Modulation of gastric acid secretion by cannabinoids in rats.

The current study aimed to evaluate the role of cannabinoid receptors in the regulation of gastric acid secretion and oxidative stress in gastric mucosa. To fulfill this aim, gastric acid secretion stimulated with histamine (5 mg/kg, subcutaneous [SC]), 2-deoxy- d-glucose (D-G) (200 mg/kg, intravenous) or -carbachol (4 µg/kg, SC) in the 4-hour pylorus-ligated rats. The CB1R agonist ( N-arachidonoyl dopamine, 1 mg/kg, SC) inhibited gastric acid secretion stimulated by D-G and carbachol but not in histamine, reduced pepsin content, and increased mucin secretion. Furthermore, it decreased malondialdehyde (MDA) and nitric oxide (NO) contents with an increase in glutathione (GSH) and paraoxonase 1 (PON-1). Meanwhile, CB2R antagonist (AM630, 1 mg/kg, SC) inhibited gastric acid secretion stimulated by D-G and reduced MDA and NO contents with an increase in GSH and PON-1. Meanwhile, CB1R antagonist rimonabant or CB2R agonist GW 405833 had no effect on stimulated gastric acid secretion. Therefore, both CB1R agonist and CB2R antagonist may exert antisecretory and antioxidant potential in the stomach.

The effect of antidepressant drugs on thioacetamide-induced oxidative stress.

OBJECTIVE: The aim of the present study was to investigate the effect of the serotonin selective reuptake inhibitors (SSRIs) fluoxetine and sertraline and the tricyclic drug imipramine on oxidative stress in the brain and liver caused by thioacetamide in rats. MATERIALS AND METHODS: Drugs were administered orally once daily at doses of 10 and 20 mg/kg for two weeks prior to intraperitoneal injection of thioacetamide (300 mg/kg). Rats were euthanized 24 h after thioacetamide. Reduced glutathione (GSH), malondialdehyde (MDA) and nitric oxide were measured in brain and liver. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) were measured in serum and histopathological evaluation of liver injury was performed. RESULTS: The administration of thioacetamide increased MDA by 151.8% and 161.2%, increased nitric oxide by 57.2% and 63.9% and decreased GSH by -40.6% and -67% in the brain and liver, respectively. Thioacetamide markedly increased serum ALT, AST and ALP by 277.8, 80.8 and 121%, respectively. In the brain, MDA was decreased in rats treated with fluoxetine or sertraline. The level of GSH increased by fluoxetine and by the higher dose of sertraline. Nitric oxide in brain was unchanged by fluoxetine, but increased after sertraline at 20 mg/kg. Brain MDA was increased by imipramine, which also decreased brain nitrite level. In the liver, fluoxetine or sertraline treatment increased GSH and nitrite levels. MDA was also increased by either drug. The drugs markedly decreased ALT, but increased ALP in serum. Meanwhile, imipramine decreased liver nitric oxide levels (at the lower dose only -32.9%), markedly increased hepatic GSH, but did not change MDA level. Serum ALT decreased by imipramine (but AST and ALP showed no change). Histopathological and histochemical examinations indicated that thioacetamide-induced liver injury was not decreased after treatment with the antidepressant drugs. CONCLUSIONS: In thioacetamide-treated rats, pretreatment with the SSRIs drugs fluoxetine and sertraline is associated with decreased lipid peroxidation in brain; liver peroxidation, however, is increased. Imipramine displayed opposite effects. The thioacetamide-induced hepatic damage was not reduced by fluoxetine, sertraline or imipramine.  

Cerebrolysin attenuates cerebral and hepatic injury due to lipopolysaccharide in rats.

