Acute effect of milnacipran on the relationship between the locus coeruleus noradrenergic and dorsal raphe serotonergic neuronal transmitters.

The present studies sought to investigate the effect of milnacipran called the serotonin (5-HT) and noradrenaline (NA) reuptake inhibitor (SNRI) on the interaction of central locus coeruleus noradrenergic and dorsal raphe nucleus serotonergic functional activity by utilizing in vivo microdialysis. A single administration of milnacipran (60 mg/kg, s.c.) markedly decreased the levels of NA and its metabolite, 4-hydroxy-3-methoxymandelic acid (HMMA), in the locus coeruleus and the levels of, a metabolite of 5-hydroxytryptamine (5-HT), 5-hydroxyindole-3-acetic acid (5-HIAA) in the dorsal raphe nucleus. Combined administration of yohimbine (2 mg/kg, s.c.),?alpha(2)-adrenoceptor?antagonist, at 2 h after milnacipran (60 mg/kg, s.c.) led to a significant increase in NA levels in the locus coeruleus, although yohimbine alone had no effect on these levels. Under similar experimental condition, 5-HIAA levels in the dorsal raphe nucleus remained unchanged. NAN-190 (1 mg/kg, s.c.), 5-HT(1A) receptor partial agonist, alone markedly decreased the levels of 5-HIAA in the dorsal raphe nucleus, although this level was not affected by WAY100635, the selective 5-HT(1A) receptor antagonist. WAY100635 recovered the milnacipran-induced decrease of 5-HIAA levels in the dorsal raphe nucleus to control levels. On the other hand, NAN-190 did not affect the milnacipran-induced decrease of 5-HIAA levels. Behavioral signs (locomotion and rearing) were markedly observed following milnacipran alone or combined administration of milnacipran and yohimbine. However, the behavioral signs after coadministration of milnacipran and WAY100635 or NAN-190 were relatively poor. These results may suggest that an increase of NA in the locus coeruleus with the treatment of yohimbine after milnacipran results from negative feedback following the blockade of alpha(2)-adrenoceptors achieved with yohimbine, and that WAY100635 but not NAN-190 recovered milnacipran-induced decrease of 5-HIAA in the dorsal raphe nucleus to control levels by preventing the activation for the presynaptic 5-HT(1A) autoreceptor.

Acceleration of gastric ulcer healing by omeprazole in portal hypertensive rats. Is its action mediated by gastrin release and the stimulation of epithelial proliferation?

BACKGROUND: Gastric ulcer healing is delayed in patients with portal hypertension (PHT) and often responds poorly to histamine H(2) blockers. Although proton pump inhibitors are more effective anti-ulcer agents, there is little information regarding their efficacy for gastric ulcer in cases of PHT. Therefore, we investigated the effects of a proton pump inhibitor, omeprazole, on the healing of acetic-acid-induced gastric ulcer in PHT rats. METHODS: Animals studied were 80 male Sprague-Dawley rats aged 7 weeks, of which half underwent two-staged portal vein ligation (PHT rats) and half underwent a sham operation (SO rats). Gastric ulcers were induced by acetic acid. Starting from day 4 after ulcer induction, rats received omeprazole or vehicle orally (50 mg/kg) for 5 or 10 days. Ulcer area, proliferating cell nuclear antigen labelling index (PCNA LI), and serum gastrin levels were recorded. RESULTS: PHT significantly inhibited epithelial cell proliferation and delayed gastric ulcer healing as indicated by a decreased PCNA LI at the ulcer margin and almost 2-fold larger ulcer area in PHT versus SO rats 14 days after ulcer induction. Ten-day treatment with omeprazole (vs. vehicle) significantly accelerated ulcer healing to a similar extent in both PHT and SO rats. Serum gastrin levels were significantly higher in PHT rats than in SO rats following treatment with omeprazole. Omeprazole (vs. vehicle) restored the decreased PCNA LI at the ulcer margin in PHT rats to that noted in SO rats. CONCLUSIONS: In PHT rats, omeprazole accelerates gastric ulcer healing, stimulates epithelial cell proliferation at the ulcer margin, and increases serum gastrin levels. Since gastrin is a potent stimulator of gastric epithelial cell proliferation, increased serum gastrin levels may be an important factor in omeprazole-induced stimulation of epithelial cell proliferation and acceleration of gastric ulcer healing in conditions of PHT.

