Role of nitric oxide in acidosis-induced intestinal injury in anesthetized rats.

We investigated the pathogenic mechanism(s) of small intestinal injury during acidosis in relation to circulating nitric oxide (NO) in an experimental rat model. Rats were anesthetized, paralyzed, and mechanically ventilated with room air. Hydrochloric acid (0.16 mmol bolus followed by 0.132 mmol/kg/h) was infused through the jugular vein for 5 hours. Control rats received a saline infusion. Arterial blood gases, blood pressure, and blood pH were measured every 30 minutes. The involvement of NO in this acidosis model was assessed by measuring plasma concentration of nitrite/nitrate (NOx) and by evaluating inducible NO synthase (iNOS) expression in small intestinal mucosa. Intestinal injury was assessed by measuring myeloperoxidase (MPO) activity, thiobarbituric acid reactants (TBARS), and histologic scores. HCl infusion was associated with hypotension, decreased blood pH, increased plasma concentration of NOx, augmented intestinal mucosal iNOS expression, MPO activity, TBARS, and histopathologic injury scores. Pretreatment with an iNOS inhibitor, aminoguanidine (AG, 50 mg/kg), reversed HCl-induced hypotension without a change in blood pH. HCl-induced lesions, MPO activity, TBARS, and plasma NOx production were decreased by AG. Our data show that the pathogenic mechanisms of acidosis-induced small intestinal lesions involve up-regulation of NO production by increased expression of iNOS and augmentation of superoxide radicals and MPO activity.

Comparison of early feeding pattern dynamics in female and male rats after reversible ventromedial nucleus of hypothalamus block.

BACKGROUND: In the hypothalamus, a number of interconnected foci, including the ventromedial nucleus of hypothalamus (VMN), interact to control food intake (FI). FI is a function of meal number (MN) and meal size (MZ). Because gender differences exist in feeding patterns, we aimed at investigating the role of the VMN in determining the relationship of MZ and MN in female and male rats. METHODS: FI and feeding patterns of 10 female and 12 male Fischer-344 rats were studied after VMN block, achieved via stereotaxically located intra-VMN microinjection of the neuronal blocker, colchicine (0.32 microgram dissolved in 50 nL of isotonic injectate and instilled on each side into the VMN). RESULTS: After colchicine injection in normal female rats, an immediate and significant increase in FI occurs as a result of the following: 1) increased MZ in dark and light phases and 2) increased light phase MN with consequent loss of the normal diurnal cycle in FI. Recovery of feeding cycle and normal vaginal smear pattern occurred by study's end. In normal male rats, VMN block resulted in the following: 1) an increase in FI resulting from increased MN occurring predominantly during the light phase, thereby 2) disrupting the usual light/dark feeding cycle. CONCLUSIONS: Sexual differences in regulation of FI occur after temporary reversible VMN block: in female rats, MZ is more sensitive to experimental modulation, whereas in male rats it is MN.

Hypophysial and meningeal melanocytes in the Zucker rat.

Melanocytes have not been described in the pituitary of mammals or in the meninges of the rat. In this paper, we report the presence of the cluster of melanocytes in the intermediate lobe of the pituitary and around the median eminence of the hypothalamus forming an 'infundibulo-hypophysial circle', and also describe the characteristics of meningeal melanocytes in Zucker rats. In the leptomeninges, numerous melanocytes were found on the ventrolateral surface of cerebral hemisphere in the area of the middle cerebral artery. Pigment granules were also observed in the surrounding tissue outside the melanocytes as well as incorporated in the cytoplasm of neural and epithelial cells. Electron microscopy revealed that melanosomes in hypophysial and meningeal melanocytes were in different (II-IV) stages of maturity. In the leptomeninges of Zucker rats, HMB-45 immunoreactivity was found in round non-melanosome-containing cells, while no HMB-45 reaction was found in the leptomeninges of the albino rat. We conclude that both obese and lean Zucker rats possess functionally active melanocytes in the meninges and the pituitary and transfer pigment granules to neighboring cells. The distributions of melanocytes in proximity to blood vessels in the leptomeninges and in the 'infundibulo-hypophysial circle' suggest an endocrine secretory function.

Infusion of nicotine into the LHA enhances dopamine and 5-HT release and suppresses food intake.

