Stimulation of gastric acid secretion by progesterone metabolites as neuroactive steroids in anesthetized rats.

The effect of neuroactive progesterone metabolites, 5alpha- and 5beta-pregnan-3alpha-ol-20-one, and their stereoisomers at the 3 C site, 5alpha- and 5beta-pregnan-3beta-ol-20-one, on gastric acid secretion was investigated in urethane-anesthetized rats. Both 5alpha- and 5beta-pregnan-3alpha-ol-20-one dose-dependently (0.3-3 mg x kg(-1), i.v.) stimulated gastric acid secretion with an early onset of action. Their potency and efficacy were almost the equivalent of one another. In contrast, their stereoisomers did not have a significant effect even at 10 mg x kg(-1) (i.v.). The 5beta-pregnan-3alpha-ol-20-one (3 mg x kg(-1), i.v.)-stimulated gastric acid secretion was remarkably inhibited by bilateral vagotomy or pretreatment with atropine (1 mg x kg(-1), i.v.). An antagonist of the GABA(A) receptor, picrotoxin, at 3 and 6 mg x kg(-1) (i.v.), significantly inhibited the 5beta-pregnan-3alpha-ol-20-one (3 mg x kg(-1), i.v.)-stimulated gastric acid secretion. These results indicate that naturally occurring neuroactive steroids, 5alpha- and 5beta-pregnan-3alpha-ol-20-one, stimulate gastric acid secretion in a stereoselective and dose-dependent manner in urethane-anesthetized rats. It is likely that the action of these neuroactive steroids is of central origin and that interaction with GABA(A) receptors and stimulation of vagal pathway are involved in its mechanism of action.     

Stimulatory effects of endogenous and exogenous nitric oxide on gastric acid secretion in anesthetized rats

We previously reported the stimulatory effect of endogenous nitric oxide (NO) on gastric acid secretion in the isolated mouse whole stomach and histamine release from gastric histamine-containing cells. In the present study, we investigated the effects of endogenous and exogenous NO on gastric acid secretion in urethane-anesthetized rats. Acid secretion was studied in gastric-cannulated rats stimulated with several secretagogues under urethane anesthesia. The acid secretory response to the muscarinic receptor agonist bethanechol (2 mg/kg, s.c.), the cholecystokinin(2) receptor agonist pentagastrin (20 microg/kg, s.c.) or the centrally acting secretagogue 2-deoxy-D-glucose (200 mg/kg, i.v.) was dose-dependently inhibited by the NO synthase inhibitor N(omega)-nitro-L-arginine (L-NNA, 10 or 50 mg/kg, i.v.). This inhibitory effect of L-NNA was reversed by a substrate of NO synthase, L-arginine (200 mg/kg, i.v.), but not by D-arginine. The histamine H(2) receptor antagonist famotidine (1 mg/kg, i.v.) completely inhibited the acid secretory response to bethanechol, pentagastrin or 2-deoxy-D-glucose, showing that all of these secretagogues induced gastric acid secretion mainly through histamine release from gastric enterochromaffin-like cells (ECL cells). On the other hand, histamine (10 mg/kg, s.c.)-induced gastric acid secretion was not inhibited by pretreatment with L-NNA. The NO donor sodium nitroprusside (0.3-3 mg/kg, i.v.) also dose-dependently induced an increase in acid secretion. The sodium nitroprusside-induced gastric acid secretion was significantly inhibited by famotidine or by the soluble guanylate cyclase inhibitor methylene blue (50 mg/kg, i.v.). These results suggest that NO is involved in the gastric acid secretion mediated by histamine release from gastric ECL cells.     

Vagus-mediated activation of mucosal mast cells in the stomach: effect of ketotifen on gastric mucosal lesion formation and acid secretion induced by a high dose of intracisternal TRH analogue.