Effects of carbon dioxide pneumoperitoneum on hemodynamics in cirrhotic rats.

BACKGROUND: The aim of our study was to investigate the effect of carbon dioxide pneumoperitoneum on systemic and splanchnic hemodynamics in cirrhotic rats. METHODS: Sprague-Dawley rats (n = 80) were used in this study. Liver cirrhosis was induced by thioacetamide administration intraperitoneally (200 mg/kg body weight, twice a week for 16 weeks). The radioactive microsphere method was used to measure systemic and regional hemodynamic parameters before, 1 h after the start, and 1 h after the release of pneumoperitoneum. RESULTS: Splanchnic blood flow and cardiac index were significantly depressed during pneumoperitoneum in liver cirrhosis and control groups, but no significant differences were seen between the two groups. In both groups, portal venous inflow decreased and hepatic arterial blood flow increased significantly during pneumoperitoneum. However, during pneumoperitoneum, total hepatic blood flow as a percentage of its value before pneumoperitoneum was lower in cirrhotic rats (71.0%) than in control rats (91.9%) (p <0.05, Mann-Whitney U-test). CONCLUSIONS: Carbon dioxide pneumoperitoneum markedly decreases total hepatic blood flow in cirrhotic rats due to the impaired hepatic arterial buffer response. Liver function should be carefully controlled in cirrhotic patients after laparoscopic surgery with pneumoperitoneum.

Evaluation of the cost for laparoscopic-assisted Billroth I gastrectomy.

BACKGROUND: Despite the rapid spread of laparoscopic gastric surgery in Japan, no one has yet evaluated the costs for this new technique. The aim of this study was to analyze and compare the hospital charges for laparoscopic-assisted gastrectomy with those for conventional open gastrectomy. METHODS: The study included 48 consecutive patients who underwent laparoscopic-assisted Billroth I gastrectomy and 43 who had a conventional open Billroth I gastrectomy for cure of early gastric cancer between May 1994 and April 2000. Hospital charges covered all costs incurred during the hospital stay; they were divided into charges for consultation, prescription, injection, nursing care, operating theater, laboratory, radiology, ward and meal, and others. RESULTS: The patients who underwent laparoscopic gastrectomy were similar to those who had open gastrectomy in terms of symptoms, concurrent illness, operation time, proximal resection margin, number of harvested lymph nodes, and stage of the disease. Hospital stay after laparoscopic gastrectomy was shorter than that after open gastrectomy (16.1 vs 20.5 days, p < 0.01). Charges for nursing care, charges for ward and meal, and total hospital charges were less in the laparoscopic group than in the open group ( yen5800 vs yen8010, p < 0.01; yen461 x 10(3) vs yen512 x 10(3), p < 0.05; yen1336 x 10(3) vs yen1411 x 10(3), p = 0.072). When we compared laparoscopic gastrectomies performed during 1994-96 with those done during 1997-2000, we found a decrease in charges for ward and meal and total hospital charges ( yen498 x 10(3) vs yen421 x 10(3), p < 0.01; yen1390 x 10(3) vs yen1277 x 103, p < 0.01). CONCLUSION: Laparoscopic-assisted Billroth I gastrectomy is less expensive than conventional open Billroth I gastrectomy because both the postoperative recovery period and the hospital stay are shorter. In patients who undergo gastrectomy, the additional costs of the disposable instruments can be fully offset by the lower charges for ward and meal and nursing care associated with laparoscopic gastrectomy.

Laparoscopic ligation of an aneurysm of the left gastric artery.

