Intestinal Injury In Rats Research Articles

Time-dependent enhancement or inhibition of endotoxin-induced vascular injury in rat intestine by nitric oxide synthase inhibitors.

1. The effects of the nitric oxide (NO) synthase inhibitors, NG-nitro-L-arginine methyl ester (L-NAME) and NG-monomethyl-L-arginine (L-NMMA), on the vascular damage induced by the endotoxin, E. coli lipopolysaccharide (LPS), in the ileum and colon were investigated in the conscious rat over a 5 h period. 2. Administration of LPS (3 mg kg-1, i.v.) increased ileal and colonic vascular injury after a lag period of 2 h, as determined by the leakage of radiolabelled albumin. 3. Administration of L-NAME (1-5 mg kg-1, s.c.) concurrently with LPS, produced a dose-dependent increase in vascular albumin leakage in the intestinal tissues, when determined over a 5 h period. Vascular albumin leakage with LPS and L-NAME (5 mg kg-1) was substantially increased after 1 h, reached maximal levels 3 h after administration, and then slowly declined. 4. L-NMMA (50 mg kg-1, s.c.), likewise elevated intestinal albumin leakage when administered concurrently with LPS, but this reached maximal levels after 1 h and rapidly declined over the subsequent 2 h. 5. In control rats, in the absence of LPS challenge, neither L-NAME (5 mg kg-1, s.c.) nor L-NMMA (50 mg kg-1, s.c.) increased intestinal vascular leakage of albumin over a 5 h period. 6. By contrast, when L-NAME (1-5 mg kg-1, s.c.) or L-NMMA (12.5-50 mg kg-1, s.c.) was injected 3 h after LPS, a dose-dependent reduction in the LPS-provoked vascular albumin leakage was observed. 7 Pretreatment with L-arginine (300 mg kg-1, s.c.) 15 min prior to the NO synthase inhibitors, reversed either the potentiation or the inhibition by L-NAME (5 mg kg-1, s.c.) or L-NMMA (50 mg kg-1, s.c.) of the LPS-induced intestinal vascular damage.8. These findings indicate that initial suppression of the constitutive NO synthase by L-NAME orL-NMMA following challenge with LPS aggravates the acute vascular injury in the ileum and colon,suggesting a defensive role of NO. By contrast, the delayed administration of NO synthase inhibitors, ata time of known expression of the inducible NO synthase, provides protection against the subsequent damage to the intestinal vasculature.

The role of endogenous nitric oxide and platelet-activating factor in hypoxia-induced intestinal injury in rats

Background/Aims: Nitric oxide is an endothelium-derived relaxing factor that promotes capillary integrity, inhibits leukocyte adherence and activation, and scavenges oxygen radicals. Because these effects are important in experimental intestinal injury, we studied the role of NO inhibition on hypoxia-induced bowel necrosis in the rat and investigated the interaction between platelet-activating factor (PAF) and NO in this model. Methods: Sprague-Dawley rats were treated with either hypoxia, NO synthase inhibition (NG-methyl-l-arginine [LNMA] or NG-nitro-l-arginine methyl ester [l-NAME]), hypoxia + LNMA, hypoxia + LNMA + NO donors, or hypoxia + LNMA + PAF receptor inhibition. Evaluations included blood pressure, superior mesenteric artery blood flow, arterial blood gases, histological intestinal injury, intestinal myeloperoxidase activity, and intestinal PAF activity. Results: We found that hypoxia alone for 90 minutes (10% O2, partial O2 pressure = 45 mm Hg) or LNMA alone had no detrimental effects. However, hypoxia + LNMA together caused hypotension, metabolic acidosis, intestinal injury, increased intestinal myeloperoxidase activity, and elevated intestinal PAF concentrations that were prevented by exogenous l-arginine. Furthermore, the hypotension and intestinal injury was prevented by PAF receptor blockade. Conclusions: We conclude that endogenous NO protects the intestine from hypoxia-induced inflammation and injury, and the balance between local PAF and NO modulates the outcome of hypoxia-stressed intestine.

Effect of difluoromethylornithine (DFMO) on NSAID-induced intestinal injury in rats.

