Impaired Adaptive Cytoprotection to Ethanol-Induced Damage in Gastric Mucosa of Portal Hypertensive Rats

Portal hypertension predisposes gastric mucosato increased damage by noxious agents. Adaptivecytoprotection has not been studied in portalhypertensive gastric mucosa. We evaluated adaptivecytoprotection in the gastric mucosa of portal hypertensiverats by exposure to ethanol. The injury index (percentgross lesions) was significantly higher in portalhypertensive rats than in sham-operated rats. The ratio of adaptive cytoprotection, calculated as thedegree of decrease in the injury index caused bypre-absolute-ethanol administration of 20% ethanol, wassignificantly impaired in portal hypertensive rats. Basal levels of gastric mucosal hexosamine werelower in portal hypertensive rats than in controls, anda blunted response to 20% ethanol was associated withportal hypertension. Nitric oxide inhibition (L-NAME, 5 mg/kg) reduced the ratio of adaptivecytoprotection in sham-operated but not in portalhypertensive rats. These results suggest that impairedadaptive cytoprotection in portal hypertensive gastric mucosa may be caused by blunted mucusproduction.     

Repair of Rat Gastric Mucosa (Effect of 16,16-Dimethyl Prostaglandin E2)

Prostaglandins protect the gastric mucosaagainst a variety of injurious agents and may acceleratethe recovery of the gastric mucosa following damage. Inprevious studies prostaglandins were given prior to the injurious agent, so it was not possibleto distinguish their potential effects on acceleratingrepair or reducing initial damage. We have investigatedthe effect of 16,16-dimethyl prostaglandin E₂ (dmPGE₂) on the repair of thegastric muscosa after injury induced by severalinjurious agents. dmPGE₂ was given orally 15min prior to aspirin or sodium salicylate, or 30 minafter aspirin, sodium salicylate, or ethanol. dmPGE₂ delivered priorto injury reduced the aspirin-induced fall in mucosalpotential difference (PD), but had no effect on thatinduced by sodium salicylate. dmPGE₂administered after ASA injury significantly increased recovery of PD (P <0.05), but did not alter the rate of recovery of PD withother damaging agents. Histological damage was decreasedin rats treated with dmPGE₂ after aspirincompared to aspirin-only-treated rats (P < 0.02).Exogenous dmPGE₂ protects and restoresgastric mucosal integrity after aspirin damage but hasno effect on the repair of sodium salicylate and ethanolinjured mucosa, suggesting that repair of the gastric mucosaafter aspirin damage is enhanced by dmPGE₂due to its ability to prevent ongoing damage, ratherthan directly enhancing repair processes.     

Protective Effect of a Novel Rice Extract Against Ethanol-Induced Gastric Mucosal Injury in Rat

The aim of this study was to investigate the protective action of rice extract on ethanol-induced mucosal damage in vivo and wound healing of epithelial cells in vitro. Also, the effect of rice extract on gastric mucosal prostaglandin E₂ level, HSP72 expression, gastric acid secretion, and contribution of vanilloid receptor-mediated action was studied. In addition, using cultured gastric mucosal cells (RGM-1), the effect of rice extract on cytoprotection and wound healing of epithelial cells was evaluated. Rice extract significantly reduced gastric mucosal damage produced by ethanol in vivo, and heat treatment (80°C, 3 min) of this agent did not alter its protective effect. Rice extract also protected RGM-1 from ethanol-induced damage in a dose-dependent manner. Rice extract accelerated wound healing of gastric epithelial cells. Our results demonstrate that rice extract could be an alternative ulcer treatment that provides cytoprotection and enhancement of wound healing not dependent on acid secretion, prostaglandin E₂ level, HSP72 expression, or vanilloid receptors.     