We describe the laparoscopic ligation of an aneurysm of the left gastric artery. The patient was admitted to the hospital with epigastric pain, and computed tomography showed a retroperitoneal hemorrhage. Celiac angiography showed a fusiform-type aneurysm 1.0 cm in diameter at the trunk of the left gastric artery. The left gastric artery was ligated at sites proximal and distal to the aneurysm under laparoscopy, and the patient's postoperative course was uneventful. Laparoscopic surgery appears useful for elective surgery of an aneurysm in the left gastric artery.

Effect of CO2 pneumoperitoneum on the systemic and peritoneal cytokine response in a LPS-induced sepsis model.

We studied the effect of carbon dioxide (CO2) pneumoperitoneum on the systemic and peritoneal cytokine response in a rat model of intraperitoneal sepsis. After intraperitoneal injection of bacterial lipopolysaccharide (LPS, 10 mg/kg), rats were divided into 3 groups (n = 49 in each group): control (abdominal puncture); CO2 pneumoperitoneum, and laparotomy. Blood and peritoneal lavage fluid (PLF) were sampled at 0, 1, 2, 3, 4, 6, and 8 h after LPS challenge. Blood cell counts, plasma endotoxin level, and the levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and interleukin-6 (IL-6) in the plasma and PLF were measured. Blood cell counts did not differ between the 3 groups. Plasma endotoxin levels in the pneumoperitoneum group were significantly increased immediately after the procedure (p < 0.05). Although peak plasma TNF-alpha levels in the pneumoperitoneum group were seen immediately after the procedure, other changes in plasma cytokine levels did not differ significantly between the 3 groups. PLF TNF-alpha and IL-1beta levels in the pneumoperitoneum group were significantly lower than levels in the control and laparotomy groups soon after the procedure (p < 0.05). PLF IL-6 levels in the pneumoperitoneum group tended to be lower than those in the laparotomy group. In conclusion, CO2 pneumoperitoneum might induce different responses between systemic and peritoneal cytokines soon after the procedure in a rat model of intraperitoneal sepsis.

The effect of gases in the intraperitoneal space on cytokine response and bacterial translocation in a rat model.

BACKGROUND: The aim of this study was to examine cytokine response and bacterial translocation after exposure of the intraperitoneal space to carbon dioxide (CO2), helium (He), and air (Air) in a rat model. METHODS: For this study, 120 Sprague-Dawley rats underwent anesthesia only (Control), 10 mmHg pneumoperitoneum (PP), or abdominal wall lift (AWL). The rats were divided into five groups according to experimental procedure: Control, PP-CO2, AWL-CO2, AWL-He, and AWL-Air. At 0, 3, 6, and 24 h after the procedures, the levels of interleukin 1beta (IL-1beta) and interleukin 6 (IL-6) in both plasma and peritoneal lavage fluid (PLF) were measured, and the translocation of bacteria to the mesenteric lymph nodes was evaluated. RESULTS: The plasma IL-1beta and IL-6 levels in the PP-CO2, AWL-CO2, and AWL-He groups were significantly lower than those in AWL-Air group at 6 h (p < 0.05). The PLF IL-1beta (at 3, 6, and 24 h) and IL-6 (at 6 h) levels in the AWL-CO2 group were significantly lower than those in the AWL-Air group (p < 0.05). There were no significant differences in IL-1beta and IL-6 responses among the PP-CO2, AWL-CO2, and AWL-He groups. The AWL-CO2 and PP-CO2 groups had lower incidences of bacterial translocation than did the AWL-Air group (p < 0.05). CONCLUSIONS: The results from this study suggest that the gas in the intraperitoneal space, but not the increased intraabdominal pressure, causes the alterations in host cytokine response and bacterial translocation. Carbon dioxide may play a primary role in the reduced immune response associated with laparoscopic surgery.

Lymphoid hyperplasia of the large intestine: a case report with immunohistochemical and gene analysis.