This study aimed to investigate the effect of cerebrolysin on oxidative stress in the brain and liver during systemic inflammation. Rats were intraperitoneally challenged with a single subseptic dose of lipopolysaccharide (LPS; 300 µg/kg) without or with cerebrolysin at doses of 21.5, 43 or 86 mg/kg. After 4 h, rats were euthanized and the brain and liver tissues were subjected to biochemical and histopathological analyses. Cerebrolysin revealed inhibitory effects on the elevation of lipid peroxidation and nitric oxide induced by LPS. In contrast, the decrease in reduced glutathione level and paraoxonase activity induced by LPS was attenuated by an injection of cerebrolysin in a dose-dependent manner. Moreover, cerebrolysin reduced LPS-induced activation of brain NF-κB and reversed LPS-induced decline of brain butyrylcholinesterase and acetylcholinesterase activities in a dose-dependent manner. Histopathological analyses revealed that neuronal damage and liver necrosis induced by LPS were ameliorated by cerebrolysin dose-dependently. Cerebrolysin treatment dose-dependently attenuated LPS-induced expressions in cyclooxygenase 2, inducible nitric oxide synthase, and caspase-3 in the cortex or striatum as well as the liver. These results suggest that cerebrolysin treatment might have beneficial therapeutic effects in cerebral inflammation. Cerebrolysin might also prove of value in liver disease and this possibility requires further exploration.

Studies on the effects of aspartame on memory and oxidative stress in brain of mice.

OBJECTIVE: The dipeptide aspartame (N-L-alpha-aspartyl-Lphenylalanine, 1-methyl ester; alpha-APM) is one of the most widely used artificial sweeteners. The present study aimed to investigate the effect of repeated administration of aspartame in the working memory version of Morris water maze test, on oxidative stress and brain monoamines in brain of mice. MATERIALS AND METHODS: Aspartame (0.625, 1.875 or 5.625 mg/kg) was administered once daily subcutaneously for 2 weeks and mice were examined four times a week for their ability to locate a submerged plate. Malondialdehyde (MDA), reduced glutathione (GSH), nitric oxide levels (the concentrations of nitrite/nitrate) and glucose were determined in brain. RESULTS: Only at the highest dose of 5.625 mg/kg, did aspartame significantly impaired water maze performance. The mean time taken to find the escape platform (latency) over 2 weeks was significantly delayed by aspartame 5.625 mg/kg, compared with the saline-treated control group. Significant differences occurred only on the first trial to find the escape platform. Significant increase in brain MDA by 16.5% and nitric oxide by 16.2% and a decrease in GSH by 25.1% and glucose by 22.5% occurred after treatment with aspartame at 1.875 mg/kg. Aspartame administered at 5.625 mg/kg significantly increased brain MDA by 43.8%, nitric oxide by 18.6% and decreased GSH by 32.7% and glucose by 25.8%. Aspartame caused dose-dependent inhibition of brain serotonin, noradrenaline and dopamine. CONCLUSIONS: These findings suggest impaired memory performance and increased brain oxidative stress by repeated aspartame administration. The impaired memory performance is likely to involve increased oxidative stress as well as decreased brain glucose availability.

Study of the analgesic, anti-inflammatory, and gastric effects of gabapentin.

Gabapentin, a drug used to treat neuropathic pain, was evaluated in models of acute nociceptive pain, in instances of haloperidol-induced catalepsy, carrageenan-induced paw edema, gastric lesions caused by indomethacin or ethanol, and gastric acid secretion in rats. Reaction time in a hot plate assay was delayed by gabapentin. The antinociceptive effect of the drug was produced with a dose of 12.5 mg/kg and a maximal increase in hot plate latency of 68% 1 h after drug administration was produced at 100 mg/kg. Gabapentin (25, 50 or 100 mg/kg) caused a significant rise in current threshold in a tail electrical stimulation test in mice, resulting in values of 20, 30, and 60.5% vs. control values, 1 h post-dosing. With the agent, the duration of paw licking following intraplantar capsaicin injection decreased in a dose-dependent manner. In contrast, gabapentin failed to have antinociceptive action in a mouse acetic-acidinduced writhing assay. The drug (12.5-50 mg/kg) increased the duration of catalepsy induced by haloperidol by 33.5, 47.4, and 53.2%, respectively. It had an anti-inflammatory effect at doses of 25 or 50 mg/kg. Gabapentin (12.5-50 mg/kg) reduced the number and severity of gastric mucosal lesions induced by subcutaneous indomethacin (20 mg/kg) or intragastric 96% ethanol, but at doses of 50 and 100 mg/kg it increased gastric acid secretion. In conclusion, gabapentin decreased thermal, electrical, and chemogenic pain but not visceral pain and had a gastric protective effect.