TRH analogue, RX 77368, injected intracisternally (i.c.) at high dose (3 microg/rat) produces gastric mucosal lesion formation through vagal-dependent pathway. The gastric mucosal hyperemia induced by i.c. RX 77368 was shown to be mediated by muscarinic vagal efferent fibres and mast cells. Furthermore, electrical vagal stimulation was observed to induce gastric mucosal mast cell degranulation. The aim of the study was to assess the influence of ketotifen, a mast cell stabilizer, on RX 77368-induced gastric lesion formation and gastric acid secretion. RX 77368 (3 microg, i.c.) or vehicle (10 microL, i.c.) was delivered 240 min prior to the sacrifice of the animals. Ketotifen or vehicle (0.9% NaCl, 0.5 mL) was injected intraperitoneally (i.p.) at a dose of 10 mg x kg(-1) 30 min before RX 77368 injection. The extent of mucosal damage was planimetrically measured by a video image analyzer (ASK Ltd., Budapest) device. In the gastric acid secretion studies, the rats were pretreated with ketotifen (10 mg x kg(-1), i.p.) or vehicle (0.9% NaCl, 0.5 mL, i.p.), 30 min later pylorus-ligation was performed and RX 77368 (3 microg, i.c.) or vehicle (0.9% NaCl, 10 microL, i.c.) was injected. The rats were killed 240 min after i.c. injection, and the gastric acid secretion was measured through the titration of gastric contents with 0.1 N NaOH to pH 7.0. RX 77368 (3 microg, i.c.) resulted in a gastric mucosal lesion formation involving 8.2% of the corpus mucosa (n = 7). Ketotifen elicited an 85% inhibition on the development of mucosal lesions (n = 7, P < 0.001) whereas ketotifen alone had no effect on the lesion formation in the mucosa (n = 7). The RX 77368 induced increase of gastric acid secretion was not influenced by ketotifen pretreatment in 4-h pylorus-ligated animals. Central vagal activation induced mucosal lesion formation is mediated by the activation of mucosal mast cells in the stomach. Mast cell inhibition by ketotifen does not influence gastric acid secretion induced by i.c. TRH analogue in 4-h pylorus-ligated rats.     

The key-role of vagal nerve and adrenals in the cytoprotection and general gastric mucosal integrity.

BACKGROUND: Our laboratory group observed earlier that the gastric mucosal cytoprotective effect of prostacyclin (PGI(2)) disappeared after surgical vagotomy in rats. Similarly to this, the beta-carotene induced gastric cytoprotection disappeared in adrenalectomized rats too. AIMS: In these studies we aimed to investigate the possible role of vagal nerve and adrenals in the development of gastric mucosal lesions induced by exogenously administered chemicals (ethanol, HCl, NaOH, NaCl and indomethacin), and on the effects of cytoprotective and antisecretory drugs (atropine, cimetidine), and scavengers (vitamin A and beta-carotene). METHODS: The observations were carried out in fasted CFY strain rats. The gastric mucosal lesions were produced by intragastric (i.g.) administration of narcotising agents (96% ethanol; 0.6 M HCl; 0.2 M NaOH; 25% NaCl) or subcutaneously (s.c.) administered indomethacin (20 mg/kg) in intact, surgically bilaterally vagatomized, and adrenalectomized rats without or with glucocorticoid supplementation (Oradexon, 0.6 mg/kg given i.m. for 1 week). The gastric mucosal protective effect of antisecretory doses of atropine (0.1-0.5-1.0 mg/kg i.g.) and cimetidine (10-25-50 mg/kg i.g.), and vitamin A and beta-carotene (0.01-0.1-1.0-10 mg/kg i.g.) was studied. The number and severity of mucosal gastric lesions was numerically or semiquantitatively measured. In other series of observations the gastric acid secretion and mucosal damage were studied in 24 h pylorus-ligated rats without and with acute bilateral surgical vagotomy. RESULTS: It was found that: (1) the chemical-induced gastric mucosal damage was enhanced in vagotomized and adrenalectomized rats, meanwhile the endogenous secretion of gastric acid, and the development of mucosal damage can be prevented by surgical vagotomy; (2) the gastric cyto- and general protection produced by the drugs and scavengers disappeared in vagotomized and adrenalectomized rats; (3) the gastric mucosal protective effects of drugs and of scavengers returned after sufficient glucocorticoid supplementation of the rats. CONCLUSION: It has been concluded that the intact vagal nerve and adrenals have a key role in the gastric mucosal integrity, and in drugs- and scavengers-induced gastric cyto- and general mucosal protection.     