A case of lymphoid hyperplasia arising in the large intestine of a 54-year-old woman is described. Barium enema X-ray and colonoscopic examination revealed multiple small polyps in the right side of the colon. Pathological findings from forceps biopsy revealed similar features to a mucosa-associated lymphoid tissue (MALT) lymphoma. A right hemicolectomy with mesenteric lymph node dissection was carried out. Histological sectioning demonstrated hypertrophic lymphoid follicles with well-formed germinal centers. Occasionally, lymphocytes infiltrated the crypts, in a way similar to that found in lymphoepithelial lesions, which was suggestive of a MALT lymphoma diagnosis. Cryptitis was also observed in the lamina propria. Immunohistochemically, proliferating lymphocytes were positive for CD20 (L26) and negative for CD45RO (UCHL-1). Analyses of immunoglobulin gene (IgHJH) rearrangement could not detect any monoclonality in these cells. These findings suggested that the present case should be categorized as lymphoid hyperplasia rather than lymphoma.

Laparoscopic cholecystectomy in the treatment of patients with gall bladder cancer.

BACKGROUND: Surgical procedures based on the depth of the primary tumor invasion (pT category) have been proposed in the treatment of gallbladder cancer (GBC). Trocar site metastases have been reported in patients who underwent laparoscopic cholecystectomy (LC) for preoperatively undiagnosed GBC. STUDY DESIGN: The aim of this study was to clarify the role of LC as a surgical strategy for GBC. From 1986 to 1998, 56 patients with GBC underwent surgical resection. Survival rates were compared retrospectively according to pT category and use of LC. RESULTS: Five-year survival was 91% for pT1 (n = 13), 64% for pT2 (n = 25), 34% for pT3 (n = 14), and 0% for pT4 tumors (n = 4; p<0.0001). LC was performed on 11 patients (4 with pT1, 5 with pT2, and 2 with pT3 tumors). Of the seven patients with pT2 or pT3 tumors, three underwent a second radical operation, three had an open radical operation to which the procedure was converted from LC, and one underwent no additional procedures. For pT1 tumors, one patient died of trocar site metastasis from bile spillage after LC. For pT2 or pT3 tumors, 5-year survival was 63% for radical surgery (n = 35) and 0% for cholecystectomy alone (n = 4; p<0.05). For pT2 or pT3 tumors treated by radical surgery, 5-year survival was 75% for laparoscopic approach (n = 6) and 60% for open surgery (n = 29; not significant). CONCLUSIONS: LC may help to establish the diagnosis and to determine the surgical strategy for undiagnosed GBC. It is important to prevent spillage or implantation of malignant cells during LC. For pT2 or pT3 tumors diagnosed laparoscopically, a second or converted open radical surgery is necessary.

Transvenous sclerotherapy for huge oesophagogastric varices using open injection sclerotherapy.

BACKGROUND: The optimum procedure for long-term management of oesophagogastric varices when endoscopic sclerotherapy or ligation fails is yet to be established. This report describes a new procedure for treating huge oesophagogastric varices by open injection sclerotherapy. METHODS: Twenty-three patients with huge oesophagogastric varices underwent laparotomy and devascularization of the upper stomach with splenectomy. The left gastric vein was catheterized for repeated injection of 5 per cent ethanolamine oleate during the postoperative period. RESULTS: In all patients, the varices were eradicated after a mean of 3 sessions of sclerotherapy. There were no deaths or major complications during the mean follow-up period of 41 months. Small recurring varices in two patients were treated successfully by endoscopic sclerotherapy and interventional radiology. CONCLUSION: Open injection sclerotherapy is an effective and safe procedure for the treatment of huge oesophagogastric varices.

Laparoscopy-assisted Billroth I gastrectomy compared with conventional open gastrectomy.