A laser doppler study of the effect of 2-alkylthio-4-ethyl-4-methyl-4,5 dihydro-1H-imidazolin-5-one oxime (oxime) on the ischaemic rat lower limb.

The potential vasodilator effect of the novel compound 2-alkylthio-4-ethyl-4-methyl-4,5 dihydro-1H-imidazolin-5-one oxime (oxime) was investigated in a model of lower limb ischaemia induced in rats by unilateral ligation of the right femoral artery using Laser Doppler Flowmetry. The effect of oxime was compared with that of isoprenaline or L-arginine. Test drugs were injected systemically into the femoral vein or applied locally on the planter surface of the rat hind paw. Serum level of nitrite (NO(2) (-)) and nitrate (NO(3) (-)) were measured by ELISA. Immediately after operative induction of right lower limb ischaemia, blood flow ratio (Right/Left limb ratio: BFR) decreased to 0.33-0.39 in different groups. The intravenous (i.v.) administration of oxime increased BFR in a dose-dependent manner. Compared with pre-drug BFR, oxime administered at doses of 0.064, 0.128 or 0.256 mg/kg increased BFR to 178.8, 328.9 and 705.9 %, respectively. Meanwhile, L-arginine given i.v. at 100 mg/kg increased BFR to 560 %. Isoprenaline given i.v. at 1 microg/kg increased BFR to 274.3 %, while isoprenaline combined with oxime (0.064 mg/kg) increased BFR to 402.7 %. Similarly, after topical application of oxime, BFR increased to 113.5, 261.1 and 433.3 %, respectively. L-arginine given at 1000 mg/kg increased BFR to 389.7 %. Isoprenaline given at 10 microg/kg increased BFR to 231.6 %, while isoprenaline administered in combination with oxime (0.064 mg/kg) increased BFR to 308.3 %. The concentration of NO in serum was significantly increased after systemic or topical administration of either 0.128 and 0.256 mg/kg oxime or 100 and 1,000 mg/kg L-arginine, respectively. It is concluded that systemic or topical oxime results in marked enhancement of blood flow in the rat ischaemic lower limb. This effect of oxime is likely to be mediated through the release of NO.

Vinpocetine ameliorates acute hepatic damage caused by administration of carbon tetrachloride in rats.

Vinpocetine is a widely used drug for the treatment of cerebrovascular and memory disorders. This study aimed to investigate the effect of vinpocetine on the acute hepatic injury caused in the rat by the administration of CCl4 in vivo. Vinpocetine (2.1, 4.2, 8.4 mg/kg) or silymarin (30 mg/kg) was given once daily orally simultaneously with CCl4 and for 15 days thereafter. Liver damage was assessed by determining serum enzyme activities and hepatic histopathology. Stained sections were subjected to morphometric evaluation using computerized image analyzer. The results showed that vinpocetine administered to CCl4-treated rats decreased the elevated alanine aminotransferase (ALT) by 49.3, 58.1 and 63.6%, aspartate aminotransferase (AST) by 10.5, 22.6 and 27.2% and alkaline phosphatase (ALP) by 52.5, 59.6 and 64.9%, respectively, and in a dose-dependent manner. Meanwhile, silymarin reduced elevated ALT, AST and ALP levels by 53.1, 26.9 and 66%, respectively. Histological examination of liver specimens revealed a marked reduction in liver cell necrosis in vinpocetine and silymarin-treated rats compared with vehicle-treated CCl4-treated rats. Quantitative analysis of the area of damage showed 85.3% reduction in the area of damage after silymarin and 72.2, 78.9 and 82.6% reduction after vinpocetine treatment at 2.1, 4.2, 8.4 mg/kg, respectively. It is concluded that administration of vinpocetine in a model of CCl4-induced liver injury in rats reduced liver damage. The reduction obtained by 4.2 mg/kg of vinpocetine was similar to that obtained by 30 mg/kg silymarin. Therefore, it is suggested that vinpocetine might be a good pharmacological agent in the treatment of liver disease besides its neuroprotective effects.

