Cell proliferation in visceral organs induced by ventromedial hypothalamic (VMH) lesions: Development of electrical VMH lesions in mice and resulting pathophysiological profiles

We have found that ventromedial hypothalamic (VMH) lesions produced by electrocoagulation induce cell proliferation in visceral organs through vagal hyperactivity, and also stimulate regeneration of partially resected liver in rats. To facilitate identification of proliferative and/or regenerative factors at the gene level, we developed electrical production of VMH lesions in mice, for which more genetic information is available compared to rats, and examined the pathophysiological profiles in these mice. Using ddy mice, we produced VMH lesions with reference to the previously reported method in rats. We then examined the pathophysiological profiles of the VMH-lesioned mice. Electrical VMH lesions in mice were produced using the following coordinates: 1.6 mm posterior to the bregma, anteriorly; 0.5 mm lateral to the midsagittal line, transversely; and 0.2 mm above the base of the skull, vertically, with 1 mA of current intensity and 10 s duration. The VMH-lesioned mice showed similar metabolic characteristics to those of VMH-lesioned rats, including body weight gain, increased food intake, increased percentage body fat, and elevated serum insulin and leptin. However, there were some differences in short period of hyperphagia, and in normal serum lipids compared to those of VMH-lesioned rats. The mice showed a similar cell proliferation in visceral organs, including stomach, small intestine, liver, and, exocrine and endocrine pancreas. In conclusion, procedures for development of VMH lesions in mice by electrocoagulation were developed and the VMH-lesioned mice showed pathophysiological profiles similar to those of VMH-lesioned rats, particularly in cell proliferation in visceral organs. These findings have not been observed previously in gold thioglucose-induced VMH-lesioned mice. This model may be a new tool for identifying factors involved in cell proliferation or regeneration in visceral organs.     

Changes in insulin, somatostatin, and glucagon secretion during the development of obesity in ventromedial hypothalamic-lesioned rats

Changes in insulin, somatostatin, and glucagon secretion during the development of obesity in rats after ventromedial hypothalamic (VMH) lesions were evaluated by measuring fasting hormone levels and their secretion from the isolated perfused pancreas. Fasting peripheral insulin levels were not altered 1 week after the VMH lesions but became progressively elevated at 3-4, 8-9, and 11-12 weeks compared to the values in sham-operated and age-matched control rats. In the portal vein, insulin levels also progressively increased in VMH-lesioned rats, but the portal-peripheral gradient of insulin in the later phase of VMH obesity was significantly lower than in the early phase after VMH lesions. On the contrary, the arginine-induced insulin release from the perfused pancreas was highest at 1 week and gradually decreased thereafter, although it continued to remain higher than that of controls. The perfusate somatostatin response to arginine also was exaggerated in the VMH-lesioned rats. However, both the peripheral glucagon level and the glucagon secretion from the perfused pancreas of the VMH-lesioned rats were not significantly different from the controls. These results show that VMH lesions result in an increased insulin and somatostatin secretion. Using the cyclically perfused liver in situ, we have found that the hepatic extraction rate of insulin is indeed reduced in rats 8-9 weeks after VMH lesioning, and so have at least partly accounted for the decreased portal-peripheral gradient of insulin in the later VMH postoperative phase.     

Restoration of circadian corticosterone rhythm in ventromedial hypothalamic lesioned rats

The effects of ventromedial hypothalamic (VMH) lesions on the circadian periodicity of blood corticosterone were studied in female rats. The rats were kept on a 12-hour light/12-hour dark illumination regimen and fed ad libitum. Three, 10 and 12 weeks after the VMH lesions, the concentrations of blood corticosterone were measured every 4 h for 48 h in the same unanesthetized rats. Three weeks after the operation, the circadian rhythm in VMH-lesioned rats was disturbed and disappeared. The corticosterone levels at 03:00, 07:00, and 11:00 were significantly higher than those in sham-operated rats. 10 and 12 weeks after the operation, the circadian rhythm, however, was notable (p less than 0.05, p less than 0.05). The elevated mean corticosterone levels over 48 h at 3 weeks after the operation decreased at 10 and 12 weeks. The sham-operated rats showed a significant circadian rhythm at 3, 10 and 12 weeks after the operation (p less than 0.001 in each period) with a peak concentration at 19:00 and through at 07:00. These findings show that the corticosterone circadian rhythms which were disturbed in the dynamic phase after VMH lesions recovered in the static phase of obesity, suggesting that the ventromedial hypothalamus is not an essential biological clock of circadian corticosterone rhythm.     