Combination therapy with difluoromethylornithine (DFMO) and a nonsteroidal antiinflammatory drug (NSAID) has been proposed for the chemoprevention of colonic neoplasia. The purpose of this study was to examine whether DFMO would affect NSAID-mediated intestinal injury. Male Sprague-Dawley rats were gavaged with 20 mg/kg of indomethacin, after seven days of exposure to drinking water with or without 2% DFMO. The rats were killed 24 or 48 hr later, and the small intestine removed for macroscopic and microscopic quantitation of intestinal injury by computerized image analysis. Seven days of DFMO alone had no effect on overall mucosal thickness, but did increase the depth of proximal intestinal crypts. Forty-eight hours after indomethacin, DFMO treatment decreased the number of indomethacin-induced ulcers and percent of the surface area ulcerated. However, DFMO also decreased the mucosal thickness, villus height, and crypt depth in indomethacin-treated rats. Thus although DFMO decreases macroscopic intestinal ulceration by indomethacin, the reduction in villus and crypt height suggests that it also impairs the mucosa's ability to recover from microscopic indomethacin-induced damage. This study shows DFMO does impact NSAID-mediated intestinal injury and therefore human trials with combinations of DFMO and NSAIDs should include monitoring for small intestinal injury.

Fructose 1–6 diphosphate prevents intestinal ischemic reperfusion injury and death in rats

This study of ischemic and postischemic reperfusion intestinal injury in rats evaluates the potential therapeutic value of fructose 1–6 diphosphate on the basis of its ability to enhance anaerobic carbohydrate metabolism during ischemia and to prevent additional tissue injury after reestablishing blood flow by inhibiting the neutrophils to produce oxygen free radicals. In pursuit of this goal, 28 rats were randomized into 4 groups: pretreated with fructose 1–6 diphosphate (n = 7); pretreated with glucose (n = 7); postreperfusion treated with fructose 1–6 diphosphate (n = 7); and postreperfusion treated with saline (n = 7). Five additional rats were sham operated. Following 30 min occlusion of the superior mesenteric artery, all rats received their respective treatments for 5 days. Postreperfusion arterial pressure was significantly lower in the control rats (p < 0.001) as well as when compared with the fructose 1–6 diphosphate groups (p < 0.001). Significant increase in white blood cell counts occurred in the controls (p < 0.001), whereas in the fructose 1–6 diphosphate groups white blood cell counts were no different from preischemic values. All control rats that died in < 5 days had transmural intestinal necrosis, whereas in 3 of the controls that survived 5 days, partial intestinal necrosis was noted. Only one fructose 1–6 diphosphate-treated rat had partial intestinal necrosis. The overall 5-day survival was 100% for shamoperated rats, 93% for fructose 1–6 diphosphatetreated rats, and 21% for controls (fructose 1–6 diphosphate vs. controls, p < 0.001; fructose 1–6 diphosphate vs. sham, NS). The results are discussed and explained in terms of the postulated mechanism based on the pharmacological properties of fructose 1–6 diphosphate.

Modification of radiation-induced intestinal injury in rats by chilling after irradiation.

SummaryChilling of the small intestine of the rat immediately after x-irradiation postponed depression of the mitotic count and degeneration of the crypt cells. Mitotic depression and cellular degeneration occurred, however, when the tissue was re-warmed. The effects of transient chilling at 18°c were essentially identical to those of chilling at 5°c. The inhibition of colchicine-induced metaphase arrest and of tritiated thymidine uptake in chilled crypt cells suggests that postponement of the signs of radiation injury resulted from suppression of metabolic activity and cell division at low temperature. Although there was some suggestion of reduced injury in the chilled tissues, the protective or recovery-promoting effectiveness of hypothermia remains to be established.

Modification of acute intestinal radiation syndrome through shielding.

Mortality associated with intestinal injury in rats occurring 3–5 days after 1000 r x-irradiation was significantly decreased by shielding, during exposure, a small exteriorized section of duodenum or ileum. Protection was not obtained by shielding either the distal half of the cecum or the whole stomach. Beginning recovery of radiation-induced small intestine weight loss was observed 4 days after 1000 r in rats irradiated with a section of ileum shielded, whereas no recovery had occurred by this time in nonshielded controls. This effect was not demonstrable at 875 r, a dose that produced no acute intestinal deaths in either control or experimental group. An intermediate dose of 500 r to the ileal section under exposure conditions otherwise identical to the 1000-r experiment decreased the incidence of early deaths but failed to affect intestinal weight significantly as compared with controls without ileal shielding.