Gastric acid secretion in streptozotocin-diabetic rats--different responses to various secretagogues.

We compared gastric acid secretion in response to various stimuli in normal and streptozotocin (STZ)-induced diabetic rats, in an attempt to characterize the alteration of acid secretory response in diabetic conditions. Animals were injected STZ (70 mg x kg(-1), i.p.) and used after 5 weeks of diabetes with blood glucose > 350 mg x dL(-1). Under urethane anesthesia, a rat stomach was mounted on an ex vivo chamber, perfused with saline and acid secretion was measured at pH 7.0 using a pH-stat method and by adding 100 mM NaOH. The acid secretion was stimulated by i.v. infusion of either histamine (4 mg x kg(-1) x h(-1)), pentagastrin (60 microg x kg(-1) x h(-1)) or carbachol (20 microg x kg(-1) x h(-1)) or i.v. injection of YM-14673 (0.3 mg x kg(-1)), an analog of thyrotropin-releasing hormone, or vagal electrical stimulation (2 ms, 3 Hz, 0.5 mA). In normal rats, gastric acid secretion was increased in response to either histamine, pentagastrin, carbachol, YM-14673 or electrical vagal stimulation. In STZ diabetic rats, however, changes in acid secretion varied depending on the stimuli; the acid secretory responses to histamine remained unchanged, those to YM-14673 and vagal electrical stimulation significantly decreased, but the responses to both pentagastrin and carbachol were significantly enhanced as compared to normal rats. Luminal release of histamine in response to both pentagastrin and carbachol was increased in STZ-diabetic rats as compared to normal animals. The altered acid secretory responses in STZ diabetic rats were partially reversed by daily injection of insulin with amelioration of high blood glucose levels. These results suggest that STZ-diabetic rats showed different changes in gastric acid secretory responses to various stimuli; no change in response to histamine, a decrease to both YM-14673 and vagal electrical stimulation and an increase to both pentagastrin and carbachol. The increased acid secretory response may be associated with an enhanced release of mucosal histamine, while the decreased response may be due to vagal neuropathy.     

Roles of capsaicin-sensitive sensory nerves, endogenous nitric oxide, sulfhydryls, and prostaglandins in gastroprotection by momordin Ic, an oleanolic acid oligoglycoside, on ethanol-induced gastric mucosal lesions in rats.

The roles of capsaicin-sensitive sensory nerves (CPSN), endogenous nitric oxide (NO), sulfhydryls (SHs), prostaglandins (PGs) in the gastroprotection by momordin Ic, an oleanolic acid oligoglycoside isolated from the fruit of Kochia scoparia (L.) SCHRAD., on ethanol-induced gastric mucosal lesions were investigated in rats. Momordin Ic (10 mg/kg, p.o.) potentially inhibited ethanol-induced gastric mucosal lesions. The effect of momordin Ic was markedly attenuated by the pretreatment with capsaicin (125 mg/kg in total, s.c., an ablater of CPSN), N(G)-nitro-L-arginine methyl ester (L-NAME, 70 mg/kg, i.p., an inhibitor of NO synthase), N-ethylmaleimide (NEM, 10 mg/kg, s.c., a blocker of SHs), or indomethacin (10 mg/kg, s.c., an inhibitor of PGs biosynthesis). The attenuation of L-NAME was abolished by L-arginine (300 mg/kg, i.v., a substrate of NO synthase), but not by D-arginine (300 mg/kg, i.v., the enatiomer of L-arginine). The effect of the combination of capsaicin with indomethacin, NEM, or L-NAME was not more potent than that of capsaicin alone. The combination of indomethacin and NEM, indomethacin and L-NAME, or indomethacin and NEM and L-NAME increased the attenuation of each alone. These results suggest that CPSN play an important role in the gastroprotection by momordin Ic on ethanol-induced gastric mucosal lesions, and endogenous PGs, NO, and SHs interactively participate, in rats.     