BACKGROUND: Although several studies compare surgical results of laparoscopic and open colonic resections, there is no study of laparoscopic gastrectomy compared with open gastrectomy. HYPOTHESIS: When compared with conventional open gastrectomy, laparoscopy-assisted Billroth I gastrectomy is less invasive in patients with early-stage gastric cancer. DESIGN: Retrospective review of operative data, blood analyses, and postoperative clinical course after Billroth I gastrectomy. SETTING: University hospital in Japan. PATIENTS: The study included 102 patients who were treated with Billroth I gastrectomy for early-stage gastric cancer from January 1993 to July 1999: 49 with laparoscopy-assisted gastrectomy and 53 with conventional open gastrectomy. MAIN OUTCOME MEASURES: Demographic features examined were operation time; blood loss; blood cell counts of leukocytes, granulocytes, and lymphocytes; serum levels of C-reactive protein, interleukin 6, total protein, and albumin; body temperature; weight loss; analgesic requirements; time to first flatus; time to liquid diet; length of postoperative hospital stay; complications; proximal margin of the resected stomach; and number of harvested lymph nodes. RESULTS: Significant differences (P<.05) were present between laparoscopy-assisted and conventional open gastrectomy when the following features were compared: blood loss (158 vs 302 mL), leukocyte count on day 1 (9.42 vs 11.14 x 10(9)/L) and day 3 (6.99 vs 8.22 x 10(9)/L), granulocyte count on day 1 (7.28 vs 8.90 x 10(9)/L), C-reactive protein level on day 7 (2.91 vs 5.19 mg/dL), interleukin 6 level on day 3 (4.2 vs 26.0 U/mL), serum albumin level on day 7 (35.6 vs 33.9 g/L), number of times analgesics given (3.3 vs 6.2), time to first flatus (3.9 vs 4.5 days), time to liquid diet (5.0 vs 5.7 days), postoperative hospital stay (17.6 vs 22.5 days), and weight loss on day 14 (5.5% vs 7.1%). There was no significant difference between laparoscopy-assisted and conventional open gastrectomy with regard to operation time (246 vs 228 minutes), proximal margin (6.2 vs 6.0 cm), number of harvested lymph nodes (18.4 vs 22.1), and complication rate (8% vs 21%). CONCLUSIONS: Laparoscopy-assisted Billroth I gastrectomy, when compared with conventional open gastrectomy, has several advantages, including less surgical trauma, less impaired nutrition, less pain, rapid return of gastrointestinal function, and shorter hospital stay, with no decrease in operative curability. When performed by a skilled surgeon, laparoscopy-assisted Billroth I gastrectomy is a safe and useful technique for patients with early-stage gastric cancer.

Significant increase in prostaglandin E-main urinary metabolite by laxative administration: comparison with ulcerative colitis.

OBJECTIVE: To assess the production of prostaglandin E(2), an important chemical mediator in diarrhea induced by laxative administration, a prostaglandin E-main urinary metabolite (7alpha-hydroxy-5,11-diketotetranor-prosta-1,16-dioic acid, PGE-MUM) was measured in healthy volunteers and compared with the values of patients with ulcerative colitis. METHODS: PGE-MUM was determined by a simplified immunoassay of bicyclic PGE-MUM and analyzed for the influence of laxative administration and active/remission phases of ulcerative colitis. RESULTS: Administration of laxatives induced a significant increase in PGE-MUM in healthy volunteers. A significant elevation was also found in the active as compared with the remission phase of ulcerative colitis. The PGE-MUM levels were significantly correlated with our modified Talstad scores, clinical disease activity indices in ulcerative colitis. It was confirmed by time course studies of individual patients that changes in PGE-MUM correlated well with colitis activity. CONCLUSION: Laxative administration induces production of prostaglandin E(2) as one of the chemical mediators, although its production grade is relatively low as compared with ulcerative colitis in the active phase.

[A case of complete regression of liver metastases by treatment with Futraful supposition].