Preventive Effect of the Flavonoid, Wogonin, Against Ethanol-Induced Gastric Mucosal Damage in Rats

Whether wogonin (5,7-dihydroxy-8-methoxyflavone), a flavonoid originated from the root of Scutellaria baicalensis Georgi, which has been shown to have antiinflammatory and antitumor activities in various cell types, possesses a gastric cytoprotective effect was investigated in an ethanol-induced gastric damage model in rats. Ethanol administration alone induced evident gastric damage including gastric hemorrhages and edema, while this gastric damage was significantly attenuated by wogonin pretreatment (30 mg/kg B.W.) 1 hr before ethanol administration. As major protective mechanisms of wogonin on ethanol-induced gastric damage, we found that wogonin showed either antiinflammatory effects through dual actions on arachidonic acid metabolism, i.e., induction of prostaglandin D2 and suppression of 5S-hydroxyeicosatetraenoic acid (5S-HETE), or preventive induction of profuse apoptosis in the stomach. Conclusively, the flavonoid wogonin could be used as a preventive agent of alcohol-induced gastropathy, whose actions were proven to be strong antiinflammation and apoptosis induction.     

Antisecretory and Ulcer Healing Effects of S-0509, a Novel CCK-B/Gastrin Receptor Antagonist, in Rats

The effects of a novel CCK-B/gastrin receptorantagonist, S-0509, on gastric acid secretion and thehealing of acetic acid ulcers in rats were examined.S-0509, orally administered 1, 6, and 12 hr prior to a 3-hr pylorus ligation, significantlyinhibited basal gastric acid secretion in both normalrats and rats with gastric ulcers. The inhibition wasnearly dose-related, persisted for more than 15 hr, and proved to be more potent in rats withulcers than in normal rats. In addition, S-0509 markedlyinhibited pentagastrin- and carbachol-stimulated acidsecretion in both normal rats and rats with ulcers, but failed to inhibit histamine-stimulatedsecretions. In chronic gastric fistula rats, S-0509 alsosignificantly inhibited pentagastrin- andcarbacholstimulated gastric acid secretion in adose-related manner, but had no effect onhistaminestimulated secretion. These effects werelargely similar to those observed with famotidine,although famotidine also inhibited histamine-stimulatedsecretion. A two-week treatment with S-0509 markedly enhanced thespontaneous healing of acetic acid ulcers and preventedthe delay in ulcer healing caused by indomethacin.Gastric secretion was significantly inhibited and the plasma gastrin level was increased in theanimals studied. It is concluded that S-0509 is apromising new antisecretory drug for the treatment ofpeptic ulcers.     

Protective Effect of Melatonin and Omeprazole Against Alendronat-Induced Gastric Damage

Alendronate causes serious gastrointestinal adverse effects. We aimed to investigate if free radicals have any role in the damage induced by alendronate and if melatonin or omeprazole is protective against this damage. Rats were administered 20 mg/kg alendronate by gavage for 4 days, either alone or following treatment with melatonin or omeprazole. On the last day, following drug administration, pilor ligation was performed, and 2 hr later rats were killed and stomachs were removed. Gastric acidity and tissue ulcer index values, lipid peroxidation, and myeloperoxidase and glutathione levels, as well as the histologic appearance of the stomach tissues, were determined. Chronic oral administration of alendronate induced significant gastric damage, increasing lipid peroxidation and myeloperoxidase activity, while tissue glutathione levels decreased. Treatment with omeprazole or melatonin prevented this damage as well as the changes in biochemical parameters, and melatonin appeared to be more efficient than omeprazole in protecting the mucosa. Intraperitoneal administration of alendronate did not cause much gastric irritation. Findings of the present study suggest that alendronate induces oxidative gastric damage by a local irritant effect and that melatonin and omeprazole are protective against this damage due to their antioxidant properties.     