Ghrelin stimulates gastric acid secretion and motility in rats

Ghrelin, a novel growth-hormone-releasing peptide, was discovered in rat and human stomach tissues. However, its physiological and pharmacological actions in the gastric function remain to be determined. Therefore, we studied the effects of rat ghrelin on gastric functions in urethane-anesthetized rats. Intravenous administrations of rat ghrelin at 0.8 to 20 microgram/kg dose-dependently increased not only gastric acid secretion measured by a lumen-perfused method, but also gastric motility measured by a miniature balloon method. The maximum response in gastric acid secretion was almost equipotent to that of histamine (3 mg/kg, i.v.). Moreover, these actions were abolished by pretreatment with either atropine (1 mg/kg, s.c.) or bilateral cervical vagotomy, but not by a histamine H(2)-receptor antagonist (famotidine, 1 mg/kg, s.c.). These results taken together suggest that ghrelin may play a physiological role in the vagal control of gastric function in rats.     

Investigation on the mechanism involved in the effects of agmatine on ethanol-induced gastric mucosal injury in rats

Effects of agmatine, an endogenous metabolite formed by decarboxylation of L-arginine, on ethanol-induced gastric mucosal injury were investigated in rats. Agmatine at 1 and 10 mg/kg i.p doses significantly increased ethanol-induced gastric mucosal injury. This effect of agmatine was abolished completely by pretreatment with idazoxan, an imidazoline receptor-antagonist and alpha2 receptor- antagonist, (0.5 mg/kg i.p), partly by yohimbine, an alpha2 receptor- antagonist, (1 mg/kg i.p) but not by L-arginine, a precursor of nitric oxide, (500 mg/kg i.p). Our results suggest that agmatine had a potent ulcerogenic effect mediated, at least in part, by both alpha2-adrenoceptors and imidazoline receptors.     

CV-3988 - a specific antagonist of platelet activating factor (PAF)

CV-3988, rac-3-(N-n-octadecylcarbamoyloxy)-2-methoxypropyl 2-thiazolioethyl phosphate was shown to be a specific inhibitor of platelet activating factor (PAF). This compound in concentrations of 3 x 10(-6) to 3 x 10(-5)M inhibited aggregation of rabbit platelets induced by PAF (3 x 10(-8)M), while it had no effect on the aggregation induced by arachidonic acid, ADP, collagen or A-23187. CV-3988 alone even at a concentration of 10(-3)M had no effect on platelet aggregation. The inhibitory action of CV-3988 on the PAF-induced aggregation was independent of the formation of micelles. The PAF (0.1 to 1.0 micrograms/kg, i.v.)-induced hypotension in anesthetized rats was also inhibited dose-dependently by the i.v. administration of CV-3988 (1 and 10 mg/kg), while the hypotensive actions induced by the i.v. administration of acetylcholine (1 micrograms/kg), arachidonic acid (1 mg/kg), bradykinin (10 micrograms/kg), isoproterenol (1 microgram/kg) and histamine (100 micrograms/kg) were not altered by CV-3988 (10 mg/kg, i.v.). All these findings indicate that CV-3988 specifically inhibits the action of PAF in vitro and in vivo. This is the first report of a PAF antagonist which can specifically inhibit the PAF-induced hypotension as well as the PAF-induced platelet aggregation.     