Different origin of hypertriglyceridemia induced by a high-fat and a high-sucrose diet in ventromedial hypothalamic-lesioned obese and normal rats

OBJECTIVE: To clarify the mechanism by which plasma triacylglycerol is affected by a high fat or a sucrose diet. DESIGN: Two sets of six groups each having six rats were prepared-(1) ventromedial hypothalamic (VMH)-lesioned rats fed a standard diet; (2) sham VMH-lesioned rats fed a standard diet; (3) VMH-lesioned rats fed a high-fat diet; (4) sham VMH-lesioned rats fed a high-fat diet; (5) VMH-lesioned rats fed a high-sucrose diet; and (6) sham VMH-lesioned rats fed a high-sucrose diet. After VMH lesions and sham operations, the rats were provided standard, high-fat and high sucrose diets for 2 weeks. Two weeks later, blood samples were collected after overnight fast to determine plasma triacylglycerol (TAG), hepatic triacylglycerol secretion rate (TGSR), fractional catabolic rate (FCR) of triacylglycerol and postheparin plasma lipoprotein lipase (LPL), plasma glucose, insulin and leptin. RESULTS: Values of TAG, TGSR, FCR and LPL in VMH-lesioned obese rats were all greater than those in sham-operated rats, regardless of the diet fed. In sham-operated rats, high-fat diet fed rats showed higher TAG with similar TGSR, higher LPL and lower FCR than those of standard diet fed rats. High-sucrose diet fed rats showed significantly higher TAG with higher TGSR, higher LPL and lower FCR than those of standard diet fed rats. Moreover, high-sucrose diet fed rats showed higher TAG with higher TGSR, lower LPL and higher FCR than those of high-fat diet fed rats. In VMH-lesioned rats, high-fat diet fed rats showed higher TAG with similar TGSR, higher LPL and lower FCR than those of standard diet fed rats. High-sucrose diet fed rats showed markedly higher TAG with notably higher TGSR, higher LPL and lower FCR than those of standard diet fed rats. High-sucrose diet fed rats showed still higher TAG with markedly higher TGSR, similar LPL and higher FCR than those of high-fat diet fed rats. CONCLUSIONS: The mechanism by which TAG metabolism is affected by a high-fat or a high-sucrose diet differed; a high-fat diet increased plasma TAG level by lowering removal of TAG without increase in hepatic TAG secretion in sham-operated (normal) rats. A high-sucrose diet, in contrast, induced much higher plasma TAG levels by both increased hepatic TAG secretion and decreased removal of TAG. The effects of a high-fat or a high-sucrose diet were similar but exaggerated in VMH lesioned animals.     

Effect of vagotomy on serum insulin in rats with paraventricular or ventromedial hypothalamic lesions

The effects of vagotomy on plasma glucose and insulin levels in rats with paraventricular nuclear (PVN) or ventromedial hypothalamic (VMH) lesions were measured during a constant glucose infusion. In one experiment, vagotomy was performed 50 min after the lesions, and in a second experiment, it was performed at the same time as the lesions. After the introduction of lesions in the PVN, there was a significantly greater rise in plasma glucose than in animals with either large or small VMH lesions, both of which had plasma glucose values similar to those in the sham-lesioned animals. The rise in insulin was greater in all three lesion groups than in the sham-operated animals. Although both plasma glucose and insulin had begun to decline before the vagotomy performed 50 min after lesioning, there was a further subsequent fall after vagotomy which was greater in the VMH-lesioned animals with large lesions than in rats with PVN lesions or small VMH lesions. In the sham-lesioned rats, there was no significant change in insulin or glucose after vagotomy. When the vagotomy and hypothalamic lesions were performed simultaneously, the glucose and insulin values in all groups were the same. The present experiments suggest that VMH and PVN exert different controls over pancreatic hormone secretion. The VMH lesions appear to remove an inhibitory effect on the vagus, with resultant hyperinsulinemia in the absence of hyperglycemia. The PVN-lesioned animals show a hyperglycemia which is abolished by vagotomy, suggesting that the PVN connects to vagal fibers which activate the glucagon secretory system in the alpha-cell of the pancreas.     

