we have now investigated endothelium-dependent and nitric oxide (NO)-mediated vascular responses in the obese Zucker rat in vivo following this pro-oxidant insult. Pro-oxidant-treated animals exhibited defective vasodepression to the endothelium-dependent agent acetylcholine and to a lesser extent, the NO donor glyceryl trinitrate, together with a reduction in circulating levels of cGMP. Our data therefore suggest that the progression to type II diabetes mellitus in the obese Zucker rat mediated by a pro-oxidant insult is associated with impairments in agonist-stimulated, endothelium-dependent vasodilation and vascular NO signalling.

Pro-oxidant challenge in vivo provokes the onset of NIDDM in the insulin resistant obese Zucker rat.

We investigated the ability of an acute pro-oxidant challenge in vivo to deteriorate glycaemic control and insulin action in the obese Zucker rat, a model of insulin resistance associated with oxidant stress. In obese animals, the daily administration for 1 week of hydroquinone (HQ) in combination with L-buthionine sulphoximine (BSO), elevated fasting plasma glycaemia and insulinaemia and markedly aggravated i.v. glucose-stimulated hyperinsulinaemia without significantly affecting i.v. glucose tolerance, suggesting exacerbated insulin resistance. Intermediate effects on hyperinsulinaemia in obese animals were determined with HQ treatment alone while BSO treatment alone had no effect. In contrast, none of the pro-oxidant treatments affected age-matched, insulin sensitive, lean Zucker rats. Our data therefore demonstrate for the first time, a vulnerability to deterioration in insulin action in an established insulin resistant state following an environmental pro-oxidative insult. This may have relevance in the conversion of insulin resistance syndrome (IRS) to non-insulin dependent diabetes mellitus (NIDDM).

A new automated system for urine analysis: a simple, cost-effective and reliable method for distinguishing between glomerular and nonglomerular sources of haematuria.

OBJECTIVE: To determine the ability, reliability and accuracy of a new automated system of urine analysis in differentiating glomerular from nonglomerular bleeding in the initial investigation of haematuria, and compare its efficacy with conventional phase-contrast microscopy (PCM). PATIENTS AND METHODS: One hundred and six urine samples from patients in whom the final diagnosis was available were analysed using electrical flow impedance to detect, enumerate and size red blood cells in a conductive fluid (the cellfacts analyser, Microbial Systems Ltd, Coventry, UK). All the samples were also tested using a dipstick method and PCM was carried out for comparison on 45 of the 106 urine specimens. The results of cellfacts analysis were correlated with the final diagnoses to assess sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of this method; the costs were also analysed. RESULTS: Sixty-nine urine samples tested positive for blood on dipstick urine analysis and all these were confirmed to have red blood cells on cellfacts analysis. The remaining 37 samples were negative for blood on dipstick testing and cellfacts analysis, although seven patients had been referred with previously detected microscopic haematuria, none of whom were found to have any detectable pathology in the urinary tract on clinical examination and investigations. The remaining 30 patients were diagnosed to have urological or nephrological conditions with no haematuria. In the positive group, 20 (29%) patients were from the glomerular group, with a mean (range) red blood cell size of 4.25 (4-5.1) micrometer, and 49 (71%) from the nonglomerular group, with red blood cells of 5.47 (4.67-5.70) micrometer. These ranges overlapped at 4.67-5.1 micrometer at the decision threshold of 4.75 micrometer, the distribution of dysmorphic and eumorphic red blood cells for the glomerular group was 18 (90%) and two (10%), respectively, and for the nonglomerular group was 2 (4%) and 47 (96%), respectively. The sensitivity, specificity, PPV and NPV were 90%, 96%, 90% and 96%, respectively. Consumable and labour costs were very low. CONCLUSIONS: Cellfacts analysis is a simple, rapid, objective and cost-effective method for differentiating glomerular from nonglomerular urinary red blood cells, especially when few such cells are present.

Is the measurement of serum testosterone routinely indicated in men with erectile dysfunction?