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.

Gastric mucosal integrity: gastric mucosal blood flow and microcirculation. An overview.

The stomach is in a state of continuous exposure to potentially hazardous agents. Hydrochloric acid together with pepsin constitutes a major and serious threat to the gastric mucosa. Reflux of alkaline duodenal contents containing bile and pancreatic enzymes are additional important injurious factors of endogenous origin. Alcohol, cigarette smoking, drugs and particularly aspirin and aspirin-like drugs, and steroids are among exogenous mucosal irritants that can inflict mucosal injury. The ability of the stomach to defend itself against these noxious agents has been ascribed to a number of factors constituting the gastric mucosal defense. These include mucus and bicarbonate secreted by surface epithelial cells, prostaglandins, sulfhydryl compounds and gastric mucosal blood flow. The latter is considered by several researchers to be of paramount importance in maintaining gastric mucosal integrity. The aim of this paper is to review the experimental and clinical data dealing with the role of mucosal blood flow and in particular the microcirculation in both damage and protection of the gastric mucosa.

Helicobacter pylori. One bacterium and a broad spectrum of human disease! An overview.

Since the historical rediscovery of gastric spiral Helicobacter pylori in the gastric mucosa of patients with chronic gastritis by Warren and Marshall in 1983, peptic ulcer disease has been largely viewed as being of infectious aetiology. Indeed, there is a strong association between the presence of H. pylori and chronic active gastritis in histology. The bacterium can be isolated in not less than 70% of gastric and in over 90% of duodenal ulcer patients. Eradication of the organism has been associated with histologic improvement of gastritis, lower relapse rate and less risk of bleeding from duodenal ulcer. The bacterium possesses several virulence factors enabling it to survive the strong acid milieu inside the stomach and possibly damaging host tissues. The sequence of events by which the bacterium might cause gastric or duodenal ulcer is still not fully elucidated and Koch's postulates have never been fulfilled. In the majority of individuals, H. pylori infection is largely or entirely asymptomatic and there is no convincing data to suggest an increase in the prevalence of peptic ulcer disease among these subjects. An increasingly growing body of literature suggests an association between colonization by H. pylori in the stomach and a risk for developing gastric mucosa-associated lymphoid tissue (MALT), MALT lymphoma, gastric adenocarcinoma and even pancreatic adenocarcinoma. The bacterium has been implicated also in a number of extra-gastrointestinal disorders such as ischaemic heart disease, ischaemic cerebrovascular disease, atherosclerosis, and skin diseases such as rosacea, but a causal role for the bacterium is missing. Eradication of H. pylori thus seems to be a beneficial impact on human health. Various drug regimens are in use to eradicate H. pylori involving the administration of three or four drugs including bismuth compounds, metronidazole, clarithromycin, tetracyclines, amoxycillin, ranitidine, omeprazole for 1-2 weeks. The financial burden, side effects and emergence of drug resistant strains due to an increase in the use in antibiotics for H. pylori eradication therapy need further reconsideration.

Small doses of capsaicin given intragastrically inhibit gastric basal acid secretion in healthy human subjects.

Although the direct inhibitory effect of small dose of capsaicin on gastric secretory responses was proved in animal observations, the role of capsaicin-sensitive afferent nerves (CSAN) and the effect of capsaicin applied in small and high doses on gastric secretion in human has not been clarified yet. In this study we investigated the influence of different small doses (100-800 microg) of capsaicin given intragastrically through an orogastric tube on gastric basal secretory responses in 10 healthy human subjects. Gastric basal secretory responses (volume, H+-concentration, H+-output) were measured from the suctions of gastric juice for a 1-h period. It has been found that: a) capsaicin dose-dependently inhibited the volume and H+-output of gastric juice; b) ID50 was found to be about 400 microg for capsaicin on gastric acid secretion; c) the time interval for capsaicin-induced gastric inhibition existed for about 1 h indifferently from the higher dose (800 microg) of capsaicin given after. It has been concluded that the capsaicin (given in small doses) inhibits the gastric basal acid output via stimulation of the inhibition of capsaicin sensitive afferent nerves.