Nicotine administration induces hypophagia. Because of the involvement of hypothalamic neurotransmitters in food intake control, we hypothesized that increased activity of the lateral hypothalamic dopamine (LHA-DA) and/or serotonin (LHA-5-HT) may be responsible for nicotine-induced hypophagia. Either 4 mM nicotine or vehicle was administered via reverse microdialysis technique into the LHA of overnight food-deprived rats for 60 min; then food was provided for 40 min. The LHA-DA, 5-HT and their intermediate metabolites, DOPAC and 5-HIAA, were continuously measured during 20-min intervals before, during, and after nicotine administration. Continuous nicotine administration for 60 min increased LHA-DA and DOPAC concentrations during the first 40 min, and induced a long-lasting increase in LHA-5-HT release, until 120 min after the start nicotine administration, even when nicotine administration was stopped. The food intake during the 40-min refeeding period was significantly lower when rats received nicotine. Eating induced a significant and short-lasting increase in the LHA-DA and a long-lasting increase in the LHA-5-HT. These findings indicate that nicotine enhances dopaminergic and serotonergic activity in the LHA, and that the enhanced LHA-5-HT activity may contribute to nicotine-induced hypophagia.

Bilateral ovarian stromal hyperplasia concealing a nonhilar, pure stromal-Leydig cell tumor. A case report.

BACKGROUND: Of ovarian stromal tumors containing Leydig cells, nonhilar, pure stromal-Leydig cell tumor is rare. CASE: An obese, diabetic, borderline hypertensive 41-year-old woman with a five-year history of oligomenorrhea and amenorrhea presented with complaints of masculinization. Physical examination revealed hirsutism and an enlarged clitoris. The only abnormal serum marker was elevated testosterone. At laparotomy both ovaries were enlarged and suspected to have bilateral stromal hyperthecosis. Histology revealed stromal hyperplasia along with a 1.5-cm, testosterone-producing pure stromal-Leydig cell tumor of the right ovary. CONCLUSION: Bilateral ovarian enlargement secondary to stromal hyperplasia in patients with masculinizing signs can conceal a small, unilateral pure stromal-Leydig cell tumor.

Dietary nucleotides augment dextran sulfate sodium-induced distal colitis in rats.

We have previously shown that enteral and parenteral supplementation of nucleotides (NT) accelerates healing of small-bowel ulcers in rats with indomethacin-induced ileitis. The purpose of this study was to evaluate whether dietary NT supplementation would similarly affect ulcer healing in dextran sulfate sodium (DSS)-induced colitis in rats. Male Sprague-Dawley rats were randomly assigned to receive either nucleotide-free (NF) or NT-supplemented diets. After 2 d of prefeeding, colitis was induced by including 40 g/L of DSS in drinking water for 3 d, followed thereafter by tap water. Rats from each group were killed at 7 and 12 d after induction of colitis. Additional rats were also used for both the groups as controls (untreated groups). The length of colon was measured and evaluated by histological score. Colonic myeloperoxidase (MPO) activity was assessed. In a separate series of experiments, rats were studied at 0, 4, 7, and 12 d for interleukin-1beta (IL-1beta) in rectal dialysate and plasma. Ulceration predominated in the distal colon in DSS-treated rats. There was no significant difference between the histological scores of the NF and NT-supplemented groups either at 7 or 12 d. MPO activity at 7 and 12 d was significantly higher in the NT-supplemented compared to NF group (7 d: 1013 +/- 172 vs. 409.9 +/- 103.2; 12 d: 471.9 +/- 112.4 vs. 223.6 +/- 21.6 units. min-1. g colon-1). IL-1beta concentration in rectal dialysate was significantly higher at 7 d in both groups compared to 0 and 4 d. At 12 d it continued to be significantly elevated in the NT-supplemented group and was greater than in the NT-free group. Our data on the proinflammatory cytokine, in conjunction with MPO activity, strongly suggest that NT supplementation aggravates the severity of DSS-induced colitis in rats.

Interleukin-1alpha injection into ventromedial hypothalamic nucleus of normal rats depresses food intake and increases release of dopamine and serotonin.