The patient was a 57-year-old man abnormalities indicated in examinations by X-ray and ultrasonography in February, 1991. X-ray and endoscopic examination revealed a Borrmann type 3 carcinoma in the posterior wall and lesser curvature of the upper body of the stomach. The liver was swollen to 3 fingerbreadths on the right mid-clavicular line. Multiple liver metastases were revealed by computed tomography (CT). Proximal gastrectomy was done. From March 24, 1991, a Futraful suppository (1,500 mg/day) was given daily. After 4 months, CT showed the reduction and partial disappearance of the low-density areas of the liver. After 2 years and 7 months, CT showed very small low-density areas, which completely disappeared by April, 1998. The patient has had a good quality of life. According to the General Rules for Gastric Cancer Study, the patient belongs to the class of complete response.

The efficacy of laparosonic coagulating shears for arterial division and hemostasis in porcine arteries.

BACKGROUND: Recently, the laparosonic coagulating shears (LCS) have been used widely in laparoscopic surgery. In the current study, the usefulness of LCS for arterial division and hemostasis was examined in porcine arteries. METHODS: Porcine arteries of several diameters (1, 3, and 5 mm) were removed and divided using LCS with different blade modes: shear, blunt, and flat. The division time and bursting pressure were registered. Additionally, divided sections stained by the Azan-Mallory method were observed microscopically. RESULTS: The division time was dependent on the blade modes used. With the flat mode, the bursting pressure of 5-mm arteries was significantly higher than the bursting pressure with shear and blunt modes. Histologically, cavitation and mild degeneration of the vessel walls occurred adjacent to the cutting edge. CONCLUSION: The LCS is a safe and useful device for arterial division and hemostasis for 5-mm arteries if an adequate blade mode is used.

Fluvastatin suppresses atherosclerotic progression, mediated through its inhibitory effect on endothelial dysfunction, lipid peroxidation, and macrophage deposition.

Fluvastatin, a potent 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, exerts an inhibitory effect on intimal thickening after mechanical injury in normocholesterolemic rabbit artery at a dose not enough to elicit a known action of lipid lowering. This study was designed to determine whether atherosclerotic progression triggered by hypercholesterolemia can be inhibited by fluvastatin under conditions without its hypocholesterolemic effect. Rabbits were fed a 0.5% cholesterol diet or normal diet for 17 weeks and were treated with either fluvastatin (0.3-2 mg/kg/day, p.o.) or pravastatin (2 mg/kg/day, p.o.). Atherogenic features manifested in the cholesterol-diet group, compared with the normal-diet group; they were the increase in serum lipid peroxide level, in the intraluminal lesion area of the aorta, and in macrophage content of the aortic cross-sectional lesion area; the attenuation of endothelium-dependent relaxing response to acetylcholine in the femoral artery; and the increase in serum lipid level. Treatment with fluvastatin, but not pravastatin, inhibited the manifestation of the atherogenic features without a serum lipid-lowering effect. Thus fluvastatin is likely to reduce the risk of atherosclerotic progression, to which endothelial dysfunction, lipid peroxidation, and macrophage accumulation in the vasculature may contribute, irrespective of changes in serum lipid levels.

Increases of vascular endothelin-converting enzyme activity and endothelin-1 level on atherosclerotic lesions in hyperlipidemic rabbits.

The aim of this study was to investigate vascular endothelin-converting enzyme activity and the tissue level of endothelin-1 in the aorta related to atherosclerotic lesions in high cholesterol diet-fed rabbits. Rabbits were fed two atherogenic diets, 0.5% and 1.5% cholesterol, and a normal diet for 16 weeks. Vascular endothelin-converting enzyme activity in the aortic arch and thoracic aorta was significantly increased (2.0-4.4 times) by the atherogenic diet as compared with the normal diet group as well as the levels of lipids and lipid peroxide in plasma were significantly increased. Tissue endothelin-1 levels in both aortas were also elevated (2.3-6.8 times), corresponding well to the increased tissue enzyme activity. In contrast, plasma endothelin-1 levels increased only in the 1.5% cholesterol diet group (2.7 times). These results indicate that the endothelin-converting enzyme activity and the corresponding endothelin-1 level in the vascular walls increase in association with the development of atherosclerotic lesions.

