Chen-Road Hung

Valproic acid suppresses the synaptic response mediated by the NMDA receptors in rat amygdalar slices.

The mechanism of action of the anticonvulsant drug valproic acid (VPA) was studied in rat amygdaloid slices using intracellular recording techniques. In the presence of bicuculline (20 microM), stimulation of the endopyriform nucleus evoked an excitatory postsynaptic potential (EPSP) followed by a paroxysmal depolarizing shift (PDS). Superfusion of VPA (2 mM) reversibly suppressed the PDS. Synaptic response mediated by the N-methyl-D-aspartate (NMDA) receptors (EPSPNMDA) was isolated pharmacologically by application of a solution containing nonNMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and gamma-aminobutyric acid receptor antagonist bicuculline (20 microM). VPA (0.2-10 mM) reversibly reduced the amplitude of the EPSPNMDA in a dose-dependent manner. Higher concentration of VPA (10 mM), in addition, suppressed the normal synaptic transmission. These results suggest that VPAs anticonvulsant effect is due, at least in part, to its blocking action on the EPSPNMDA.

Importance Of Histamine, Glutathione And Oxyradicals In Modulating Gastric Haemorrhagic Ulcer In Septic Rats

1. The ulcerogenesis of gastric haemorrhagic damage during sepsis is unclear. The present study first proposes that gastric haemorrhagic ulcer is modulated by mucosal glutathione, histamine and oxyradicals in lipopolysaccharide (LPS)‐induced sepsis in rats. The protective effects of several drugs on the ulcerogenic parameters also were evaluated.

Role of Acid Back‐diffusion in the Formation of Mucosal Ulceration and Its Treatment with Drugs in Diabetic Rats

We have studied the role of acid back‐diffusion in the formation of gastric mucosal ulceration and its treatment with several drugs in streptozotocin‐induced diabetic rats. After vagotomy, the stomach of 1–8 week‐old diabetic rats and age‐matched control rats were irrigated with acid solutions of graded concentrations (50–150 mm HCl) for 1 or 3 h.

Gastric mucosal damage induced by arecoline seizure in rats.

In an attempt to know the relation of seizure and gastric mucosal damage, we challenged arecoline (ACL) centrally to induce seizure and investigated gastric hemorrhagic injury in acid-irrigated stomachs of rats. The protective effects of several drugs also were evaluated. After deprivation of food for 24 h, rats were received laparotomy under diethylether-anesthesia. Both pylorus sphincters and carotid esophagus were ligated. The forestomach was equipped with a cannula for gastric irrigation. After recovery from anesthesia (approximately 1 h), the stomach was irrigated for 2 h with an acid solution containing 100 mM HCl and 54 mM NaCl or the same volume of normal saline. Intracerebroventricular (i.c.v.) ACL (0, 1, 3 or 10 mg/kg dissolved in 10 microl of CSF) was challenged to rats immediately after gastric irrigation. The seizure in rats was produced by ACL in a dose-related manner. The ulcerogenic parameters such as decrease of gastric mucosal glutathione levels and increase of histamine concentrations and lipid peroxide generations as well as the raise of luminal hemoglobin contents and exacerbated mucosal lesions were obtained depending on the doses of ACL challenged. These ulcerogenic parameters produced in ACL (10 mg/kg, i.c.v.) seizure rats were markedly ameliorated by gastric vagotomy or central anticholinergics. Intraperitoneal ketotifen, zinc sulfate, diphenhydramine or cimetidine also produced significant (p<0.05) inhibitions of these ulcerogenic parameters in ACL seizure rats. In conclusion, central ACL seizure may produce gastric oxidative stress and hemorrhagic lesions via vagal nervous activation and histamine release in acid-irrigated stomachs of rats.

Protective effect of cimetidine on tannic acid-induced gastric damage in rats

Abstract— The effect of cimetidine on the acidified tannic acid‐induced back diffusion of gastric acid and mucosal damage was investigated in the vagotomized rat. After intragastric irrigation for 1 to 3 h, tannic acid (20–500 mg kg−1) produced a dose‐related increase in gastric volume and the loss of luminal H+. The change of mucosal permeability to the electrolyte, either the loss of H+ or the gain of Na+, K+, and Ca2+, induced by tannic acid was significantly diminished by the combination with intragastric cimetidine. However, intravenous injection of cimetidine did not protect this damage and back diffusion of acid neutralized intragastric cimetidine did not reduce the back diffusion of acid and Na+, K+, and Ca2+ output provoked by acid solution. Thus, the neutralizing action of cimetidine seems responsible.