The Role of Zinc Sulfate and Metallothionein in Protection Against Ethanol-Induced Gastric Damage in Rats

In this study, the effects of zinc sulfate against ethanol-induced acute gastric damage in rats were investigated, morphologically and biochemically. In addition, the present investigation has demonstrated the distribution of metallothionein stimulated by zinc in gastric mucosal tissues, immunohistochemically. The gastric damage was induced by intragastric administration of 1 ml absolute ethanol per rat. Rats received zinc sulfate (100 mg/kg/day) for 3 consecutive days 2 hr prior to the administration of absolute ethanol. Acute ethanol exposure caused degenerative morphological changes, a decrease in metallothionein immunreactivity; an increase in lipid peroxidation (LPO) levels, and a decrease in reduced glutathione (GSH) levels in gastric mucosa. On the other hand, zinc sulfate administration to ethanol-treated rats caused a significant reduction in the histological damage, an increase in metallothionein immunreactivity, a decrease in LPO levels, and an increase in GSH levels in gastric mucosa. As a result, the present study indicates that zinc sulfate has a protective effect against ethanol-induced acute gastric damage. In addition, we might say that the zinc given as exogenous protection against acute gastric damage has a protective effect both by stimulation of metallothionein synthesis and through GSH as well as having antioxidative potential.     

Protective Effect of Vitamin E Against Ethanol-Induced Hyperhomocysteinemia, DNA Damage, and Atrophy in the Developing Male Rat Brain

Background:  Chronic alcoholism leads to elevated plasma and brain homocysteine (Hcy) levels, as demonstrated by clinical investigations and animal experiments. It has been posited that elevated levels of Hcy mediate DNA damage, brain atrophy, and excitotoxicity. The current study sought to elucidate the effect of vitamin E on ethanol-induced hyperhomocysteinemia, DNA damage, and atrophy in the developing hippocampus and cerebellum of rats.
Methods:  Pregnant Wistar rats received ethanol with or without vitamin E from gestation day 7 throughout lactation. Weight changes in the brain, hippocampus and cerebellum, DNA damage, and Hcy levels in the plasma, hippocampus, and cerebellum of male offspring were measured at the end of lactation.
Results:  The results revealed that along with a significant decrease in brain, cerebellum, and hippocampus weights in animals that received alcohol, the levels of DNA damage and Hcy significantly increased. Significant amelioration of brain atrophy and DNA damage as well as restoration of the elevated level of Hcy to that of controls were found in vitamin E-treated rats.
Conclusions:  These findings strongly support the idea that ethanol intake by dams during pregnancy and lactation induces Hcy-mediated oxidative stress in the developing hippocampus and cerebellum of offspring rats, and that these effects can be alleviated by vitamin E as an antioxidant.     

Protective Effect of Famotidine, Omeprazole, and Melatonin Against Acetylsalicylic Acid-Induced Gastric Damage in Rats

It has been reported that both omeprazole and famotidine have a protective effect against gastric mucosal damage induced by acetylsalicylic acid (ASA) and other nonsteroidal antiinflammatory drugs. Since active oxygen species and lipid peroxidation were reported to play a role in the pathogenesis induced by ASA, we aimed to study if omeprazole and famotidine have any antioxidant effect by comparing their protective effect with that of melatonin, an effective antioxidant and free radical scavenger. Mucosal damage was evaluated by macroscopic examination, histological analysis and by measurement of lipid peroxidation (LPO), glutathione (GSH), and myeloperoxidase (MPO) activity. Omeprazole (20 mol/kg per os), famotidine (3 mg/kg per os), and melatonin (10 mg/kg intraperitoneally) significantly prevented gastric ulcerogenesis induced by ASA (200 mg/kg per os) and decreased the ulcer index. Gastric LPO and MPO activity that were increased significantly by ASA were decreased after treatment with omeprazole, famotidine, and melatonin. ASA treatment decreased significantly the gastric GSH levels, and pretreatment with omeprazole, famotidine, or melatonin increased it significantly. Famotidine and omeprazole decreased the gastric acidity, which was increased by ASA, whereas melatonin had no effect on this parameter. These findings suggest that active oxygene species and LPO have an important role in the pathogenesis of gastric mucosal damage induced by ASA and that both famotidine and omeprazole may be protective against this damage, although they were not as efficient as melatonin as an antioxidant. On the other hand, the antisecretory effect of omeprazole and famotidine may also be contributing to their antiulcer effect.     