A microdialysis injector probe administered IL-1alpha into ventromedial hypothalamus (VMN) and concurrently measured release of dopamine (DA), DOPAC, 5-HT, and 5-HIAA. After baseline dialyses, six rats received 2-ng IL-1alpha and six rats received vehicle (1 microl saline) into VMN. Sixty minutes later, food was provided for 40 min while VMN monoamines were measured every 20 min. Vehicle had no significant effect on monoamines, their metabolites, or food intake. Food intake was significantly lower in IL-1alpha rats vs. controls (p < 0.01). Baseline levels of VMN monoamines (pg/10 microl dialysate) in IL-1alpha and vehicle groups were similar. DA and 5-HT rose immediately on injecting IL-1alpha and remained higher (p < 0.05) than basal during the first 60 min and 40 min sampling period, respectively. Levels of 5-HIAA also increased (p < 0.01). Eating decreased VMN DA in controls, and decreased VMN DOPAC in IL-1alpha-treated rats. During eating, VMN 5-HT in control rats significantly increased while increasing VMN 5-HIAA occurred in IL-1alpha rats. Findings show that an IL-1alpha pathophysiological dose injected into the VMN was associated with anorexia and significantly increased dopaminergic and serotonergic activities and suggest that enhanced VMN DA and 5-HT activities may be part of an IL-1alpha-initiated cascade involved in IL-1alpha-associated anorexia.

Acidosis stimulates nitric oxide production and lung damage in rats.

Systemic hypotension during sepsis is thought to be due to nitric oxide (NO) overproduction, but it may also be due to acidosis. We evaluated in healthy rats the consequences of acid infusion on NO and blood pressure. Sprague-Dawley rats were anesthetized, and ventilated with room air. The animals were randomized into four groups. Group 1 (C, n = 10) received only normal saline at rates comparable to the other groups. Group 2 (A1, n = 10) received hydrochloric acid at 0.162 mmol in the first 15 to 30 min, followed by a continuous infusion of 0.058 mmol/h for 5 h. Group 3 (AG+A1, n = 6) was pretreated with aminoguanidine (AG, 50 mg/kg), and HCl was infused as above. Group 4 (A2, n = 7) received HCl at twice the rate used in A1. Nitric oxide concentration in the exhaled gas (ENO), blood gases, and mean arterial pressure were measured every 30 min. Acid infusion in A1 caused the pH to fall gradually from 7.43 +/- 0. 01 to 7.13 +/- 0.05. This moderate decrease in pH was associated with a marked increase in ENO (1.6 +/- 0.3 to 114.2 +/- 22.3 ppb), an increase in plasma nitrite/nitrate (17.3 +/- 3.7 to 35.2 +/- 4.3 microM), and a significant decrease in blood pressure (110.5 +/- 6.3 to 63.3 +/- 15.0 mm Hg). Furthermore, acidosis caused lung inflammation, as suggested by the increase in lung myeloperoxidase activity (282.2 +/- 24.7 to 679.3 +/- 57.3 U/min/g) and lung injury score (1.7 +/- 0.2 to 3.5 +/- 0.6). Acidosis after AG pretreatment was associated with a similar change in pH, but the increase in ENO, nitrite/nitrate, and systemic hypotension were prevented. Furthermore, lung injury was attenuated by AG, as suggested by a lower myeloperoxidase activity, though lung injury score was not altered. In this model, moderate acidosis causes increases in NO, hypotension, and lung inflammation. Lung inflammation and injury are due in part to acidosis and NO production. This is the first report to show a direct effect of chronic acidosis on NO production and lung injury. These results have profound implications on the role of acidosis on NO production and lung injury during sepsis.

Ventromedial nucleus of hypothalamus is related to the development of cancer-induced anorexia: in vivo microdialysis study.