Capsaicin-sensitive afferent sensory nerves in modulating gastric mucosal defense against noxious agents.

In the rat stomach, evidence has been provided that capsaicin-sensitive sensory nerves (CSSN) are involved in a local defense mechanism against gastric ulcer. In the present study capsaicin or resiniferatoxin (RTX), a more potent capsaicin analogue, was used to elucidate the role of these sensory nerves in gastric mucosal protection, mucosal permeability, gastric acid secretion and gastrointestinal blood flow in the rat. In the rat stomach and jejunum, intravenous RTX or topical capsaicin or RTX effected a pronounced and long-lasting enhancement of the microcirculation at these sites, measured by laser Doppler flowmetry technique. Introduction of capsaicin into the rat stomach in very low concentrations of ng-microg x mL(-1) range protected the gastric mucosa against damage produced by topical acidified aspirin, indomethacin, ethanol or 0.6 N HCl. Resiniferatoxin exhibited acute gastroprotective effect similar to that of capsaicin and exerted marked protective action on the exogenous HCl, or the secretagogue-induced enhancement of the indomethacin injury. The ulcer preventive effect of both agents was not prevented by atropine or cimetidine treatment. Capsaicin given into the stomach in higher desensitizing concentrations of 6.5 mM markedly enhanced the susceptibility of the gastric mucosa and invariably aggravated gastric mucosal damage evoked by later noxious challenge. Such high desensitizing concentrations of capsaicin, however, did not reduce the cytoprotective effect of prostacyclin (PGI2) or beta-carotene. Capsaicin or RTX had an additive protective effect to that of atropine or cimetidine. In rats pretreated with cysteamine to deplete tissue somatostatin, capsaicin protected against the indomethacin-induced mucosal injury. Gastric acid secretion of the pylorus-ligated rats was inhibited with capsaicin or RTX given in low non-desensitizing concentrations, with the inhibition being most marked in the first hour following pylorus-ligation. Low intragastric concentrations of RTX reduced gastric hydrogen ion back-diffusion evoked by topical acidified salicylates. It is concluded that the gastropotective effect of capsaicin-type agents involves primarily an enhancement of the microcirculation effected through local release of mediator peptides from the sensory nerve terminals. A reduction in gastric acidity may contribute to some degree in the gastric protective action of capsaicin-type agents. The vasodilator and gastroprotective effects of capsaicin-type agents do not depend on vagal efferents or sympathetic neurons, involve prostanoids, histaminergic or cholinergic pathways.

Capsaicin increases gastric emptying rate in healthy human subjects measured by 13C-labeled octanoic acid breath test.

The role of capsaicin-sensitive primary afferent sensory nerves in the regulation of gastrointestinal motility in human is not clarified yet. In this study, we investigated the effect of 400 microg capsaicin given intragastrically on gastric emptying measured by 13C-octanoic acid breath test in ten healthy human subjects. Four parameters of gastric emptying curves were taken into consideration: 1) maximum value of the curve, 2) time belonging to this maximum, 3) slope of the rising part of the curve and 4) time belonging to the 50% of the area under the curve. Administration of 400 microg capsaicin significantly increased the slope of gastric emptying curve (from 0.1 +/- 0.01 to 0.139 +/- 0.014 U x min(-1), P < 0.05) and significantly decreased the time belonging to the maximum value of emptying curve (from 150 +/- 18 to 75 +/- 12 min, P < 0.05) and the time belonging to the 50% of the area under the curve (from 112 +/- 15 to 99 +/- 14 min, P < 0.05). According to our results 400 microg capsaicin enhances gastric emptying rate in healthy human subjects.

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.

Capsaicin and the stomach. A review of experimental and clinical data.

