Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0013395 (dyspepsia)
 4,879 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Proximal gastric relaxation is a vago-vagal reflex upon food intake. The efferent neurons involved at the level of the stomach are nonadrenergic noncholinergic. Deficient proximal gastric relaxation is observed in a portion of patients with functional dyspepsia, while exaggerated relaxation might contribute to the development of gastroesophageal reflux disease via triggering of transient lower esophageal sphincter relaxations. Nitric oxide (NO) is mediating, together with vasoactive intestinal polypeptide (VIP) as parallel cotransmitter, the nonadrenergic noncholinergic neurotransmission of the proximal stomach. Evidence for a sequential link between VIP as neurotransmitter and muscular NO generation was obtained when studied in isolated gastric smooth muscle cells; inducible NO synthase seems expressed. The endogenous gastric nitrergic neurotransmitter is not sensitive to superoxide anion generators and NO scavengers, that reduce the relaxation to exogenous NO. This is not due to the release of a nerve-derived hyperpolarizing factor in addition of NO, nor to binding to thiols, but Cu/Zn superoxide dismutase is involved in the protection of endogenous NO versus superoxide anions and scavenging. The release of NO from gastric nitrergic neurons is not sensitive to negative feedback but is inhibited via presynaptic alpha 2-adrenoceptors. Nitric oxide functionally antagonizes acetylcholine in the smooth muscle cells but does not influence the release of acetylcholine at the cholinergic varicosities. Stimulating or inhibiting the gastric nitrergic neurons might be a target for drug therapy in functional dyspepsia or gastro-esophageal reflux, respectively.
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PMID:Pharmacological characterization of the nitrergic innervation of the stomach. 1223 40

Functional dyspepsia can be associated with impaired gastric relaxation in response to food intake and delayed gastric emptying. In this study, we investigated whether luminal hydrochloric acid (HCl) may reproduce these motor alterations in phenobarbital-anaesthetized rats via activation of extrinsic neural pathways. Intragastric pressure (IGP) changes induced by a 2-mL fluid bolus were recorded with an oesophageal catheter, and gastric emptying was determined via the fluid volume recovered from the stomach 30-min post-bolus. Experiments involving acute nerve transections or pharmacological blockade of nitric oxide synthesis revealed that the initial increase of IGP after a 0.35 mol L(-1) HCl bolus is dampened by duodenogastric and gastrogastric relaxation reflexes depending on vagal and splanchnic pathways as well as nitric oxide. Compared with saline, HCl (0.15-0.5 mol L(-1)) delayed the subsequent decrease (adaptation) of IGP, inhibited gastric emptying and stimulated gastric fluid secretion as seen in stomachs with ligated pylorus. The acid-evoked delay in IGP adaptation and inhibition of gastric emptying involved duodenogastric and duodenopyloric extrinsic nerve reflexes, whereas the gastric fluid secretion was independent of the extrinsic innervation. It is proposed that the gastropyloric motor changes induced by luminal acid challenge have a bearing on the motor disturbances underlying functional dyspepsia.
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PMID:Acid challenge delays gastric pressure adaptation, blocks gastric emptying and stimulates gastric fluid secretion in the rat. 1258 68

It has been demonstrated that nitric oxide (NO) is a major inhibitory nonadrenergic, noncholinergic (NANC) neurotransmitter in the gastrointestinal (GI) tract. NO released in response to nerve stimulation of the myenteric plexus causes relaxation of the smooth muscle. NO is synthesized by the activation of neuronal NO synthase (nNOS) in the myenteric plexus. Released NO plays an important physiological role in various parts of the GI tract. NO regulates the muscle tone of the sphincter in the lower esophagus, pylorus, sphincter of Oddi, and anus. NO also regulates the accommodation reflex of the fundus and the peristaltic reflex of the intestine. Previous studies have shown that NOS inhibitors delay gastric emptying and colonic transit. The reduction of nNOS expression, associated with impaired local production of NO, may be responsible for motility disorders in the GI tract. There is accumulated evidence that dysfunction of NO neurons in the myenteric plexus may cause various GI diseases. These reports are reviewed and possible mechanisms of altered nNOS expression are discussed in this article. In particular, impaired nNOS synthesis of the myenteric plexus seems to be an important contributing factor to the pathogenesis of achalasia, diabetic gastroparesis, infantile hypertrophic pyloric stenosis, Hirschsprung's disease, and Chagas' disease. Reduced NO release and/or nNOS expression are suspicious in a subset of patients with functional dyspepsia. Although the etiology of intestinal pseudo-obstruction remains unknown, it is conceivable that extrinsic denervation may upregulate nNOS expression, resulting in enhanced muscular relaxation and disturbed peristalsis. An animal model of colitis showed impaired nNOS expression in the colonic myenteric plexus. Antecedent infection may be associated with the impaired NO pathways observed in functional dyspepsia, colitis, and Chagas' disease.
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PMID:Pathophysiological significance of neuronal nitric oxide synthase in the gastrointestinal tract. 1276 83