Paradoxical Role of Helicobacter pylori Infection: Protective Effect Against Ethanol-Induced Gastric Mucosal Injury in Mongolian Gerbils

We investigated the effect of ethanol (a representative necrotizing agent) on gastritis induced by Helicobacter pylori infection in Mongolian gerbils. Seventy-eight gerbils were used. Four and 12 weeks after H. pylori inoculation, 30% ethanol was administered into the stomach. The stomachs were removed after 30 min, the intramucosal prostaglandin (PG) E₂ concentration was measured, and histopathology was recorded. H. pylori infection caused chronic active gastritis, gastric erosion, hypersecretion of mucin from gland mucus cells, and a rise in the activity of intramucosal PGE₂. After ethanol administration, gastric erosion was significantly less in animals infected with H. pylori than in uninfected animals. In conclusion, in the early stage of H. pylori infection, accentuation of intramucosal PGE₂ and hypersecretion of mucin from gland mucus cells have a protective effect against gastric mucosal injury induced by necrotizing agents.     

Seroprevalence of Helicobacter pylori, Incidence of Gastric Cancer, and Peptic Ulcer-Associated Hospitalizations in a Canadian Indian Population

The living conditions of many aboriginalcommunities in Canada may place their residents at riskfor H. pylori infection. Our aims were to determine: (1)the seroprevalence of H. pylori in a traditional Indian community, (2) the clinical relevance ofH. pylori infection in this population, and (3) if H.pylori could be identified by polymerase chain reactionfrom the local water. A demographic questionnaire was administered, and blood was collected fromsubjects in an Indian community in northwesternManitoba. The serum was analyzed by ELISA for IgG to H.pylori and to CagA. ABO and Lewis antigens were tested. Age-adjusted incidence of gastric cancer and ofhospitalizations associated with diagnoses of pepticulcer were determined for the Indian and non-IndianManitoba population in the years 1989-1993. Nested PCR was performed on lake water using H.pylori-specific primers and the amplicons probed with aninternal Dig-labeled probe. Three hundred six (59%) ofapproximately 518 individuals who were resident in the community at the time of the study wereenrolled. The ELISA for H. pylori was positive in 291(95%). There was no association between H. pyloriseropositivity and age, sex, gastrointestinalcomplaints, medications, housing characteristics, and ABOor Lewis antigen status. CagA was positive in 84.5% ofinfected subjects. The average annual age-adjustedincidence of hospitalizations associated with diagnoses of peptic ulcer disease in Manitoba was higherfor treaty-status Indians (394.3/100,000) than fornon-Indians (203.8/100,000), but gastric cancer rateswere similar (11.2/100,000 vs 11.6/ 100,000). No H. pylori DNA was detected in the lake water. Inconclusion, the seroprevalence of CagA-positive H.pylori is high in this representative Manitoban Indiancommunity. This may be associated with an increased risk for peptic ulcer disease but is notassociated with an increased risk for gastriccancer.     

Relationship Between Changes of Active Oxygen Metabolism and Blood Flow and Formation, Progression, and Recovery of Lesions in Gastric Mucosa of Rats with a Single Treatment of Compound 48/80, a Mast Cell Degranulator