Capsaicin, the pungent principle of hot pepper, because of its ability to excite and later defunctionalize a subset of primary afferent neurons, has been extensively used as a probe to elucidate the function of these sensory neurons in a number of physiological processes. In the rat stomach, experimental data provided clear evidence that capsaicin-sensitive (CS) sensory nerves are involved in a local defense mechanism against gastric ulcer. Stimulation of CS sensory nerves with low intragastric concentrations of capsaicin protected the rat gastric mucosa against injury produced by different ulcerogenic agents. High local desensitizing concentrations of capsaicin or systemic neurotoxic doses of the agent markedly enhanced the susceptibility of the rat gastric mucosa to later noxious challenge. Resiniferatoxin, a potent analogue of capsaicin possesses an acute gastroprotective effect similar to that of capsaicin in the stomach. The gastroprotective effect of capsaicin-type agents involves an enhancement of the microcirculation effected through the release of mediator peptides from the sensory nerve terminals with calcitonin gene-related peptide being the most likely candidate implicated. They do not depend on vagal efferent or sympathetic neurons or involve prostanoids. The gastric mucosal protective effect of prostacyclin is retained after systemic or topical capsaicin desensitization. Capsaicin-sensitive fibers are involved in the repair mechanisms of the gastric mucosa. A protective role for CS sensory nerves has also been demonstrated in the colon. In most studies, capsaicin given into the stomach of rats or cats inhibited gastric acid secretion. In humans, although recent studies provide evidence in favor of a beneficial effect of capsaicin on the gastric mucosa, an exact concentration-related assessment of the effect of the agent is still lacking.

The indomethacin-induced gastric mucosal damage in rats. Effect of gastric acid, acid inhibition, capsaicin-type agents and prostacyclin.

In pylorus-ligated rats subcutaneous (s.c.) pentagastrin (325.5 nmol/kg) or histamine (54.3 mumol/kg), but not the cholinergic agent bethanechol (7.6 or 15.2 mumol/kg), increased gastric mucosal injury by s.c. indomethacin (55.8 mumol/kg). Intragastric (i.g.) administration of 0.15 or 0.3 N HCl greatly potentiated injury by s.c. indomethacin with widespread ulceration, intragastric bleeding and even perforation. The gastric mucosal damage produced by indomethacin plus 0.3 N HCl was reduced by i.g. capsaicin (3.1-25.1 microM), i.g. resiniferatoxin (0.38-6.1 microM), by s.c. atropine (0.15-1.2 mumol/kg) and to a lesser extent by i.g. prostacyclin (40-267 microM) or s.c. cimetidine (198.2 mumol/kg). The protective effect of capsaicin or resiniferatoxin was not prevented by atropine or cimetidine treatment. Capsaicin (6.5 mM) enhanced gastric injury by s.c. or i.g. indomethacin. Results indicate the importance of early vascular events in the pathogenesis of mucosal injury induced by indomethacin in the stomach and suggest a role for gastric acid in potentiation of such injury. Results further strengthen the idea of a protective role for capsaicin-sensitive sensory nerves in the stomach.

Effect of capsaicin and resiniferatoxin on gastrointestinal blood flow in rats.

The effect of capsaicin and resiniferatoxin on gastrointestinal blood flow was studied in anaesthetized rats by laser Doppler flowmetry. Resiniferatoxin injected into the jugular vein (0.08-1.6 nmol/kg) produced a marked and dose-dependent increase in gastric blood flow, while the effect of capsaicin (0.33-19.6 nmol/kg) was transient, variable and accompanied by profound systemic blood pressure changes. After acute bilateral cervical vagotomy combined with sympathetic neurone blockade (guanethidine 16 mumol/kg) or alpha-adrenoceptor blockade (phentolamine 1.6 mumol/kg), the vasodilator response to injected resiniferatoxin was more pronounced, indicating that the resiniferatoxin-induced gastric vasodilatation is not due to reflexes via parasympathetic or sympathetic efferent fibres. Resiniferatoxin given i.v. (0.08-0.64 nmol/kg) evoked a similar increase in the blood flow of the jejunum. Capsaicin (0.33-33 microM) or resiniferatoxin (0.16-1.6 microM) applied topically to the serosal surface of the stomach or jejunum produced a pronounced and long-lasting increase in blood flow after vagotomy and guanethidine treatment. The blood flow and blood pressure responses to capsaicin and resiniferatoxin were absent in rats desensitized with systemic capsaicin pretreatment. These laser Doppler data provide the first evidence for the effect of resiniferatoxin on gastrointestinal microcirculation and indicate the advantages of this agent and technique to study the sensory-efferent function of capsaicin-sensitive fibres.