OBJECTIVE: To investigate the usefulness of serum testosterone levels as a relevant or useful indicator of sexual potency in men attending an erectile dysfunction clinic. PATIENTS AND METHODS: Ninety consecutive men attending the erectile dysfunction clinic completed a sexual-activity questionnaire, and underwent a focused physical examination and questioning about their medical history. The serum testosterone level was measured in all patients and the results analysed in relation to the patient's age. Patients with low serum testosterone levels commenced replacement therapy comprising three intramuscular injections of testosterone (Sustanontrade mark, Organon, The Netherlands) 250 mg every third week. Potency status and serum testosterone were reassessed after 3 months' treatment. RESULTS: Of the 90 men, 28 (31%) were aged < 50 years whilst 62 (69%) were >/=50 years old. Nineteen (21%) patients overall had low testosterone levels; four of these were < 50 and 15 were >/=50 years old. Five of 90 patients had a decreased libido; two of these also had low testosterone levels and all were < 50 years old. Testosterone levels returned to normal in all patients who received replacement therapy but potency returned in only two (10%); both were in the older group. CONCLUSION: Measuring testosterone was not helpful in assessing potency or libido and low serum levels were not related to age. Correcting low testosterone did not improve either impotence or libido.

F2-isoprostane evidence of oxidant stress in the insulin resistant, obese Zucker rat: effects of vitamin E.

We have concurrently investigated oxidant stress, glucose tolerance and glucose-stimulated insulin responses in the obese Zucker rat, a widely used model of insulin resistance. The plasma level of the lipid peroxidation product 8-epi-prostaglandin F2alpha, a sensitive in vivo marker of oxidant stress, was elevated approximately 5-fold in 13-week old obese relative to age-matched, insulin-sensitive lean Zucker rats. Supplementation of the diet with vitamin E (as (+)-alpha-tocopherol acetate, 0.5% w/w) for 4 weeks, reduced plasma 8-epi-prostaglandin F2alpha and concomitantly reversed glucose-stimulated hyperinsulinaemia in the obese Zucker rat without worsening glucose tolerance. We therefore provide evidence of oxidant stress, measured as elevated plasma 8-epi-prostaglandin F2alpha, for the first time in the obese Zucker rat which now provides a rationale for the beneficial effects of antioxidants on insulin action previously reported in this model of insulin resistance.

Nitric oxide synthase inhibitors attenuate transforming-growth-factor-beta 1-stimulated capillary organization in vitro.

Angiogenesis is a complex process involving endothelial cell (EC) proliferation, migration, differentiation, and organization into patent capillary networks. Nitric oxide (NO), an EC mediator, has been reported to be antigenic as well as proangiogenic in different models of in vivo angiogenesis. Our aim was to investigate the role of NO in capillary organization using rat microvascular ECs (RFCs) grown in three-dimensional (3D) collagen gels. RFCs placed in 3D cultures exhibited extensive tube formation in the presence of transforming growth factor-beta 1. Addition of the NO synthase (NOS) inhibitors L-nitro-arginine methylester (L-NAME, 1 mmol/L) or L-monomethyl-nitro-l-arginine (1 mmol/L) inhibited tube formation and the accumulation of nitrite in the media by approximately 50%. Incubation of the 3D cultures with excess L-arginine reversed the inhibitory effect of L-NAME on tube formation. In contrast to the results obtained in 3D cultures, inhibition of NO synthesis by L-NAME did not influence RFC proliferation in two-dimensional (2D) cultures or antagonize the ability of transforming growth factor-beta 1 to suppress EC proliferation in 2D cultures. Reverse transcriptase-polymerase chain reaction revealed the constitutive expression of all three NOS isoforms, neuronal, inducible, and endothelial NOSs, in 2D and 3D cultures. Moreover, Western blot analysis demonstrated the presence of immunoreactive protein for all NOS isoforms in 3D cultures of RFCs. In addition, in the face of NOS blockade, co-treatment with the NO donor sodium nitroprusside or the stable analog of cGMP, 8-bromo-cGMP, restored capillary tube formation. Thus, the autocrine production of NO and the activation of soluble guanylate cyclase are necessary events in the process of differentiation and in vitro capillary tube organization of RFCs.

Elevated blood pressures in mice lacking endothelial nitric oxide synthase.