The relationship between the changes of activeoxygen metabolism and blood flow and the formation,progression, and recovery of lesions was examined in thegastric mucosa of rats treated once with compound 48/80, a mast cell degranulator. Gastricmucosal lesions appeared 0.5 hr after compound 48/80treatment, became worst at 3 hr, and recovered fairlywell at 12 hr. Increases in gastric mucosal lipidperoxide content and xanthine oxidase andmyeloperoxidase activities and decreases in gastricmucosal vitamin E and hexosamine contents andSe-dependent glutathione peroxidase activity occurredwith the formation and progression of gastric mucosal lesions.These changes were attenuated with the recovery of thelesion. Gastric mucosal nonprotein SH content decreasedwith the formation of gastric mucosal lesions, and this decreased SH content returned to nearthe original level with lesion progression. No changesin gastric mucosal superoxide dismutase and catalaseactivities occurred with the formation, progression, and recovery of gastric mucosal lesions.Gastric mucosal blood flow decreased with the formationof gastric mucosal lesions, and this decreased bloodflow recovered with lesion progression. Serum serotonin concentration, an index of mast celldegranulation, increased with the formation of gastricmucosal lesions, and this increased serotonin level wasattenuated with lesion progression and recovery.Pretreatment with ketotifen, a connective tissue mast cellstabilizer, prevented the formation of gastric mucosallesions, the increases of gastric mucosal lipid peroxidecontent, xanthine oxidase and myeloperoxidase activities, and serum serotonin level; and thedecreases of gastric mucosal nonprotein SH content,glutathione peroxidase activity, and blood flow found at0.5 hr after compound 48/80 treatment. These results indicate that the changes of gastric mucosalactive oxygen metabolism and blood flow are closelyrelated to the formation, progression, and recovery ofgastric mucosal lesions in rats with a single compound 48/80 treatment. The present results alsosuggest that this compound 48/80-induced gastric mucosalinjury could be a kind of ischemia-reperfusion-inducedinjury occurring through degranulation of connective tissue mast cells.     

Effects of GLP-1 on Gastric Emptying, Antropyloric Motility, and Transpyloric Flow in Response to a Nonnutrient Liquid

Glucagon-like polypeptide 1 (GLP-1) may be amajor enterogastrone, slowing gastric emptying whenreleased by intestinal nutrients. In six conscious dogs,we studied the effects of GLP-1, on antropyloric motility, gastric emptying, and transpyloricflow after instillation of 500 ml of saline into thestomach. The meal was given and recordings were started15 min after intravenous bolus and infusion of either saline or three different doses of GLP-1.Intravenous GLP-1 produced a dose-related retardation ofgastric emptying associated with a decrease in thenumber and volume of flow pulses in comparison tosaline. This change in transpyloric flow was associatedwith an inhibition of antropyloric pressure waves, astimulation of isolated pyloric pressure waves, and anincrease in basal pyloric tone induced by intravenous GLP-1 infusion. Our findings show that GLP-1has a potent dose-dependent inhibitory effect ontranspyloric flow and gastric emptying. This effect istemporally associated with inhibition of antralpumping and stimulation of pyloricbraking mechanisms.     

Effects of Laropiprant,a Selective Prostaglandin D2 Receptor 1 Antagonist,on the Pharmacokinetics of Rosiglitazone

Laropiprant (LRPT), a prostaglandin D₂ receptor‐1 antagonist shown to reduce niacin‐induced flushing symptoms, has been combined with niacin for treatment of dyslipidemia. This open‐label, randomized, 2‐period crossover study assessed the pharmacokinetics of single‐dose rosiglitazone in the presence and absence of multiple‐dose LRPT. Twelve healthy male and female subjects, 34–64 years of age, received two, once‐daily oral treatments in random sequence separated by ≥3‐day washout: (1) multiple‐dose LRPT 40 mg/day for 7 days (Days 1 to 7) coadministered with single‐dose rosiglitazone 4 mg on Day 6; (2) single‐dose rosiglitazone 4 mg on Day 1. Comparability was declared because the 90% confidence interval (CI) for the AUC_0‐∞ geometric mean ratio (GMR; rosiglitazone + LRPT/rosiglitazone alone) [0.92 (0.86, 0.99)], was contained within prespecified bounds (0.70, 1.43). The C_max GMR (90% CI) for rosiglitazone was 0.98 (0.95, 1.02). There was no evidence of clinically meaningful alterations in the pharmacokinetics of rosiglitazone, a probe CYP2C8 substrate, following coadministration of multiple‐dose LRPT in healthy subjects. Therefore, findings suggest that LRPT does not inhibit CYP2C8‐mediated metabolism.     