We have developed a novel technique to measure gastric volume in vivo in mice; this will be invaluable for revealing gastric alterations in genetically modified mice models, thus expanding our understanding of the mechanisms underlying functional disorders. Experimental data on gastric tone currently available has focused on rats using isovolumetric techniques to measure pressure changes, whereas clinical studies use barostatic techniques to measure volume changes. For better translational approaches, we assessed the feasibility of using a miniaturized barostat to measure gastric volume changes in urethane-anaesthetized and unanaesthetized-decerebrate mice. Additionally, we assessed whether central vagal stimulation alters gastric volume in urethane-anaesthetized mice. Nitric oxide donor sodium nitroprusside (1mg kg-1 i.p.) increased gastric volume (+134 +/- 20 microL), whereas the cholinergic agonist carbachol (3 microg kg-1 i.p.) decreased gastric volume (-153 +/- 20 microL). Similar responses were obtained in urethane-anaesthetized and unanaesthetized-decerebrate animals. Microinjection of L-glutamate (25 nmol) into dorsal motor nucleus of the vagus (DMV) altered gastric volume; microinjection into rostral DMV led to gastric contraction (-83 +/- 18 microL) while stimulation of caudal DMV resulted in gastric relaxation (+95 +/- 16 microL). This reveals a functional organization of DMV in mice. This study validates barostatic techniques for application to mice. An understanding of gastric contractility and tone is clinically relevant as impaired gastric accommodation reflex may be an underlying cause of functional dyspepsia.
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PMID:Central vagal stimulation evokes gastric volume changes in mice: a novel technique using a miniaturized barostat. 1476 99

The mechanism of action of the phosphodiesterase type 5 (PDE5) inhibitors (i.e., sildenafil, tadalafil, and vardenafil) involves inhibition of the PDE5 isoenzyme located in penile vascular smooth muscle cells. Sexual stimulation triggers the release of nitric oxide (NO), stimulating the release of guanylyl cyclase, leading to an increase in intracellular cyclic guanosine monophosphate (cGMP) concentrations, a decrease in intracellular calcium, and ultimately relaxation of the vascular smooth muscle in the corpus cavernosum and penile erection. The PDE5 inhibitors have no effect on the penis in the absence of sexual stimulation. Although the various PDE5 inhibitors differ with respect to selectivity and pharmacokinetic profiles, efficacy and safety of these agents are comparable in broad populations of men with erectile dysfunction (ED), including those with diabetes or those taking multiple antihypertensive agents. The most frequently reported adverse events of the PDE5 inhibitors are related to their mild vasodilatory effects and include headache, flushing, dyspepsia, and nasal congestion or rhinitis. Side effects are generally reversible and tend to diminish during continued treatment. Differences in pharmacokinetic properties among the PDE5 inhibitors include the fact that sildenafil and vardenafil have a shorter duration of action (approximately 4 h) compared with the longer period of responsiveness observed with tadalafil (up to 36 h). In addition, in the presence of high-fat food, absorption of sildenafil and vardenafil may be delayed; however, the rate and extent of tadalafil absorption are unaffected by high-fat food.
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PMID:Phosphodiesterase type 5 inhibitor differentiation based on selectivity, pharmacokinetic, and efficacy profiles. 1511 91