UNLABELLED: Based on reports that increased hypothalamic ventromedial nucleus (VMN)-serotonin (5-HT) is associated with cancer anorexia and recent findings in our laboratory that low levels of dopamine (DA) in the VMN are associated with prolonged inter meal intervals thus decreased food intake, and reports that setting up satiation is concomitant with descending levels of DA in the rostromedial hypothalamus, we hypothesized that an elevated 5-HT to low DA ratio in the VMN modulates food intake in cancer anorexia. METHODS: In Expt 1: A microdialysis cannula guide was placed stereotactically into the VMN of methylcholanthrene (MCA) sarcoma tumor-bearing (TB) Fischer rats and in non-tumor-bearing (NTB) and pair-fed (PF) controls. When TB rats manifested anorexia by a decrease in food intake, VMN-5-HT, its metabolite 5-hydroxyindolacetic acid (5-HIAA), and DA with its metabolite 3,4,-dihydroxyphenylacetic acid (DOPAC) were measured by in vivo microdialysis using HPLC during baseline, in response to food, and after feeding. In Expt 2: TB rats had tumor removed and VMN microdialysis performed 7 days later. RESULTS: Increased 5-HT release and turnover, and significantly reduced DA release with increased DOPAC occurred in TB vs NTB or PF rats. When food was offered, intake in TB rats was significantly lower than in NTB control rats. During eating, VMN-5-HT rose and peaked significantly earlier in TB vs NTB rats, while DA release was significantly reduced. With eating, the 5-HT and DA metabolism became reduced in all rats. Seven days after surgical removal of the tumor, 24 h food intake had increased to the level of controls; and when food was offered during microdialysis, intake in TB rats increased (ns relative to control), but was not yet normal. VMN microdialysis showed that 5-HT was normal at baseline, as well as during and after eating, while DA remained depressed. The metabolic turnover of 5-HT and DA was significantly lower in TB-r and PF vs NTB rats. We conclude that increased 5-HT/DA ratio is related to the development of cancer-induced anorexia.

Treatment of septic shock in rats with nitric oxide synthase inhibitors and inhaled nitric oxide.

OBJECTIVE: To evaluate the effect of treatment with a combination of nitric oxide synthase inhibitors and inhaled nitric oxide on systemic hypotension during sepsis. DESIGN: Prospective, randomized, controlled study on anesthetized animals. SETTING: A cardiopulmonary research laboratory. SUBJECTS: Forty-seven male adult Sprague-Dawley rats. INTERVENTIONS: Animals were anesthetized, mechanically ventilated with room air, and randomized into six groups: a) the control group (C, n=6) received normal saline infusion; b) the endotoxin-treated group received 100 mg/kg i.v. of Escherichia coli lipopolysaccharide (LPS, n=9); c) the third group received LPS, and 1 hr later the animals were treated with 100 mg/kg i.v. Nw-nitro-L-arginine (LNA, n=9); d) the fourth group received LPS, and after 1 hr, the animals were treated with 100 mg/kg i.v. aminoguanidine (AG, n=9); e) the fifth group received LPS and 1 hr later was treated with LNA plus 1 ppm inhaled nitric oxide (LNA+NO, n=7); f) the sixth group received LPS and 1 hr later was treated with aminoguanidine plus inhaled NO (AG+NO, n=7). Inhaled NO was administered continuously until the end of the experiment. MEASUREMENTS AND MAIN RESULTS: Systemic mean blood pressure (MAP) was monitored through a catheter in the carotid artery. Mean exhaled NO (ENO) was measured before LPS (T0) and every 30 mins thereafter for 5 hrs. Arterial blood gases and pH were measured every 30 mins for the first 2 hrs and then every hour. No attempt was made to regulate the animal body temperature. All the rats became equally hypothermic (28.9+/-1.2 degrees C [SEM]) at the end of the experiment. In the control group, blood pressure and pH remained stable for the duration of the experiment, however, ENO increased gradually from 1.3+/-0.7 to 17.6+/-3.1 ppb after 5 hrs (p< .05). In the LPS treated rats, MAP decreased in the first 30 mins and then remained stable for 5 hrs. The decrease in MAP was associated with a gradual increase in ENO, which was significant after 180 mins (58.9+/-16.6 ppb) and reached 95.3+/-27.5 ppb after 5 hrs (p< .05). LNA and AG prevented the increase in ENO after LPS to the level in the control group. AG caused a partial reversal of systemic hypotension, which lasted for the duration of the experiment. LNA reversed systemic hypotension almost completely but only transiently for 1 hr, and caused severe metabolic acidosis in all animals. The co-administration of NO with AG had no added benefits on MAP and pH. In contrast, NO inhalation increased the duration of the reversal in MAP after LNA, alleviated the degree of acidosis, and decreased the mortality rate (from 55% to 29%). CONCLUSIONS: In this animal model, LPS-induced hypotension was alleviated slightly and durably after AG, but only transiently after LNA. Furthermore, co-administration of NO with AG had no added benefits but alleviated the severity of metabolic acidosis and mortality after LNA. We conclude that nitric oxide synthase (NOS) inhibitors, given as a single large bolus in the early phase of sepsis, can exhibit some beneficial effects. Administration of inhaled NO with NOS inhibitors provided more benefits in some conditions and therefore may be a useful therapeutic combination in sepsis. NO production in sepsis does not seem to be a primary cause of systemic hypotension. Other factors are likely to have a major role.