Effect of ventromedial hypothalamic lesions on the secretion of somatostatin,insulin, and glucagon by the perfused rat pancreas

Somatostatin, insulin, and glucagon secretion by the perfused pancreas were studied in adult female rats 10 days after ventromedial hypothalamic (VMH) lesions and in sham operated controls to assess the role of their hypothalamic control. Insulin secretion was significantly greater in VMH-lesioned rats both under basal conditions and after stimulation by theophylline and arginine plus theophylline. Basal glucagon secretion was greater in VMH-lesioned rats as was the glucagon response to theophylline alone and in combination with arginine. Basal somatostatin secretion was similar in VMH and control rats but somatostatin secretion induced by theophylline and by arginine plus theophylline was significantly increased in VMH-lesioned rats. Both the pancreatic content and concentration of somatostatin were increased in VMH-lesioned rats. These results indicate the presence of hyperresponsiveness of A, B, and D cells following VMH destruction and provide new evidence for a role of the hypothalamus in the regulation of pancreatic somatostatin secretion.     

The trophic effect of epidermal growth factor on morphological changes and polyamine metabolism in the small intestine of rats

This study was undertaken to evaluate the effect of epidermal growth factor (EGF) on the morphological changes and polyamine metabolism in the atrophic small intestinal mucosa of rats caused by feeding elemental diet (ED; Elental^?, Ajinomoto, Tokyo) for several weeks. Four-week-old Wistar male rats were given ad libitum ED (1 kcal/ml) for 4 weeks. The body weight increased to the same extent as the control group fed a pellet diet. However, the small intestine became atrophic: the mucosal wet weight of the jejunum decreased to 70%, while that of the ileum decreased to 60%. EGF (10 Μg/kg) was subcutaneously injected into these rats every 8 hours. Ornithine decarboxylase (ODC) activities of the jejunal and ileal mucosa rose within 12 hours of the initial EGF administration. Mucosal DNA specific activities tended to increase. Next, EGF (30 Μg/kg/day) was intraperitoneally administered with a Mini-osmotic pump for one week. The wet weight, protein and DNA contents of the ileal mucosa increased significantly compared with those of the saline administered controls, while the crypt cell production rate (CCPR) also increased. Histologically, increases in both villus height and crypt depth were confirmed. These findings indicate that EGF causes mucosal proliferation through polyamine metabolism even in the atrophie small intestine of mature rats after ED administration for 4 weeks.     

Selective increase in cytochrome P450 content in hepatic microsomes from rats with ventromedial hypothalamic lesions

Changes in the components of hepatic microsomal electron transport systems and in drug hydroxylase activities were investigated in ventromedial hypothalamus (VMH) lesioned obese rats. Eight weeks after electrolysis of the bilateral VMH, the content of cytochrome P450 per mg microsomal protein (0.79 +/- 0.07 nmol/mg protein) was significantly higher (P less than 0.02) than that in the sham-operated rats (0.59 +/- 0.02). Cytochrome P450 per whole liver in the VMH-lesioned obese rats had also significantly increased (87 +/- 9 nmol vs 56 +/- 3, P less than 0.02). No significant differences were found in the cytochrome b5 contents, and the activities of NADPH- and NADH-cytochrome c reductases between the VMH-lesioned obese and sham-operated rats. The demethylation activities of aminopyrine (1.04 +/- 0.02 nmol/mg protein/min vs 0.94 +/- 0.02, P less than 0.05) and p-nitroanisole (0.96 +/- 0.02 vs 0.89 +/- 0.02 , p less than 0.02) and the aniline hydroxylase activity (0.22 +/- 0.01 vs 0.16 +/- 0.01, P less than 0.01) were enhanced, but 7-ethoxycoumarin O-deethylase activity was unchanged in the VMH-lesioned obese rats. These results indicate a selective increase in the content of cytochrome P450 among the components of the P450-dependent mixed function oxidase system in the liver of VMH-lesioned obese rats. Our observations suggest that drug metabolism may be enhanced in the hypothalamic obesity.     