Erection is a neurovascular event that involves spinal and supra spinal pathways. The final common pathway involves the release of nitric oxide (NO) from both endothelial cells and neurons, which acts as a vasodilator causing penile engorgement and erection. NO is degraded by the enzyme phosphodiesterase (PDE) type 5 in the penis. Erectile dysfunction (ED), defined as the persistent inability to achieve and/or maintain an erection sufficient for satisfactory sexual performance, results when the neurovascular pathway is interrupted by medical conditions or drugs. A 15-item self-administered questionnaire, the International Index of Erectile Function (IIEF), is one of the most useful tools to evaluate erectile function (EF) in clinical trials, although of much less use in routine clinical practice. The MMAS (Massachusetts Male Aging Study) was the first major epidemiological investigation to study the prevalence of ED. The study found that ED was three times more common in patients with diabetes mellitus. The aetiopathogenesis of ED in diabetes is multifactorial, with vascular and neural factors being equally implicated. Hyperglycaemia is believed to give rise to biochemical perturbations that lead to these microvascular changes. In the MMAS, ED in diabetes was strongly correlated with glycaemic control, duration of disease and diabetic complications. The incidence increased with increasing age, duration of diabetes and deteriorating metabolic control, and was higher in individuals with type 2 diabetes than those with type 1.ED in men with diabetes often affects their quality of life and, as patients are often reluctant to come forward with their symptoms, a carefully taken history is one of the most useful approaches in identifying affected individuals. The PDE inhibitors have revolutionised the management of ED and oral drug therapy is currently first-line therapy for the condition. These agents act by potentiating the action of intracavernosal NO, thereby leading to a more sustained erection. Sildenafil was the first PDE5 inhibitor to undergo evaluation and has been studied extensively. More recently two other agents, vardenafil and tadalafil, have been introduced. All the drugs have been shown to be effective across a wide range of aetiologies of ED, including diabetes. The drugs have been shown to improve EF domain scores, penetration and maintenance of erection, resulting in more successful intercourse. Their effects are greater at higher doses. Sildenafil and vardenafil are shorter-acting agents, while tadalafil has a longer half-life allowing the user more flexibility in sexual activity. Common adverse effects include headache, nasal congestion and dyspepsia, all actions related to inhibition of PDE5. The drugs are generally well tolerated and withdrawal from the clinical studies as a result of drug-related adverse effects were rare. The use of PDE5 inhibitors in the presence of oral nitrates is absolutely contraindicated. The clinical studies to date have not evaluated the use of one drug in the case of treatment failure with another agent. Sublingual apomorphine, which stimulates central neurogenic pathways, is a new agent and may be a suitable alternative in those patients in whom PDE5 inhibitors are ineffective or contraindicated. In clinical trials, all IIEF domains except sexual desire were found to have improved after apomorphine. The median times to erection in these studies were 18.9 and 18.8 minutes for the 2 and 3mg doses, respectively. Intraurethral and intracavernosal alprostadil may be a useful alternative when oral drug therapy is ineffective or contraindicated. The management of ED in the diabetic patient may often involve a multidisciplinary approach where psychosexual counselling and specialist urologist advice is required in addition to the skills and expertise of the diabetologist. Finally, the introduction of the new oral agents have completely revolutionised the management of ED and allowed more individuals to come forward for treatment.
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PMID:New treatment options for erectile dysfunction in patients with diabetes mellitus. 1553 69

Nonsteroidal anti-inflammatory drugs (NSAIDs) and Helicobacter pylori (H. pylori) are major factors in gastritis and peptic ulcer However, the role of NSAIDs and H. pylori infection in dyspepsia remains unclear. Gastric adaptive relaxation may be related to the pathogenesis of functional dyspepsia because the response is often disturbed in dyspeptic patients. In this study, we investigated the effects of indomethacin or H. pylori water extracts on gastric adaptive relaxation. This experiment was performed using the modified method of Desai et al. Isolated guinea-pig stomach in an organ bath was monitored for intragastric pressure and volume. Adaptive relaxation was induced by gastric luminal distention. The effects of indomethacin and H. pylori on gastric relaxation were tested in this system. Indomethacin (> 1 x 10(-5) M) significantly inhibited adaptive relaxation. Indomethacin (> 3 x 10(-6) M) induced gastric relaxation in a dose-dependent fashion. However, aspirin at a concentration sufficient for cyclooxygenase (COX)-1 inhibition did not induce gastric relaxation. Preincubation with N-nitro-L-arginine methyl ester, a nitric oxide (NO)-synthase inhibitor, inhibited indomethacin-induced gastric relaxation. Adaptive relaxation was not affected by H. pylori water extracts. In conclusion, indomethacin inhibited adaptive relaxation via prior gastric relaxation. NO production, but not COX-1 inhibition, may be involved in this effect of indomethacin. H. pylori water extracts may not have direct effects on adaptive relaxation. Inhibition of adaptive relaxation may be one of the major mechanisms underlying NSAID-induced dyspepsia.
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PMID:Indomethacin, but not Helicobacter pylori, inhibits adaptive relaxation in isolated guinea-pig stomach. 1570 Jul 51