Bilateral hypothalamic dopamine infusion in male Zucker rat suppresses feeding due to reduced meal size.

Lateral hypothalamic area dopamine activity (LHA-DA) appears to play a contributory role in regulating food intake, in particular, meal size. In this study we examined our hypothesis that bilateral LHA-DA injection induced depression of food intake via reduced meal size. Dopamine (11 mg/ml) or vehicle was infused into bilateral LHA at 0.5 microliter/h via two osmotic minipumps in six study or six control obese male Zucker rats for 13 days, respectively. Meal size, meal number, as well as food intake were continuously measured before, during, and after dopamine infusion. Intra-LHA-DA infusion significantly depressed food intake. The decreased food intake was solely caused by a significant and profound reduction in meal size. There was a modest compensatory rise in meal number that gradually increased food intake so that it reached control level on 10th dopamine infusion day. However, feeding pattern did not normalize until dopamine infusion ceased. The findings support our hypothesis that LHA-DA may participate in regulating meal size. Data also demonstrate that meal size and meal number are regulated in a reciprocal and independent manner to compensate for each other.

Dietary supplementation of nucleotides and arginine promotes healing of small bowel ulcers in experimental ulcerative ileitis.

We previously showed that intravenous total parenteral nutrition supplemented with nucleosides and nucleotides (NS/NT) promoted ulcer healing in rats with indomethacin-induced ileitis. The present study evaluated whether dietary NT supplementation would similarly affect ulcer healing in this model. Female Lewis rats were randomized into either control or experimental groups receiving yeast RNA containing NT or arginine, glutamine, fish oil, guar gum, or a combination of yeast RNA+arginine diets. Ileitis was induced by two doses of indomethacin (7.5 mg/kg) administered subcutaneously 24 hr apart. Ulcer number and length were determined at 4, 8, and 14 days after induction of ileitis. Ileal villous and crypt length, crypt-villous ratio, and bromodeoxyuridine (BrdU) labeling were studied in the control and yeast RNA-supplemented diet groups. Ileal ulceration was present in all groups at 4 and 8 days and was almost healed by 14 days. Rats receiving yeast RNA, arginine, and yeast RNA + arginine diets showed a significant decrease in ulcer number (56%, 28%, and 34%, respectively) and length (67%, 41%, and 48%, respectively) compared to controls at 8 but not at 4 days. Glutamine, fish oil, and guar gum had no effect on ulcer healing at 4, 8, or 14 days. Among the histological parameters, a significant decrease in crypt length in the yeast RNA-supplemented group at 8 days suggested an acceleration of the healing process and restoration to a near-normal crypt-villous architecture. We conclude that the yeast RNA, arginine, and yeast RNA + arginine diets accelerated ulcer healing, as indicated by decreased ulcer number and length. We postulate that the underlying mechanism(s) contributing to ulcer healing may be related, in part, to increased cell proliferation.

Eating-associated VMN-dopamine levels of rats: comparison of oral and intragastric feeding.

Eating is associated with persistently low dopamine (DA) concentration in the ventromedial hypothalamic nucleus (VMN), postulated to influence postprandial satiety. Whether pregastric factors contribute to eating-associated low VMN-DA was examined. VMN-DA levels were continuously measured in awake rats, food-deprived for 24 h, and either subsequently allowed to eat solid chow freely available for 20 min, an oral liquid diet, or an isovolemic isocaloric liquid diet infused intragastrically to bypass the oropharynx. Eating either solid chow or a liquid diet was associated with an immediate decrease in VMN-DA concentration. The lower VMN-DA concentration lasted longer after solid chow was consumed than following consumption of the liquid diet. When the oropharynx was bypassed no significant change in VMN-DA concentration was observed either during or after the liquid diet was infused. Results suggest that pregastric oropharyngeal factors contribute to eating-associated low VMN-DA concentration.

Periareolar Breast Abscess: Redefining the Disease and Its Treatment.