Roles of histamine receptors and oxyradicals in aggravation of acid-induced gastric haemorrhagic ulcers in endotoxaemic rats

We clarified the roles of histamine H1-, H2-, H3-receptors and oxyradicals in the exacerbation of acid-induced gastric haemorrhage and stomach ulcer in endotoxaemic rats by measuring changes in gastric mucosal glutathione concentrations, lipid peroxide generation and histamine levels as well as in luminal electrolytes and haemoglobin contents. Stomach ulcers were evaluated by morphological and histological examination. Rats were deprived of food for 24 h, and challenged intravenously with lipopolysaccharide (LPS, 3 mg/kg) at 0, 12, 18 and 24 h after withdrawal of food. Control rats received saline only. Gastric truncal vagotomy was performed and followed by irrigation for 3 h with an acid solution containing 100 mmol/L HC1 and 54 mmol/L NaCl. The augmentation of mucosal permeability to electrolytes (acid back-diffusion), haemoglobin contents and lipid peroxide levels as well as the lowered mucosal glutathione concentrations were dependent on the duration of LPS intoxication. Serious damage of corpus mucosal cells was observed in acid-perfused stomachs of LPS rats. Intraperitoneal diphenhydramine, an H1-receptor antagonist, or ranitidine, an H2-receptor blocker, caused dose-dependent inhibition of these ulcerogenic factors. Antioxidants, including ascorbate and sodium benzoate, also were effective in inhibition. Moreover, intraperitoneal R-(α)-methylhistamine, an H3-receptor agonist, produced elimination, while thioperamide, an H3-receptor antagonist, and exogenous histamine elevated mucosal histamine concentrations and haemorrhagic ulcers in LPS rats. It is concluded that gastric haemorrhage and stomach ulcers produced by acid solution in LPS-treated rats are modulated by oxyradicals and histamine H1-, H2- and H3-receptors.

The involvement of metabotropic glutamate receptors in long-term depression of N-methyl-D-aspartate receptor-mediated synaptic potential in the rat hippocampus.

The frequency-dependent long-term modifications of pharmacologically isolated N-methyl-D-aspartate (NMDA) receptor-mediated excitatory postsynaptic potential (EPSPNMDA) was studied. Intracellular recordings were obtained from CA1 cells of rat hippocampal slices and in the presence of 6-cyano-7-nitroquinoxaline-2,3-dione (10 microM) and bicuculline (20 microM) which block non-NMDA and GABAA receptors, respectively. Low-frequency stimulation at 5 Hz resulted in a long-term depression (LTD) of EPSPNMDA in 12 of 17 cells. However, when the stimulus frequency was increased to 30 Hz, a long-term potentiation (LTP) of EPSPNMDA was observed in 7 out of 9 cells. The LTD was not affected by pretreating the slices with okadaic acid (0.5-1 microM) suggesting that activation of endogenous protein phosphatase is not responsible for this process. In the presence of L-2-amino-3-phosphonopropionic acid (50 microM) or (RS)-alpha-methyl-4-carboxyphenylglycine (200 microM), 5 Hz tetanization resulted in LTP instead of LTD. These results suggest that activation of metabotropic glutamate receptor (mGluR) is necessary for the induction of EPSPNMDA LTD and blockade of mGluR unmasks a LTP.

Modulation of gastric hemorrhage and ulceration by oxidative stress and histamine release in Salmonella typhimurium-infected rats

Infection with Salmonella typhimurium can produce multiple organ dysfunctions. However, document concerning with gastric hemorrhagic ulcers occur in this infectious disease is lacking. The aim was to study modulation of gastric hemorrhagic ulcer by oxidative stress and mast cell histamine in S. typhimurium-infected rats. Additionally, the protective effects of drugs, such as ofloxacin, lysozyme chloride, ketotifen, ranitidine, and several antioxidants, including exogenous glutathione (GSH), allopurinol and dimethylsulfoxide (DMSO) were evaluated. Male Wistar rats were injected intrajejunally with a live culture of S. typhimurium (1 × 1010 colony-forming units/rat) and followed by deprivation of food for 36 h. Age-matched control rats received sterilized vehicle only. Rat stomachs were irrigated for 3 h with either normal saline or a simulated gastric juice containing 100 mM HCl, 17.4 mM pepsin and 54 mM NaCl. S. typhimurium caused aggravation of offensive factors, including enhancing gastric acid back-diffusion, mucosal lipid peroxide generation, histamine release, microvascular permeability and hemorrhagic ulcer, as well as an attenuation of defensive substances, such as mucosal GSH and mucus level. Intragastric irrigation of gastric juice caused further aggravation of these gastric biochemical parameters. This exacerbation of ulcerogenic factors was abolished by pretreatment of ofloxacin and lysozyme chloride. Antioxidants, such as reduced GSH, allopurinol and DMSO also produced significant (P < 0.05) amelioration of gastric damage in S. typhimurium-infected rats. In conclusion, gastric oxidative stress and histamine play pivotal roles in the formation of hemorrhagic ulcers that were effectively ameliorated by ofloxacin, lysozyme chloride, ketotifen, ranitidine, diamine oxidase and various antioxidants in S. typhimurium-infected rats.