The effect of etodolac on bile salt and histamine-mediated gastric mucosal injury in the rat

The effect of the selective cyclo-oxygenase-type-2 (COX-2) inhibitor etodolac on gastric mucosal integrity and gastric acid secretion was investigated in the rat. Etodolac was given in doses comparable with those being used in man for therapy of rheumatic conditions. The effect of etodolac was studied in the presence of a mild barrier breaker and in the presence of increased rates of endogenous acid secretion. In conscious pylorus-ligated rats, etodolac given intragastrically in 16 or 32 mg /kg for 3 h did not by itself give rise to visible gastric mucosal injury. Etodolac, however, exacerbated gastric mucosal injury evoked by intragastric application of acidified sodium taurocholate (5 mM in 150 mM HCl) in a dose-dependent manner. This effect of edotolac was independent of changes in gastric acid secretory responses. In rats whose gastric acid secretion was stimulated by intraperitoneal histamine (5 mg/kg), and etodolac (given i.g. in doses of 16 or 32 mg/kg) also increased gastric mucosal injury caused by histamine dose-dependently in the 3-h pylorus-ligated rats. Etodolac decreased gastric mucus in the saline- and in the sodium taurocholate-treated rats. In urethane-anaesthetized acute gastric fistula rats, intragastric etodolac (32 mg/kg) did not modify basal gastric acid secretion. Our data suggest that etodolac, a selective COX-2 inhibitor, impairs gastric mucosal resistance and can exacerbate gastric mucosal injury caused by other mucosal barrier breaking agents. Cyclooxygenase type-2 thus contributes to the gastric mucosal defences.     

Inhibition of endothelin-converting enzyme for protection against neointimal proliferation following balloon angioplasty of the rat carotid artery

Clinical success of percutaneous transluminal coronary angioplasty is limited by restenosis within months of the initial intervention. A number of vasoactive mediators and growth factors have been reported to participate in this process. The aim of the present experiments was to examine the effects of nonselective neutral endopeptidase (NEPi)/endothelin-converting enzyme (ECEi) inhibitors against neointimal proliferation (NIP) following balloon angioplasty of the left carotid artery of Sprague-Dawley rats with the right vessel serving as the uninjured control. The rats were divided in several groups: group 1, nontreated (vehicle); group 2, treated with a selective NEPi i.p.; groups 3-7, treated with nonselective NEPi/ECEi either i.p., s.c., i.v., or p.o. at various doses. After 2 weeks, cross-sectional histopathological and morphometrical examination of the left carotids revealed a severe NIP in vehicle-treated angioplastic rats compared with the control uninjured right carotid of the same rats. The selective NEPi CGS 24592 had no significant effect on restenosis, nor did the dual NEPi/ECEi CGS 26303 at 5 mg x kg(-1) x day(-1) i.p. Both s.c and i.v. NEPi/ECEi treatment (10 mg x kg(-1) x day(-1) b.i.d. s.c. or 10 mg x kg(-1) x day(-1) i.v.) reduced NIP by up to 35%. The prodrug CGS 26393 (p.o.) also attenuated NIP by 23%. Plasma concentrations of these compounds correlated with the degree of inhibition. These data support the participation of the endothelin system in the rat model of balloon angioplasty and suggest that selective ECEi may be effective.     

A novel method to produce extensive gastric antral ulcer in rats: pharmacological factors involved in the etiology of antral ulceration.

Gastric antral area is the most susceptible region to gastric ulceration in man. However, only limited information is available on animal models. In the present paper, we have developed an improved method for inducing gastric antral ulcers by the administration of 1.0 M HCl after refeeding for 1 h in rats. On day 4, the severe ulcer was found covering extensively the whole area of the antrum, and penetrated through the muscularis mucosae. The incidence of ulceration was 100% and the mean ulcer index was 37.1 +/- 16.6 mm2. In contrast, none of the erosive lesions were observed in the corpus area. Before 24 h, only slight hyperemia was observed in the antral region, suggesting that some submucosal mechanisms are involved in the ulceration processes other than the direct erosive action of HCl on the mucosal surface. Additional treatment with diethyldithiocarbamate (125 mg x kg(-1), s.c.), superoxide dismutase inhibitor, significantly aggravated this antral ulcer, and the ulcer index was 66.0 +/- 13.6 mm2. Allopurinol (50 mg x kg(-1), p.o.) significantly prevented ulcer formation induced by HCl plus DDC. GSH (150 mg x kg(-1), i.p.) also markedly prevented the ulceration. However, DMSO (0.5%, 5 mL x kg(-1), p.o.) was found not to affect ulcer formation. Famotidine (20 mg x kg(-1), p.o.) almost completely inhibited ulcer formation. From the above results, it was concluded that gastric antral ulcer can be induced by the simple treatment of 1.0 M HCl in refed rats, and the antrum has a different defensive mechanism from that in the corpus area. In addition. oxygen derived radicals, especially superoxide anion and endogenous acid secretion were found to be involved in the etiology of the aggravation of the gastric antral ulcer induced by DDC.     