Hepatocyte proliferation in rats after ventromedial hypothalamic lesions: Immunoreactivity patterns of proliferating cell nuclear antigen (PCNA)

Ventromedial hypothalamic (VMH) lesions result in increased DNA content in the rat liver. However, little information is available concerning the proliferative activity and lobular distribution of different cell populations in VMH-lesioned rat liver. The aim of the present study was to quantitatiely assess these parameters in VMH-lesioned rat liver by measuring proliferating cell nuclear antigen (PCNA) reactivity. We investigated to determine whether this mitotic response involves acinar zones 1, 2, or 3. Changes in immunohistochemical labeling indices in rat liver were measured with an antibody against PCNA until 7 days after VMH lesioning. The effects of hepatic vagotomy on proliferation were also examined. Proliferation of hepatocytes in acinar zones 1–3 began to increase on day 1, and reached a maximum at 3 days. The area of most intense proliferation progressively shifted from acinar zone 1 to zone 3 in several days. The proliferation was completely inhibited by hepatic vagotomy, indicating that VMH lesions induce cell proliferation in rat liver via hepatic vagus nerve activity. This study implicates the information available on neural factors which initiate hepatocyte proliferation. (Received Sept. 4, 1997; accepted Dec. 19, 1997)     

Hypersecretion of IAPP from the islets of VMH-lesioned rats and obese Zucker rats.

To investigate the possible role of islet amyloid polypeptide (IAPP) in the development of type 2 diabetes mellitus, we examined the IAPP content and secretion in pancreatic islets isolated from ventromedial hypothalamic (VMH)-lesioned rats and genetically obese Zucker rats, using a specific radioimmunoassay for IAPP. Obesity and hyperinsulinemia were observed in rats 21 days after VMH lesioning. IAPP content was increased in the islets of VMH-lesioned rats compared with findings in the sham-operated controls (100.9 +/- 6.6 vs 72.8 +/- 3.85 fmol/islet; P less than 0.01). Isolated islets of VMH-lesioned rats secreted larger amounts of IAPP in the presence of 2.8 and 16.7 mM glucose (2.99 +/- 0.98 and 11.2 +/- 0.29 fmol islet-1 3 h-1) than was noted in sham-operated rats (ND and 6.65 +/- 0.78 fmol islet-1 3 h-1). In the obese Zucker rats, aged 14 weeks, IAPP concentrations in the islets were elevated compared with lean rats (133.3 +/- 10.6 vs 84.4 +/- 8.5 fmol/islet; P less than 0.01). The isolated islets secreted larger amounts of IAPP in response to 2.8 and 16.7 mM glucose (2.83 +/- 0.88 and 15.81 +/- 1.35 fmol islet-1 3 h-1) than did those from lean control rats (0.36 +/- 0.19 and 12.49 +/- 1.20 fmol islet-1 3 h-1). These results strongly suggest that overproduction and hypersecretion of IAPP occur in animals with obesity and hyperinsulinemia.     

Medium-chain triglycerides enhance mucous secretion and cell proliferation in the rat

Background  The specific purpose of this study was to investigate the effects of medium-chain triglycerides (MCTs) on intestinal cell proliferation and mucous secretion of the small intestine in the rat. Methods  Rats were fed chow diet and given MCTs or the same weight of corn oil (5 g/kg per day) by gavage daily for 2 weeks, and then tissue samples of the small intestines were harvested. Leptin concentration in the small intestine was measured. Cell proliferation and apoptosis in the small intestine was determined by immunohistochemistry. Diamine oxidase (DAO) activity was measured by colorimetric assay. Results  In rats fed only chow diet (normal rats), the number of goblet cells per villi was 14.2 ± 0.75 in the jejunum and 15.2 ± 1.12 in the ileum. The number of goblet cells increased significantly in rats given MCTs compared with rats given corn oil or normal rats. Ki-67-positive cells were detected on the entire villi and the crypts in the small intestine. Furthermore, the proliferative index and the apoptotic index were also significantly greater in rats given MCTs than rats given corn oil or normal rats. Moreover, DAO activity and leptin concentration in the small intestine were significantly greater in rats given MCTs than rats given corn oil or normal rats. Conclusions  MCTs enhance cell proliferation of the intestinal epithelium and mucous secretion from goblet cells in the small intestine. These effects may protect the gut in patients suffering from inflammatory bowel disease or enterogenous infection.     