Cinnamomum cassia has been widely used for treating dyspepsia, gastritis, and inflammatory disease. In the present study, several of cinnamaldehyde derivatives were synthesized from various cinnamic acid based on the 2'-hydroxycinnamaldehyde isolated from the bark C. cassia Blume was investigated to compare their NO production and NF-kappa B activity from Raw 264.7 cell since nitric oxide (NO) and NF-kappa B have been shown to be implicated factors in the inflammatory disease. The results show that HCA, among the derivatives, most significantly inhibited lipopolysaccharide (LPS)-induced NO production and NF-kappa B transcriptional activity in a dose-dependent manner with an IC(50) value of 8 and 22 microM, respectively. We next investigated putative possible mechanisms of inhibitory effect of HCA on NO production. The inhibition of NO by HCA was consistent with the inhibitory effect on LPS-induced inducible nitric oxide synthase (iNOS) expression. Moreover, HCA inhibited LPS-induced p50 and p65 translocation resulting in the inhibition of the DNA binding activity of the NF-kappa B, a central regulator of iNOS. The present results provided evidence that HCA, among cinnamaledhyde derivatives, has the most inhibitory effect on NO production through inhibition of NF-kappa B activation, and thus can be used as an anti-inflammatory agent.
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PMID:Inhibitory effect of 2'-hydroxycinnamaldehyde on nitric oxide production through inhibition of NF-kappa B activation in RAW 264.7 cells. 1571 Mar 56

The hematosalivary barrier state was studied using the values of peroxidation of lipids and nitric oxide, antioxidant defense and macroelements in children with chronic gastroduodenitis and functional dyspepsia. The disturbances of the barrier functioning were shown to be important in the mechanisms of stomach and duodenum lesions. Taking into account significant changes in the metabolic profile of the sputum, which are different for different inflammatory and functional diseases of the gastroduodenal zone, we have suggested using its parameters for noninvasive screening diagnostics of this pathology.
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PMID:[Functional state of the hematosalivary barrier in children with gastroduodenal diseases]. 1625 59

The maintenance of gastrointestinal mucosal integrity depends on the rapid alarm of protective mechanisms in the face of pending injury. To this end, the gastric mucosa is innervated by intrinsic sensory neurons and two populations of extrinsic sensory neurons: vagal and spinal afferents. Extrinsic afferent neurons constitute an emergency system that is called into operation when the gastrointestinal mucosa is endangered by noxious chemicals. The function of these chemoceptive afferents can selectively be manipulated and explored with the use of capsaicin which acts via a cation channel termed TRPV1. Many of the homeostatic actions of spinal afferents are brought about by transmitter release from their peripheral endings. When stimulated by noxious chemicals, these afferents enhance gastrointestinal blood flow and activate hyperaemia-dependent and hyperaemia-independent mechanisms of protection and repair. In the rodent foregut these local regulatory roles of sensory neurons are mediated by calcitonin gene-related peptide and nitric oxide. The pathophysiological potential of the neural emergency system is best portrayed by the gastric hyperaemic response to acid back-diffusion, which is governed by spinal afferent nerve fibres. This mechanism limits damage to the surface of the mucosa and creates favourable conditions for rapid restitution and healing of the wounded mucosa. Other extrinsic afferent neurons, particularly in the vagus nerve, subserve gastrointestinal homeostasis by signalling noxious events in the foregut to the central nervous system and eliciting autonomic, emotional-affective and neuroendocrine reactions. Under conditions of inflammation and injury, chemoceptive afferents are sensitized to peripheral stimuli and in this functional state contribute to the hyperalgesia associated with functional dyspepsia and irritable bowel syndrome. Thus, if GI pain is to be treated by sensory neuron-directed drugs it needs to be considered that these drugs do not inhibit nociception at the expense of GI mucosal vulnerability.
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PMID:Efferent-like roles of afferent neurons in the gut: Blood flow regulation and tissue protection. 1654 83


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