Bunazosin,a Selective α1 ‐Adrenoceptor Antagonist,as an Anti‐glaucoma Drug: Effects on Ocular Circulation and Retinal Neuronal Damage

Bunazosin hydrochloride is a potent and selective α₁‐adrenoceptor antagonist that has been clinically used both as a systemic antihypertensive as well as an ocular hypotensive drug. In a number of studies, we have examined some effects of bunazosin hydrochloride that might indicate its potential as an anti‐glaucoma drug. In normal rabbit eyes, topically instilled bunazosin hydrochloride reached the posterior retina by local penetration at concentrations sufficient to attenuate the phenylephrine‐ or endothelin‐1 (ET‐1)‐induced constriction of retinal arteries. Furthermore, bunazosin hydrochloride improved the impairment of optic nerve head (ONH) blood flow, the prolongation of visual‐evoked potentials (VEP) implicit time, the enlargement of the optic disk cup, and the decrease in the number of retinal ganglion cell layer cells induced by repeated injections of ET‐1 in rabbits. Topically instilled bunazosin hydrochloride improved the reductions in ONH capillary blood flow and VEP amplitude induced in rabbit eyes by nitric oxide synthase inhibition. In rat primary retinal cultures, bunazosin hydrochloride reduced glutamate‐induced neuronal cell death, presumably through a Na⁺ channel blocking effect. In healthy humans, topically instilled bunazosin hydrochloride reportedly increases blood velocity in the ONH, retina and choroid, without significantly altering either blood pressure or heart rate. These results indicate that bunazosin hydrochloride exerts both an improvement effect within the ocular circulation and a direct neuroprotective effect. Hence, bunazosin hydrochloride may be useful as a therapeutic drug against ischemic retinal diseases (such as glaucoma and retinal vascular occlusive diseases) that are associated with disturbances of the ocular circulation.     

Electronic-endoscopic Observation of ET-1 Induced Mucosal Ischemia and Preventive Effect of ETA Recepter Selective Antagonist,FR139317, in Rat Distal Colon

For investigation of the effects of Endothelin-1 (ET-1) on colonic mucosa, ET-1 (10–160 nmol/kg) was sprinkled on rat colonic mucosa under observation with a new electronic endoscopic system (TOSHIBA TRE-3000, Japan). A high dose of ET-1 induced complete obstruction of submucosal arterioles, but not venules, without affecting arterial blood pressure. The ET-1 -induced contraction of both vessel types was maintained for 50 min and was followed by intramucosal dot hemorrhages. In this experimental model, the effects of ET-1 on the mucosal microcirculation were further analyzed with a laser doppler blood flowmeter (LDF) during endoscopic observation. The maximum decrease in mucosal blood flow was to 20 % of the control value and this decrease was maintained for 20 min at a dose of 80 nmol/kg. An ETA receptor selective antagonist, FR139317 (800 nmol/kg), inhibited ET-1 -induced changes in endoscopic findings and LDF, shifting the concentration-response curve of LDF to the right. FR139317 is a potentially useful new therapy for inflammatory bowel diseases, conditions which have been reported to be associated with high local concentrations of ET-1. Our electronic-endoscopic system was demonstrated to be a useful basic research tool for studying gastrointestinal pathophysiology.     

mGluR1选择性拮抗剂LY367385对脑星形胶质细胞Na^＋-K^＋-ATP酶和Ca^2＋-Mg^2＋-ATP酶的影响

背景：脑星形胶质细胞肿胀是肝衰竭时脑水肿的特征,但其机制尚未完全阐明。目的：研究代谢型谷氨酸受体1亚型（mGluR1）选择性拮抗剂LY367385对脑星形胶质细胞Na^＋-K^＋-ATP酶和Ca^2＋-Mg^2＋-ATP酶的影响。方法：分离、培养小鼠脑星形胶质细胞,分为谷氨酸组、谷氨酸＋LY367385组、谷氨酸＋DMSO组和空白对照组,以定磷法检测Na^＋-K^＋-ATP酶和Ca^2＋-Mg^2＋-ATP酶活性,以高效液相色谱法测定ATP含量。结果：与空白对照组相比,谷氨酸组、谷氨酸＋LY367385组和谷氨酸＋DMSO组Na^＋-K^＋-ATP酶活性、Ca^2＋-Mg^2＋-ATP酶活性和ATP水平显著降低（P〈0.05）;谷氨酸＋LY367385组和谷氨酸＋DMSO组显著高于谷氨酸组（P〈0.001）,两组间则无明显差异。结论：mGluR1选择性拮抗剂LY367385可提高Na^＋-K^＋-ATP酶和Ca^2＋-Mg^2＋-ATP酶活性,减少ATP消耗,从而有效保护脑星形胶质细胞,有望成为预防和治疗肝性脑病的药物。     