酒精通过抑制肠上皮干细胞增殖损伤肠上皮的更新修复能力

目的 研究酒精对肠上皮干细胞(ISC)和肠上皮更新修复能力的影响。方法 将18只C57BL/6小鼠随机分为对照组(n=9)和酒精处理组(n=9)。采用Gao-Binge法制备慢性酒精中毒模型。在造模成功后,腹腔注射5-溴-2-脱氧脲苷(BrdU),分别在注射后2 h、24 h和72 h取小肠组织,采用免疫组化法检测BrdU阳性细胞和ISC特异性标志物Lgr5表达。结果 与对照组小鼠比,酒精处理组小鼠小肠绒毛高度显著缩短、萎缩;酒精处理组小鼠ISC细胞Lgr5表达显著弱于对照组;酒精处理组小鼠每个肠隐窝BrdU阳性细胞数量为(3.50±0.65)个/肠隐窝,显著少于对照组【(7.90±1.08)个/肠隐窝,P＜0.05】;在注射BrdU 后2 h、24 h和72 h,酒精处理组小鼠小肠BrdU阳性细胞迁移距离分别为(66.67±1.60)μm、(219.40±12.11)μm和(313.90±9.76)μm,显著短于对照组【分别为(111.10±1.60)μm、(319.00±10.04)μm和(625.90±3.34)μm,P＜0.05】。结论 酒精通过抑制ISC引起肠上皮细胞增殖和迁移能力下降,从而损伤肠上皮的更新修复能力,导致肠上皮屏障功能障碍。     

Hypersecretion of islet amyloid polypeptide from pancreatic islets of ventromedial hypothalamic-lesioned rats and obese Zucker rats

To investigate the possible role of islet amyloid polypeptide (IAPP) in the development of type 2 diabetes mellitus, we examined the IAPP content and secretion in pancreatic islets isolated from ventromedial hypothalamic (VMH)-lesioned rats and genetically obese Zucker rats, using a specific RIA for IAPP. Obesity and hyperinsulinemia were observed in rats 21 days after VMH lesioning. IAPP content was increased in the islets of VMH-lesioned rats compared with findings in the sham-operated controls (100.9 +/- 6.6 vs. 72.8 +/- 3.85 fmol/islet; P less than 0.01). Isolated islets of VMH-lesioned rats secreted larger amounts of IAPP in the presence of 2.8 mM and 16.7 mM glucose (2.99 +/- 0.98 and 11.2 +/- 1.29 fmol.islet(-1).3 h-1) than was noted in sham-operated rats (ND and 6.65 +/- 0.78 fmol.islet(-1).3 h-1). In the obese Zucker rats, aged 14 weeks, IAPP concentrations in the islets were elevated compared with lean rats (133.3 +/- 10.6 vs. 84.4 +/- 8.5 fmol/islet; P less than 0.01). The isolated islets secreted larger amounts of IAPP in response to 2.8 mM and 16.7 mM glucose (2.83 +/- 0.88 and 15.81 +/- 1.35 fmol.islet(-1).3 h-1) than did those from lean control rats (0.36 +/- 0.19 and 12.49 +/- 1.20 fmol.islet(-1).3 h-1). These results strongly suggest that overproduction and hypersecretion of IAPP occur in animals with obesity and hyperinsulinemia.     

Distinct role of adiposity and insulin resistance in glucose intolerance: studies in ventromedial hypothalamic-lesioned obese rats

It remains unclear whether adiposity plays an important role in glucose intolerance independently of insulin resistance. We investigated whether adiposity and insulin resistance had distinct roles in glucose intolerance in rats. We examined glucose tolerance and insulin resistance using ventromedial hypothalamic (VMH)-lesioned rats in the dynamic and the static phases of obesity (2 and 14 weeks after lesioning, respectively). Rats were fed either normal chow or a fructose-enriched diet (60% of total calories). The intravenous glucose tolerance test (IVGTT) was performed by bolus injection of glucose solution (1 g/kg) and blood sampling after 0, 5 10, 30, and 60 minutes. Insulin resistance was evaluated from the steady-state plasma glucose (SSPG) value during continuous infusion of glucose, insulin, and somatostatin. SSPG was not increased in VMH-lesioned rats in the dynamic phase of obesity, but increased markedly in the static phase. The area under the glucose curve (glucose AUC) during IVGTT was increased in VMH-lesioned rats in the static phase, but not in the dynamic phase, when compared with their sham-operated counterparts. A fructose-enriched diet for 2 or 14 weeks increased SSPG values to a similar extent in both sham-operated and VMH-lesioned rats without inducing excess adiposity, but glucose intolerance was only developed in the obese rats. The plasma leptin level, an excellent indicator of adiposity, was significantly related to the glucose AUC independently of the insulin level. Insulin resistance or increased adiposity alone is not sufficient to impair glucose tolerance, but increased adiposity plays an important role in the development of glucose intolerance in an insulin-resistant state.     