Capsaicin inhibits the pentagastrin-stimulated gastric acid secretion in anaesthetized rats with acute gastric fistula.

The effect of capsaicin on basal and pentagastrin-stimulated gastric acid secretion was investigated in the urethane anaesthetized acute gastric fistula rat. Gastric acid secretion was measured by flushing of the gastric lumen with saline every 15 min or by continuous gastric perfusion. Capsaicin given into the rat stomach at 120 ng x mL(-1) prior to pentagastrin (25 microg x kg(-1), iv) reduced gastric acid secretory response to pentagastrin by 24%. Intravenous (iv) capsaicin (0.5 microg x kg(-1)) did not reduce the pentagastrin-stimulated gastric acid secretion. After topical capsaicin desensitization (3 mg x mL(-1)), basal gastric acid secretion and that in response to pentagastrin (25 microg x kg(-1), intraperitonaeally) was unaltered compared with the control group. Data indicate that topical capsaicin inhibits gastric acid secretion stimulated with pentagastrin in anaesthetized rats.     

Effect of hypophysectomy, adrenalectomy, pituitary hormone secretion and gastric acid secretion on neurotensin induced gastric protection against stress gastric lesions

In previous studies we have established that intracisternal (i.c.) but not peripheral (intravenous) administration of neurotensin (NT), a brain and gastrointestinal tridecapeptide, totally prevents the development of gastric lesions produced by cold-restraint stress (CRS) with food-deprived rats. In this investigation, removal of the pituitary and adrenal gland, anterior pituitary hormone secretion and gastric acid secretion were evaluated independently as potential intermediates for NT's protective effect. NT (30 micrograms) produced a significant reduction of gastric lesions incidence and severity in intact and sham-operated controls. Adrenalectomy, but not hypophysectomy totally blocked the protective effect of i.c. NT. In addition, replacement therapy with s.c. prednisone (1 mg/kg) for 5 days following adrenalectomy did not restore the protective activity of central (i.c.) NT in adrenalectomized rats. A significant reduction of serum levels of TSH, PRL and GH following i.c. NT (30 micrograms) was observed after 2h of CRS. The gastrosecretory studies revealed that i.c. NT (30 micrograms) did not affect gastric acid secretion in pylorus ligated rats. However, blockade of peripheral (gut) cholinergic (muscarinic) receptors with i.p. atropine methylbromide (1 mg/kg) significantly raised gastric pH and reduced gastric acid concentration and output. In conclusion, the results of this study indicate that the acute protective effect of brain NT appears to be mediated, at least in part, by the sympathoadrenomedullary axis, and not by the pituitary gland or substances derived from the pituitary or by inhibition of gastric acid secretion.     

Significance of glutamate and dopamine neurons in the ventral pallidum in the expression of behavioral sensitization to amphetamine