Nitric oxide produced in endothelial cells affects vascular tone. To investigate the role of endothelial nitric oxide synthase (eNOS) in blood pressure regulation, we have generated mice heterozygous (+/-) or homozygous (-/-) for disruption of the eNOS gene. Immunohistochemical staining with anti-eNOS antibodies showed reduced amounts of eNOS protein in +/- mice and absence of eNOS protein in -/- mutant mice. Male or female mice of all three eNOS genotypes were indistinguishable in general appearance and histology, except that -/- mice had lower body weights than +/+ or +/- mice. Blood pressures tended to be increased (by approximately 4 mmHg) in +/- mice compared with +/+, while -/- mice had a significant increase in pressure compared with +/+ mice (approximately 18 mmHg) or +/- mice (approximately 14 mmHg). Plasma renin concentration in the -/- mice was nearly twice that of +/+ mice, although kidney renin mRNA was modestly decreased in the -/- mice. Heart rates in the -/- mice were significantly lower than in +/- or +/+ mice. Appropriate genetic controls show that these phenotypes in F2 mice are due to the eNOS mutation and are not due to sequences that might differ between the two parental strains (129 and C57BL/6J) and are linked either to the eNOS locus or to an unlinked chromosomal region containing the renin locus. Thus eNOS is essential for maintenance of normal blood pressures and heart rates. Comparisons between the current eNOS mutant mice and previously generated inducible nitric oxide synthase mutants showed that homozygous mutants for the latter differ in having unaltered blood pressures and heart rates; both are susceptible to lipopolysaccharide-induced death.

The Golgi association of endothelial nitric oxide synthase is necessary for the efficient synthesis of nitric oxide.

The particulate enzyme, endothelial nitric oxide synthase (eNOS), produces nitric oxide to maintain normal vasodilator tone in blood vessels. In this study, we demonstrate that eNOS is a Golgi-associated protein in cultured endothelial cells and intact blood vessels. Using a heterologous expression system in HEK 293 cells, we show that wild-type myristoylated and palmitoylated eNOS, but not mutant, non-acylated eNOS targets to the Golgi. More importantly, HEK 293 cells expressing wild-type eNOS release substantially more NO than cells expressing the mutant, non-acylated enzyme. Thus, eNOS is a novel Golgi-associated protein, and Golgi compartmentalization is necessary for the enzyme to respond to intracellular signals and produce NO.

Nitric oxide, and not vasoactive intestinal peptide, as the main neurotransmitter of vagally induced relaxation of the guinea pig stomach.

1. Nitric oxide synthase (NOS) was localized in the guinea pig stomach by immunocytochemistry. In vitro experiments were carried out on the isolated stomach of the guinea pig to study any possible links between nitric oxide (NO) and vasoactive intestinal peptide (VIP) in mediating relaxations induced by vagal stimulation. 2. NOS was localized to nerve cell bodies and nerve fibre varicosities of the myenteric plexus in wholemounts of the longitudinal muscle-myenteric plexus of the stomach fundus. The NOS-positive cells had a Dogiel type I morphology characteristic of motor neurones. 3. The cross-sections of the stomach wall showed NOS-positive neurones mainly in the myenteric plexus ganglia and NOS-positive nerve fibre varicosities in the circular muscle layer. 4. Relaxations induced by vagal stimulation were almost completely prevented by L-NAME with an IC50 value of 5.5 x 10(-6) M. This inhibition was reversed by L-arginine (2 mM). 5. VIP (100 nM) induced reproducible relaxations of the stomach. These were unaffected by tetrodotoxin (2 microM) or N omega-nitro-L-arginine methyl ester (L-NAME, 100 microM). 6. Desensitization to the relaxant effect of VIP partially reduced relaxations induced by vagal stimulation, glyceryl trinitrate or sodium nitroprusside but not noradrenaline. 7. These results show that NO has a neuronal origin in the guinea pig stomach, and support NO, and not VIP, as the major neurotransmitter of vagally induced gastric relaxation in the guinea pig.

5-HT3 receptors do not mediate vagally-induced relaxation or contraction of the isolated stomach of the guinea-pig.

1. We have tested whether 5-HT3 receptors mediate vagally-induced relaxation or contraction of the isolated stomach of the guinea-pig. 2. The antagonists of 5-HT3 receptors, ondansetron (1-10 microM) or metoclopramide (1-30 microM) did not inhibit vagally-induced relaxations at low concentrations but partially inhibited them at 30 microM or 60 microM, respectively. These higher concentrations of ondansetron and metoclopramide also inhibited relaxations induced by 1,1-dimethyl-4-phenylpiperazinium iodide (30 microM) but did not affect those induced by glyceryl trinitrate (0.7-1.1 microM). 3. Desensitization to 5-HT (100 microM) or 2-Me-5-HT (100 microM) did not affect relaxations or contractions induced by vagal stimulation. 4. Ondansetron (30 microM) or metoclopramide (60 microM) did not inhibit vagally-induced gastric contraction. 5. Thus, 5-HT3 receptors do not mediate vagally-induced relaxation or contraction in the guinea-pig stomach.