Periareolar breast abscess has been an elusive condition, with much debate about its etiology over the last several decades. Presenting symptoms include nipple discharge, mastalgia, and recurrent abscesses with draining fistulas. Many experts disagree about whether this condition develops when inflammation of the duct leads to dilation or whether it begins with dilation that leads to inflammation. Because the frequency of asymptomatic dilated ducts found incidentally in patients during surgery or upon autopsy exceeds that of patients with symptomatic duct dilation or ectasia, we believe that mechanical obstruction with associated retention of secretions is at the core of this disease process. In this article, we term and characterize mammary-duct-associated inflammatory disease as a 3-phase pathologic process that leads to recurrent nonlactational periareolar breast abscess in nonpuerperal women. Effective treatment of abscesses should be based on the disease's pathogenic process and should include excision of all involved ducts. Treated by this method, patients appear to experience minimal sequelae and low recurrence of abscesses.

Adding heparin to aspirin reduces the incidence of myocardial infarction and death in patients with unstable angina. A meta-analysis.

OBJECTIVE: To estimate the risk of myocardial infarction (MI) and death in patients with unstable angina who are treated with aspirin plus heparin compared with patients treated with aspirin alone. DATA SOURCES: Studies were retrieved using MEDLINE, bibliographies, and consultation with experts. STUDY SELECTION: Only published trials that enrolled patients with unstable angina, randomized participants to aspirin plus heparin vs aspirin alone, and reported incidence of myocardial infarction or death were included in the meta-analysis. DATA EXTRACTION: Patient outcomes including MI or death, recurrent ischemic pain, and major bleeding during randomized treatment; revascularization procedures after randomization; and MI or death during the 2 to 12 weeks following randomization were extracted by 2 authors, 1 of whom was blinded to the journal, institution, and author of each study. DATA SYNTHESIS: Six randomized trials were included. The overall summary relative risk (RR) of MI or death during randomized treatment was 0.67 (95% confidence interval [CI], 0.44-1.02) in patients with unstable angina treated with aspirin plus heparin compared with those treated with aspirin alone. The summary RRs for secondary endpoints in patients treated with aspirin plus heparin compared with those treated with aspirin alone were 0.68 (95% CI, 0.40-1.17) for recurrent ischemic pain; 0.82 (95% CI, 0.56-1.20) for MI or death 2 to 12 weeks following randomization; 1.03 (95% CI, 0.74-1.43) for revascularization; and 1.99 (95% CI, 0.52-7.65) for major bleeding. We found no statistically significant heterogeneity among individual study findings. CONCLUSIONS: Our findings are consistent with a 33% reduction in risk of MI or death in patients with unstable angina treated with aspirin plus heparin compared with those treated with aspirin alone. The bulk of evidence suggests that most patients with unstable angina should be treated with both heparin and aspirin.

Mode of food intake reduction in Lewis rats with indomethacin-induced ulcerative ileitis.

The mechanism of anorexia in inflammatory bowel disease is poorly understood. To gain insight into possible pathophysiologic mechanisms, the feeding indices and food intake were studied in an animal model of Crohn's disease. The anorexia of indomethacin-induced ulcerative ileitis was compared with that of the well-known anorexia of total parenteral nutrition (TPN). Forty-five female Lewis rats were randomized to four groups: Control, Indomethacin, Indomethacin + TPN, and TPN. Feeding indices and food intake were continuously measured using the Automated Computerized Rat Eater Meter. Interleukin-1 alpha (IL-1 alpha), tumor necrosis factor-alpha (TNF-alpha), prostaglandin E2 (PGE2), and leukotriene B4 (LTB4) were assayed in plasma, mononuclear cell culture, or ileum to determine their role in mediating anorexia. In the TPN group, spontaneous food intake (SFI) decreased (52%; p < 0.05), primarily via reduction in meal number (MN, 54%; p < 0.05) and, to a lesser extent, meal size (MZ, 35%; p < 0.05). In comparison, in the Indomethacin group SFI decreased (74%; p < 0.05) primarily via reduction in MZ (67%, p < 0.05); MN also decreased but to a lesser extent (27%; p < 0.05). In the Indomethacin + TPN group, SFI decreased (55%; p > 0.05) primarily via reduction in MN (79%; p < 0.05), whereas MZ decreased slightly (19%; p < 0.05). Only in the Indomethacin group were IL-1 alpha and TNF-alpha detected in the mononuclear cell culture and plasma, respectively. In the Indomethacin group, an inverse correlation existed between MZ and TNF-alpha (p < 0.05). In the Indomethacin group, IL-1 alpha, PGE2, and LTB4 concentrations did not correlate with feeding indices. SFI reduction in this model was mediated primarily via a decrease in MZ. TNF-alpha is proposed to mediate this effect and TPN was shown to overcome the effect on MZ.