To explore the significance of ventral pallidum (VP) during the amphetamine sensitization, we first investigated if there are neurochemical alterations in the VP during amphetamine withdrawal period. Chronic amphetamine-treated (5 mg/kg x 14 days) rats displayed an apparent locomotion sensitization as compared with saline controls when challenged with 2 mg/kg amphetamine at withdrawal days 10-14. A microdialysis analysis revealed that output of the dopamine metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid, in the VP of amphetamine-sensitized rats increased approximately two-fold as compared to controls at both pre- and post-amphetamine challenge period. On the other hand, the in vivo glutamate output in the VP increased upon amphetamine challenge in the behaviorally sensitized rats, but not in the controls. To evaluate if drug manipulation in the VP would affect the behavioral sensitization, we treated both groups of rats with NMDA receptor antagonist, MK-801 (5 microg/microl for 5 days; bilateral) in the VP during withdrawal days 6-10. Animals were challenged with 2 mg/kg amphetamine at withdrawal day 11. The behavioral profile exhibited that MK-801 pre-treatment significantly blocked the locomotion hyperactivity in amphetamine-sensitized rats. Taken together, the current results suggest that the excitatory amino acid in the VP plays a significant role during the expression of behavioral sensitization to amphetamine.     

Effect of 2-deoxy- -glucose on acetylcholine and histamine levels in gastric juice of pylorus-ligated rats anesthetized with urethane

Acetylcholine (ACh) in gastric juice was detected and measured by pretreatment of acetylcholinesterase inhibitor, 1 mM eserine (1 ml/rat, p.o.), in pylorus-ligated rats, by liquid chromatography with electrochemical detection. In order to elucidate whether or not the ACh level in gastric juice reflects the activity of cholinergic neurons, the effect of 2-deoxy- -glucose (2-DG), a vagus stimulant, on the levels of ACh, histamine and gastric acid in gastric juice was investigated in pylorus-ligated rats anesthetized with urethane (1.25 g/kg, i.p.). Under the non-anesthetic condition, ACh, histamine and gastric acid levels were 100±25 pmol/h, 120±10 ng/h, and 240±32 μequiv./h, respectively. These levels were completely inhibited by urethane anesthesia. Under the anesthetized condition, 2-DG (50–200 mg/kg, i.v.) significantly increased ACh and histamine levels in gastric juice, as well as acid secretion. The 2-DG (200 mg/kg, i.v.)-induced increases in these levels were completely inhibited by vagotomy. These results suggest that ACh level measured in gastric juice reflects the activity of cholinergic transmission. Furthermore, these results also support the conclusion that vagus stimulation facilitates not only cholinergic transmission but also histaminergic transmission related to gastric acid secretion.     

Effect of chronic D-fenfluramine administration on rat hypothalamic serotonin levels and release

D-fenfluramine, an anorectic agent in rats and man, was administered daily at doses 1.25, 2.5, 5 or 10 mg/kg/day for 10 days, and sacrificed 6 days later. Hypothalamic serotonin (5-HT) levels were unchanged in rats receiving 1.25-5 mg/kg/day of d-fenfluramine but reduced by 22% (p less than 0.01) at the highest drug dose (10 mg/kg/day); hypothalamic 5-hydroxyindole acetic acid (5-HIAA) levels were reduced by 15% (p less than 0.05) or 28% (p less than 0.01) in rats receiving 5 or 10 mg/kg/day of the drug, respectively. Hypothalamic slices prepared from rats which were previously treated with any of the drug doses spontaneously released endogenous 5-HT at rates that did not differ from those of vehicle-treated rats. 5-HT released with electrical field-stimulation was unaffected by prior d-fenfluramine treatment at doses of 1.25-5 mg/kg/day, and was reduced by 20% (p less than 0.05) from slices prepared from rats which received 10 mg/kg/day. 5-HIAA efflux was also attenuated by the highest drug dose. These data indicate that chronic administration to rats of customary anorectic doses of d-fenfluramine (i.e. 0.06-1.25 mg/kg) fail to cause long-lasting reductions in brain 5-HT release.     

Solanum paniculatum L. (Jurubeba): potent inhibitor of gastric acid secretion in mice.