Simulatory effect of porcine insulin on noradrenaline secretion in guinea‐pig ileum myenteric nerve terminals

The effect of insulin on the release of noradrenaline (NA) from nerve terminals was investigated in isolated ileal synaptosomes of guinea‐pig. Release was determined as the amount of NA, quantified by h.p.l.c.‐electrochemical detection, from samples incubated with insulin minus that in parallel blanks treated with some volume of vehicle. Porcine insulin stimulated the secretion of NA in a concentration‐dependent manner from 0.01 i.u. ml−1, while the value of lactate dehydrogenase in the incubated medium was not influenced by insulin. The presence of insulin receptors in this preparation was illustrated by immunoblotting with insulin receptor monoclonal antibodies. The release of NA by insulin was reduced by guanethidine and bretylium and it was markedly lowered in the samples obtained from guinea‐pigs that had received an intraperitoneal injection of DSP‐4, the noradrenergic neurotoxin. Tetrodotoxin attenuated the action of insulin at concentrations sufficient to block sodium channels. The depolarizing effect of insulin on the membrane potential was also illustrated by a concentration‐dependent increase in the fluorescence of bisoxonol, a potential‐sensitive dye. The action of insulin was attenuated by removal of calcium chloride from the bathing medium. The induction of calcium ion influx by insulin into the synaptosomes is supported by the inhibitory effects of the calcium channel blockers ω‐conotoxin GVIA (for the N‐type channels) and nifedipine (for the L‐type channels). These findings suggest that insulin can stimulate NA release from noradrenergic terminals via activation of calcium influx.

Protective Effects of Arginine-vasopressin on Aspirin-induced Gastric Mucosal Damage in Anaesthetized Dogs

Abstract— The protective effects of graded doses of arginine‐vasopressin (AVP) on acidified acetylsalicylic acid (ASA) solution‐induced changes in gastric prostaglandin E2 (PGE2) secretion, mucus production, acid back‐diffusion and mucosal damage were studied in the bilateral truncal vagotomized stomach of anaesthetized dogs. After 1–4 h intragastric irrigation of the stomach with AVP (1–100 ng kg−1) plus 20 min acidified ASA solution, a significant (P < 0·05) inhibition in gastric mucosal lesions and acid back‐diffusion produced by acidified ASA solution was observed. The reduction in the gastric PGE2 secretion and in mucus production provoked by the same dose of acidified ASA solution was also diminished. Furthermore, a correlation (r = 0·883; P < 0·01) between AVP‐induced inhibition in ASA‐provoked reduction in gastric PGE2 secretion and in mucus production was found. During the experiment, the heart rate, the peripheral arterial blood pressure and the gastric arterial blood pressure were not altered by AVP (1–100 ng kg−1). Thus, intragastric AVP protects gastric mucosa against ASA‐induced damage without producing cardiovascular side effects. The inhibitory effects of AVP (100 ng kg−1) on acidified ASA‐induced reduction in PGE2 and mucus secretion, as well as on ASA‐induced enhancement in acid back‐diffusion and erosion production were dose‐dependently reversed by a specific V1 antagonist, 1‐(β‐mercapto‐β,β‐cyclopentamethylene‐propionic acid), 2‐(o‐methyl)tyrosine‐Arg8‐vasopressin. From the above results, it is suggested that the protective effects of intragastric AVP on gastric mucosa against acidified ASA‐induced damage is at least partly due to stimulation of the biosynthesis of gastric PGE2, which may contribute to the increase in the gastric mucus secretion and to the decrease in acid back‐diffusion. Furthermore, the endogenous PGE2 stimulated by AVP may be mediated by V1‐receptor activation.