Intravenous nucleosides and a nucleotide promote healing of small bowel ulcers in experimental enterocolitis.

Our aim was to evaluate the possible beneficial effect of intravenous nucleosides and a nucleotide in healing small bowel ulceration in a rat model of enterocolitis. Fourteen Lewis female rats were randomized into total parenteral nutrition (TPN, N = 7) and TPN + nucleosides and a nucleotide (NS/NT, N = 7) groups. After adaptation, two doses of indomethacin (7.5 mg/kg) were administered subcutaneously 24 hr apart to each animal in both groups. Concomitant with the first dose of indomethacin, TPN or TPN + NS/NT were infused for four days. The TPN and TPN + NS/NT were isocaloric and isonitrogenous. At the end of four days, total ulcer length in the entire small bowel was measured. The mucosa surrounding ulcers was studied by optical microscopy. Immunohistochemistry was performed for proliferating cell nuclear antigen (PCNA). Ileal crypt and villus lengths were measured with an eyepiece micrometer, crypt-villus ratios were calculated, and crypt mitotic index and percentage of PCNA-labeled cells determined to assess cellular proliferation. Total ulcer length decreased significantly in the TPN + NS/NT group compared to the TPN group (42 vs 76 mm). In the TPN + NS/NT versus TPN group, the ileal mucosa surrounding ulcers showed significantly greater crypt length (21%) and there was increased crypt-villus ratio (0.53 vs 0.39), crypt mitotic index (1.2 vs 0.9), and PCNA labeling (43% vs 30%). We conclude that in rats with indomethacin-induced enterocolitis, administration of TPN + NS/NT for four days resulted in significant healing of small bowel ulcers, as indicated by decreased ulcer length. This effect of NS/NT appears to relate, in part, to increased cell proliferation, evidenced by increased crypt length, crypt-villus ratio, mitotic index, and PCNA labeling.

Innervated liver plays an inhibitory role in regulation of food intake.

BACKGROUND: With the onset of eating, the associated rise of dopamine in the lateral hypothalamus (LHA-DA) is thought to regulate quantity of food consumed per meal. Early release of LHA-DA induced by eating is facilitated by oronasal stimulation; we propose that the subsequent LHA-DA response induced by nutrients in the portal vein is dampened by the innervated liver. This was tested by measuring LHA-DA in normal rats: during parenteral feeding to bypass oronasal stimulation, while eating during parenteral feeding, and while eating only. METHODS: Rats had either total liver denervation or sham operation, with placement of a jugular vein catheter and LHA-DA microdialysis cannula. After a 3-week recovery period total liver denervated rats were randomized to parenterally fed, food only, and parenteral plus food groups each with sham-operated controls in which LHA-DA was measured. RESULTS: No difference in LHA-DA release in food only groups occurred between total liver denervated or sham-operated rats. A significantly higher rise in LHA-DA was observed in total liver denervated versus sham-operated rats in parenterally fed (129% +/- 4% versus 116% +/- 2%; p < 0.05) and parenteral plus food (151% +/- 4% versus 134% +/- 4%; p < 0.05) groups. CONCLUSIONS: In total liver denervation versus sham operation, an increase in LHA-DA release occurs during parenteral feeding and eating during parenteral feeding, suggesting that innervated liver inhibits LHA-DA release.

Increased food intake and body weight gain after lateral hypothalamic dopaminergic cell implantation.

To examine our hypothesis that dopamine activity in the lateral hypothalamic area (LHA) may play a role in enhancing the process of eating, a fetal cell suspension of predominantly dopaminergic cells was bilaterally transplanted into the LHA of study rats via direct injection; controls had carrier medium injection. Thereafter, mean daily food intake was 1 g per day greater in dopaminergic cell transplanted rats vs. controls for each day of the 10-week observation period. This resulted in a significantly greater cumulative body weight gain in study rats vs. controls (386 +/- 5.1 g vs. 354 +/- 3.8 g, respectively). On sacrifice at the end of the study, transplanted cells in the LHA were viable. Our data suggest that bilateral LHA dopaminergic cell transplant which presumably resulted in chronically and persistently enhanced dopaminergic activity in the LHA is associated with overeating and consequently, an excess weight gain.