Preventive effect of atropine on indomethacin-induced gastrointestinal mucosal and vascular damage in rats.

The protective effect of 'chemical vagotomy' (atropine given in three doses: 0.1, 0.5 and 1.0 mg/kg i.p.) was examined on indomethacin (IND, 20 mg/kg s.c.)-induced macroscopic gastrointestinal (GI) mucosal erosions and changes of vascular permeability in the stomach and three equal parts of small intestine and colon in rats. The different doses of atropine were administered at 0, 5, 10, 15 and 20 h after IND administration, then the number and severity of lesions were noted and the vascular damage was measured by Evans blue extravasation into the mucosa and intraluminal juice at 24 h after the IND treatment. Our results indicate that atropine ('chemical vagotomy') dose-dependently and significantly decreases the IND-induced mucosal erosions and vascular permeability in the vagal nerve-innervated parts of GI tract (i.e. the stomach, small intestine and proximal colon). Atropine in 0.5 and 1.0 mg/kg doses has a significantly higher protective effect on the vascular damage than on the macroscopic mucosal lesions in the stomach, small intestine and proximal colon. The vascular permeability is only one of those factors which have a role in the appearance of the GI mucosal erosions after IND treatment. These results suggest that the decrease of vascular permeability is involved in the protective effect of atropine against IND-induced GI mucosal damage.

Studies on the effect of intragastric capsaicin on gastric ulcer and on the prostacyclin-induced cytoprotection in rats.

The effect of intragastric (i.g.) capsaicin on experimental gastric ulcer was studied in the 1 h pylorus-ligated rats. Capsaicin applied in 40 ng ml-1 concentration (0.1 microgram kg-1) protected against gastric mucosal injury evoked by i.g. application of acidified aspirin, 96% ethanol or 0.6 M HCl. After a capsaicin concentration of 400 micrograms ml-1 (1 mg kg-1) protection occurred initially, while several hours later mucosal damage evoked by acidified aspirin was enhanced. Capsaicin in 2 and 6 ml kg-1 (10 and 30 mg kg-1) invariably aggravated the aspirin and ethanol-induced gastric mucosal damage. Capsaicin in 0.1 microgram kg-1 did not modify the mucosal protective action of prostacyclin (5 micrograms kg-1) on gastric mucosal injury produced by i.g. application of acidified aspirin, 96% ethanol or 0.6 M HCl. Local capsaicin desensitization induced by application of capsaicin in 2 mg ml-1 (10 mg kg-1) did not interfere with the mucosal cytoprotective effects of prostacyclin against ethanol and aspirin-induced mucosal damage. It is concluded that i.g. capsaicin exerts a dual dose-dependent effect on development of experimental gastric ulcer. Neither i.g. capsaicin in small doses nor local capsaicin desensitization modify the mucosal cytoprotective effects of prostacyclin.

Effect of resiniferatoxin on stimulated gastric acid secretory responses in the rat.

The effect of the capsaicin analogue 'resiniferatoxin' (RTX) was studied on basal and stimulated gastric acid secretory responses following sc bethanechol (1.5 mg/kg), sc pentagastrin (50 micrograms/kg) and sc histamine (0.5 and 2.5 mg/kg) in the 1-h pylorus-ligated plus saline (2 ml ig)-treated rats. Resiniferatoxin applied intragastrically in doses of 0.6 and 1 microgram/kg at time of pylorus-ligation and administration of the above secretagogues reduced acid secretory responses to bethanechol by 18.3 and 26.4%, to 0.5 mg/kg histamine by 39.9 and 44.6%, to 2.5 mg/kg histamine by 21.3 and 40.8% and to pentagastrin by 10.2 and 30.9% respectively. A single sc injection of 0.4 microgram/kg of RTX abolished basal secretion in pylorus ligated rats (which did not receive ig saline). Our results indicate that locally applied RTX is capable of inhibiting basal secretory responses and modifying gastric acid responses stimulated with histamine, bethanechol or pentagastrin in the rat.