lactulose和glutamine对梗阻性黄疸大鼠空肠黏膜的影响

目的:研究梗阻性黄疸时空肠黏膜的变化及lactulose和glutamine对梗阻性黄疸大鼠空肠黏膜的影响．方法:Wistar大鼠84只,随机分为4组．通过手术结扎切断大鼠胆总管得到梗阻性黄疸模型．对梗阻性黄疸大鼠分别经胃灌注lactulose和glutamine药物,比较给药前及给药后5,10 d各组大鼠空肠黏膜绒毛高度变化,同时与未行胆管结扎的假手术对照组进行比较．结果:无论胆总管结扎与否,给药前各组空肠黏膜的绒毛高度无明显差异．胆总管结扎后大鼠空肠黏膜高度减低(5 d:q=4．32,P<0．01;10 d:q=11．03,P<0．01);应用生理盐水组大鼠的空肠黏膜绒毛高度明显低于应用lactulose和glutamine组大鼠的空肠黏膜绒毛高度,且应用glutamine组与胆总管未结扎组相近(5 d:q= 3．62,P>0．05;10 d:q=3．83,P>0．05);而应用lactulose和glutamine的2组大鼠空肠黏膜绒毛高度无明显差异(P>0．05)．结论:结扎大鼠胆总管可导致其空肠黏膜萎缩．经胃肠道应用lactulose或glutamine对胆道梗阻所致的大鼠空肠黏膜萎缩均具有保护作用,且二者对肠黏膜的保护作用无明显差异．     

Dietary lipids alter the effect of steroids on the uptake of lipids following intestinal resection in rats

Steroids alter the transport function of the intestine. This study was undertaken to assess the effect of glucocorticosteroids on lipid uptake in rats fed either a saturated (SFA) or a polyunsaturated fatty acid (PUFA) diet. Sprague-Dawley rats underwent transection or 50% resection of the small intestine. The steroids had no effect on the uptake of lipids. However, resection decreased the jejunal uptake of palmitic acid in animals fed SFA and increased the jejunal uptake of palmitic and linoleic acids in those fed PUFA. In animals undergoing intestinal resection, fed SFA, and given control vehicle, there was a reduction in jejunal proglucagon mRNA expression as compared to those fed chow or PUFA. Ornithine decarboxylase (ODC) mRNA expression in the jejunum of resected animals was reduced. In summary, dietary lipids modify the uptake of lipids in resected animals and ODC and proglucagon may be involved in this adaptive response.     

Functional mechanism underlying cyclooxygenase-2 expression in rat small intestine following administration of indomethacin: relation to intestinal hypermotility

BACKGROUND AND AIM: We recently reported that cyclooxygenase (COX)-2 is upregulated in the rat small intestine after administration of indomethacin, and this may be the key to non-steroidal anti-inflammatory drug (NSAID)-induced intestinal damage. The present study investigated the mechanism for COX-2 expression induced in the rat small intestine by indomethacin, in relation with ulcerogenic processes. METHODS: Animals were given indomethacin or SC-560 p.o., and the intestinal mucosa was examined 24 h later. RESULTS: Indomethacin caused hemorrhagic lesions in the small intestine, accompanied with an increase in intestinal motility, bacterial invasion and inducible nitric oxide synthase (iNOS) activity, as well as the expression of COX-2 mRNA in the mucosa. Although SC-560 did not cause any damage, this agent caused intestinal hypermotility, the bacterial invasion and the upregulation of COX-2 expression. The mucosal PGE2 content was decreased by SC-560 at 3 h but recovered 12 h later, and this recovery of PGE2 was attenuated by both atropine and ampicillin, in addition to rofecoxib. The intestinal hypermotility response to indomethacin was prevented by both 16,16-dimethyl PGE2 and atropine, but not ampicillin. Yet all these agents inhibited not only the bacterial invasion but also the expression of COX-2 and iNOS activity in the intestinal mucosa following indomethacin treatment, resulting in the prevention of intestinal lesions. CONCLUSION: These results suggest that COX-2 expression in the intestinal mucosa following the administration of indomethacin is associated with intestinal hypermotility and bacterial invasion. The intestinal hypermotility caused by COX-1 inhibition may be a key to COX-2 expression after administration of NSAIDs and their intestinal ulcerogenic properties.     