Pharmacological Mechanisms of Clinically Favorable Properties of a Selective β1‐Adrenoceptor Antagonist,Nebivolol

Nebivolol is a racemic mixture of d‐ and 1‐enantiomers. The drug is characterized by β₁‐adrenoceptor selectivity and long‐acting β₁‐blockade exerted predominantly by d‐enantiomer. Nebivolol is devoid of intrinsic sympathomimetic activity and has no relevant membrane stabilizing action. Antiproliferative properties of nebivolol were demonstrated in endothelial and smooth muscle cell cultures. Infusion of nebivolol causes a vasodilation in all vascular beds by endothelial‐dependent mechanism involving stimulation of β₃‐adrenoceptors as well as by endothelial‐independent mechanism. Nebivolol possesses not only direct vasodilator properties but also augments the action of endothelium‐dependent vasodilators. The antioxidant property of nebivolol can at least in part explain why treatment with this drug enhances eNOS activity and minimizes the reperfusion‐induced myocardial injury. The systemic effects of nebivolol in humans have an unusual hemodynamic profile. In contrast to traditional β‐adrenoceptor antagonists, nebivolol reduces preload and afterload due to systemic vasodilation and improves arterial distensibility. At 5 mg daily nebivolol effectively reduces systolic and diastolic blood pressure over a 24‐h period. During treatment with nebivolol arterial pressure follows the natural circadian rhythm. Trough‐to‐peak ratio for nebivolol is 0.9. It has been demonstrated in numerous placebo‐controlled studies that exercise tolerance is not reduced during nebivolol therapy. By chronic administration to patients with left ventricular dysfunction nebivolol increases myocardial contractility. Nebivolol produced no significant changes in lipid levels, insulin sensitivity or glucose tolerance. These findings make nebivolol a promising therapeutic tool for the treatment of arterial hypertension and chronic heart failure.     

Protective Effect of Lafutidine, a Novel Histamine H2-Receptor Antagonist, on Dextran Sulfate Sodium-Induced Colonic Inflammation Through Capsaicin-Sensitive Afferent Neurons in Rats

Lafutidine, a histamine H2-receptor antagonist, exhibits gastric mucosal protective action mediated by capsaicin-sensitive afferent neurons, in addition to a potent antisecretory effect. In this study we examined the effect of lafutidine on dextran sulfate Na (DSS)-induced ulcerative colitis in rats, in relation to capsaicin-sensitive afferent neurons. Experimental colitis was induced in rats by daily treatment with 3% DSS in drinking water for 7 days. Lafutidine, capsaicin, and cimetidine were administered per os twice daily for 6 days. The ulceration area, colon length, and myeloperoxidase (MPO) activity were measured on day 7 after the onset of DSS treatment. DSS caused severe mucosal lesions in the colon, accompanied by an increase in MPO activity as well as a decrease in body weight gain and colon length. Daily administration of lafutidine dose-dependently reduced the severity of DSS-induced colitis and significantly mitigated changes in the colon length and MPO activity. The effects of lafutidine were mimicked by daily administration of capsaicin but not cimetidine and were totally abolished by chemical ablation of capsaicin-sensitive afferent neurons. In contrast, desensitization of afferent neurons significantly worsened the colonic inflammation induced by DSS. It was also found that both lafutidine and capsaicin increased the secretion of mucus in the colonic mucosa. These results suggest that lafutidine is effective against the ulcerative colitis induced by DSS through capsaicin-sensitive afferent neurons. This action might be attributable at least partly to the enhancement of colonic mucus secretion.