Solanum paniculatum L. is used commonly in Brazilian folk medicine for the treatment of liver and gastrointestinal disorders. The freeze-dried aqueous extracts (WEs) obtained from distinct parts of the plant (flowers, fruits, leaves, stems and roots) were tested to determine their antiulcer and antisecretory gastric acid activities using mice. The aqueous extracts of roots, stems and flowers inhibited gastric acid secretion in pylorus-ligated mice with ED50 values of 418, 777 and 820 mg/kg body wt. (i.d.), respectively. Extracts of leaves (0.5-2 g/kg body wt., i.d.) did not affect gastric secretion, whereas fruit extracts (0.5-2 g/kg body wt., i.d.) stimulated gastric acid secretion. The stimulatory effect of the fruit extract was inhibited by pretreatment with atropine (5 mg/kg body wt., i.m.) but not with ranitidine (80 mg/kg body wt., i.p.) suggesting that the fruit extract activates the muscarinic pathway of gastric acid secretion. In contrast, administration of the root extract into the duodenal lumen inhibited histamine- and bethanechol-induced gastric secretion in pylorus-ligated mice. In addition, the aqueous extract of roots (ED50 value, 1.2 g/kg body wt., p.o.) protected the animals against production of gastric lesions subsequent to the hypersecretion induced in mice by stress following cold restraint. This effect was not reproduced when the lesions were induced by blockade of prostaglandins synthesis via subcutaneous injection of indomethacin. Thus, antiulcer activity of the plant extracts appears to be related directly to a potent anti-secretory activity. No toxic signs were observed following administration of different extracts up to 2 g/kg body wt., p.o. Collectively, the results validate folk use of Solanum paniculatum L. plant to treat gastric disorders.     

Effects of endothelin-1 on duodenal bicarbonate secretion and mucosal integrity in rats

Effects of endothelin-1 on gastric acid secretion, duodenal HCO3- secretion, and duodenal mucosal integrity were investigated in anesthetized rats, in comparison with those of TY-10957, a stable analogue of prostacyclin. A rat stomach mounted on an ex-vivo chamber or a proximal duodenal loop was perfused with saline, and gastric acid or duodenal HCO3- secretion was measured using a pH-stat method and by adding 100 mM NaOH or 10 mM HCl, respectively. Duodenal lesions were induced by mepirizole (200 mg/kg) given subcutaneously. Intravenous administration of endothelin-1 (0.6 and 1 nmol/kg) caused an increase of duodenal HCO3- secretion with concomitant elevation of blood pressure; this effect was antagonized by co-administrahon of BQ-123 (ET(A) antagonist; 3 mg/kg, i.v.) and significantly mitigated by vagotomy. Likewise, endothelin-1 caused a significant decrease in histamine-stimulated acid secretion, and this effect was also significantly antagonized by BQ-123. Although TY-10957 (10 and 30 mg/kg, i.v.) produced a temporal decrease of blood pressure, this agent caused not only an increase of duodenal HCO3- secretion, independent of vagal nerves, but also a decrease of acid secretion as well. In addition, both endothelin-1 and TY-10957 significantly prevented mepirizole-induced duodenal lesions at the doses that caused an increase of duodenal HCO3- secretion and a decrease of gastric acid secretion. These results suggest that endothelin-1 affects the duodenal mucosal integrity by modifying both gastric acid and duodenal HCO3- secretions, the effects being mediated by ET(A) receptors.     

Gastro-protective effect of methanol extract of Ficus asperifolia bark on indomethacin-induced gastric ulcer in rats

The gastro-protective and antioxidant effects of methanol extract of Ficus asperifolia bark on indomethacin induced gastric ulcer were investigated in male rats. Thirty two male rats divided into 4 equal groups and were treated as follows: group1 (control), 0.5ml of 5% tween 80 (vehicle for the extract), groups 2 and 3, 100 and 500mg/kg of Ficus asperifolia extract respectively and group 4, cimetidine (100mg/kg). After two weeks of daily oral administration of vehicle, extract or cimetidine, gastric ulcer was induced in all rats with indomethacin (40 mg/kg, p.o). Gastric juice pH, gastric acid concentration, gastric ulcer score, percentage gastric ulcer inhibition, activity levels of superoxide dismutase (SOD), catalase and malondiadehyde (MDA) were determined. Ficus asperifolia extract significantly increased gastric pH (p.