Delayed healing of acetic-acid-induced gastric ulcer in portal hypertensive rats.

The aim of the present study was to determine the effect of portal hypertension on the healing of gastric ulcers in rats. Portal hypertension was induced by staged portal vein ligation. Sham-operated (SO) rats served as controls. Gastric ulcers were induced by application of acetic acid to the serosal surface of the stomach. Healing was assessed by determining the ulcer area on days 3, 7, and 10 after ulcer induction. Epithelial proliferation at the ulcer margin was assessed by evaluating the proliferating cell nuclear antigen labeling index. On days 3 and 7, the proliferating cell nuclear antigen labeling index was lower in portal hypertensive (PHT) rats than in SO rats. On day 10, the ulcer area in PHT rats was nearly twice that in SO rats (4.13 +/- 0.29 vs. 2.28 +/- 0.22 mm(2), p < 0.05). These results suggest that portal hypertension may delay gastric ulcer healing. Furthermore, the inhibition of epithelial proliferation at the ulcer margin may be involved in the delayed healing in portal hypertension.

Impaired adaptive cytoprotection to ethanol-induced damage in gastric mucosa of portal hypertensive rats.

Portal hypertension predisposes gastric mucosa to increased damage by noxious agents. Adaptive cytoprotection has not been studied in portal hypertensive gastric mucosa. We evaluated adaptive cytoprotection in the gastric mucosa of portal hypertensive rats by exposure to ethanol. The injury index (percent gross lesions) was significantly higher in portal hypertensive rats than in sham-operated rats. The ratio of adaptive cytoprotection, calculated as the degree of decrease in the injury index caused by pre-absolute-ethanol administration of 20% ethanol, was significantly impaired in portal hypertensive rats. Basal levels of gastric mucosal hexosamine were lower in portal hypertensive rats than in controls, and a blunted response to 20% ethanol was associated with portal hypertension. Nitric oxide inhibition (L-NAME, 5 mg/kg) reduced the ratio of adaptive cytoprotection in sham-operated but not in portal hypertensive rats. These results suggest that impaired adaptive cytoprotection in portal hypertensive gastric mucosa may be caused by blunted mucus production.

The role of nitric oxide in the inhibition of gastric epithelial proliferation in portal hypertensive rats.

BACKGROUND/AIM: Portal hypertension is associated with inhibition of gastric epithelial proliferation and increased gastric nitric oxide synthase activity. Whether the nitric oxide inhibits gastric epithelial proliferation is unclear. METHODS: Portal vein ligation was performed to induce portal hypertension in rats. The rats were treated for 7 days with either vehicle or N(G)-nitro-L-arginine methyl ester (L-NAME) at 5 mg/kg or 25 mg/kg doses (gastric gavage, twice a day). Sham-operated rats treated with vehicle served as controls. Hemodynamic parameters were measured using radiolabeled microspheres in anesthetized animals. Gastric epithelial proliferation was assessed by evaluating the proliferative cell nuclear antigen labeling index. RESULTS: The cardiac index and gastric fundic blood flow were higher, and the gastric fundic proliferative cell nuclear antigen labeling index was lower in the portal hypertensive rats than in the controls. In portal hypertensive rats, the 5 mg/kg dose of L-NAME decreased the cardiac index and increased the gastric fundic proliferative cell nuclear antigen labeling index to levels similar to those found in the controls, but did not affect gastric fundic blood flow significantly. The 25 mg/kg dose of L-NAME further decreased both the cardiac index and the gastric fundic blood flow, but did not affect the gastric proliferative cell nuclear antigen labeling index significantly. CONCLUSIONS: In portal hypertensive rats, the correction of systemic hyperdynamic circulation by NO inhibition is associated with normalization of gastric epithelial proliferation. Excessive nitric oxide may inhibit gastric epithelial proliferation in portal hypertension.