Decreased apoptosis and increased ornithine decarboxylase activity in the intestinal mucosa of rats with bilateral ventromedial hypothalamus lesions

Background It has not been clearly demonstrated whether the ventromedial hypothalamus regulates intestinal cell growth. Ornithine decarboxylase is a key enzyme in polyamine synthesis, which plays an important role in intestinal mucosal growth. The aim of this study was to investigate whether bilateral ventromedial hypothalamus lesions affect mucosal cell growth. This was done by evaluating ornithine decarboxylase activity and apoptosis in rat small intestines.Methods Bilateral ventromedial hypothalamus lesions were produced by thermocoagulation, done with rats under halothane anesthesia 7 days before the experiments. Rats with lesions were pair-fed with sham-operated rats. Total (truncal) vagotomy was performed before the development of ventromedial hypothalamus lesions. Ornithine decarboxylase activity and apoptosis were evaluated in the jejunal mucosa.Results Ornithine decarboxylase activity in the jejunal mucosa increased significantly 1 week after the development of the bilateral ventromedial lesions, and was attenuated by truncal vagotomy. Apoptosis in the jejunal mucosa was suppressed in rats with ventromedial hypothalamus lesions. In contrast to the effect on ornithine decarboxylase activity, the truncal vagotomies had no effect on apoptosis in rats with lesions. Apoptosis increased in the sham-operated rats after 24-h and 48-h fasting. Apoptosis in the jejunal mucosa of rats with ventromedial hypothalamus lesions did not increase after 24-h fasting. After 48-h fasting, jejunal apoptosis increased in rats with lesions, but not markedly.Conclusions The ventromedial hypothalamus may regulate cell growth in the intestinal mucosa partly through the vagal nerve; however, the vagal nerve was not related to intestinal apoptosis controlled by the ventromedial hypothalamus.     

The effect of a ventral medial hypothalamic lesion on the insulin-induced hypotensive response in normal rats

The cardiovascular responses to insulin-induced hypoglycemia were studied in normal and ventral medial hypothalamic (VMH)-lesioned rats. The goal of this study was to investigate the role of the VMH in mediating the insulin-induced decreases in cardiovascular tone. Male Wistar rats were anesthetized with urethane/chloralose. Following the induction of anesthesia, the trachea, femoral artery, and femoral vein were cannulated. The femoral artery was attached to a pressure transducer for cardiovascular monitoring. The cardiovascular activity was recorded using a Modular Instruments Micro 5000 signal processing system. The mean arterial pressure and pulse pressures and heart rate were evaluated. In control studies, a stable plasma glucose and blood pressure were obtained with urethane/chloralose anesthesia for the duration of the experiments. Insulin (2.0 or 5.0 U/kg) significantly decreased the plasma glucose as well as the blood pressure. In VMH-lesioned rats, the lesions were accomplished by radiofrequency, and the cardiovascular response to insulin-induced hypoglycemia was investigated 1 or 6 weeks later. There was no difference in the cardiovascular response to insulin-induced hypoglycemia between the low or high insulin dose after 1 week in VMH-lesioned animals. The low dose after 6 weeks in VMH-lesioned animals did not produce a change in the mean arterial pressure response compared with controls. The pulse pressure was higher than in the sham-lesioned animals, and the plasma glucose response was greater. The high dose after 6 weeks in VMH-lesioned animals in contrast to sham-lesioned animals led to an increased cardiovascular response instead of a decrease. We propose that the decrease in cardiovascular activity in response to insulin-induced hypoglycemia in normal animals can be attributed to a direct or indirect effect on vascular dilation as well as possibly to an inhibition of sympathetic firing. However, it appears that insulin increases the vascular dilation as well as the parasympathetic tone after 1 week in the VMH-lesioned animals, similar to the findings in sham-lesioned animals. However, after 6 weeks, the insulin-induced decreased cardiovascular tone is minimal. Thus, we believe hat the VMH does not have a direct effect in modulating the insulin-induced decrease in cardiovascular tone, but its destruction appears to influence other regulatory centers.