In vivo antithrombotic effects of a nitric oxide-releasing aspirin derivative, NCX-4016.
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Animals↗
Biomedical subjects
J L Wallace
Publications and source records attributed to J L Wallace.
Upper gastrointestinal ulceration with alendronate.
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Alendronate↗
Prolonged colonic epithelial hyporesponsiveness after colitis: role of inducible nitric oxide synthase.
Colonic epithelial secretion is an important host defense mechanism. We examined whether a bout of colitis would produce long-lasting changes in epithelial function that persisted after resolution of mucosal inflammation. Colitis was induced in rats with intracolonic trinitrobenzenesulfonic acid. Six weeks later, colonic damage and inducible nitric oxide synthase (iNOS) mRNA expression and activity were measured. Segments of distal colon were mounted in Ussing chambers for measurement of permeability and responsiveness to secretory stimuli. Basal electrolyte transport parameters and permeability were not different from untreated controls. Despite normal macroscopic and histological appearance, secretory responses to electrical field stimulation (EFS), isobutylmethylxanthine (IBMX), and carbachol were significantly depressed (by 60-70%) relative to controls. iNOS mRNA expression and enzyme activity were significantly elevated. Dexamethasone reversed epithelial hyporesponsiveness and significantly reduced iNOS mRNA expression. A selective iNOS inhibitor normalized the secretory responses to EFS and IBMX but not to carbachol. These data suggest that ongoing synthesis of nitric oxide by iNOS contributes to chronic suppression of epithelial secretory function after episodes of colitis.
Animals↗
Proteinase-activated receptor 2 (PAR2)-activating peptides: identification of a receptor distinct from PAR2 that regulates intestinal transport.
The effects of PAR2-activating PAR2-activating peptides, SLIGRL (SL)-NH2, and trans-cinnamoyl-LIGRLO (tc)-NH2 were compared with the action of trypsin, thrombin, and the PAR1 selective-activating peptide: Ala-parafluoroPhe-Arg-cyclohexylAla-Citrulline-Tyr (Cit)-NH2 for stimulating intestinal ion transport. These agonists were added to the serosa of stripped rat jejunum segments mounted in Ussing chambers, and short circuit current (Isc) was used to monitor active ion transport. The relative potencies of these agonists also were evaluated in two bioassays specific for the activation of rat PAR2: a cloned rat PAR2 cell calcium-signaling assay (PAR2-KNRK cells) and an aorta ring relaxation (AR) assay. In the Isc assay, all agonists, except thrombin, induced an Isc increase. The SL-NH2-induced Isc changes were blocked by indomethacin but not by tetrodotoxin. The relative potencies of the agonists in the Isc assay (trypsin>>SL-NH2>tc-NH2>Cit-NH2) were strikingly different from their relative potencies in the cloned PAR2-KNRK cell calcium assay (trypsin>>>tc-NH2 congruent with SL-NH2>>>Cit-NH2) and in the AR assay (trypsin>>>tc-NH2 congruent with SL-NH2). Furthermore, all agonists were maximally active in the PAR2-KNRK cell and AR assays at concentrations that were one (PAR2 -activating peptides) or two (trypsin) orders of magnitude lower than those required to activate intestinal transport. Based on the distinct potency profile for these agonists and the considerable differences in the concentration ranges required to induce an Isc effect in the intestinal assay compared with the PAR2-KNRK and AR assays, we conclude that a proteinase-activated receptor, pharmacologically distinct from PAR2 and PAR1, is present in rat jejunum and regulates intestinal transport via a prostanoid-mediated mechanism.
Animals↗
Lack of beneficial effect of a tachykinin receptor antagonist in experimental colitis.
Nerves within the wall of the intestine may contribute to inflammatory responses, such as those occurring in inflammatory bowel disease. Studies in an experimental model of colitis have demonstrated that neuromodulation, through chemical sympathectomy or administration of lidocaine, can markedly attenuate granulocyte infiltration and tissue injury. Given the many pro-inflammatory effects of substance P, we have evaluated the effects of a tachykinin receptor (NK-1) antagonist, RP 67580, in models of acute colitis in the rat and guinea pig. While administration of RP 67580 and a second NK-1 antagonist (CP-96,345-1) significantly reduced the infiltration of granulocytes into colonic tissue during the first 12 h after induction of colitis in the rat, repeated administration of RP 67580 over a three day period failed to significantly affect granulocyte recruitment or the severity of tissue injury. In contrast, lidocaine enemas were effective in reducing both indices of inflammation/injury. In the guinea pig, similar observations were made. These observations demonstrate that blockade of NK-1 receptors over a three day period failed to significantly modify the course of experimental colitis. It remains possible that the beneficial effects of lidocaine may be due, in part, to inhibition of substance P release, and that the contribution of substance P to inflammation in experimental colitis occurs through NK-1 receptor-independent mechanisms.
Analgesics↗
Nitric oxide: a regulator of mucosal defense and injury.
There is an abundance of evidence that nitric oxide plays a critical role in regulating several components of gastrointestinal mucosal defense. Suppression of nitric oxide synthesis increases susceptibility to injury, while administration of nitric oxide donors increases resistance to injury. On the other hand, nitric oxide has been implicated as a mediator of tissue injury in the gastrointestinal tract during inflammatory reactions. In these cases, the nitric oxide is generally believed to be derived from an inducible isoform of nitric oxide synthase. In this review, we provide an overview of the evidence for and against these dual roles of nitric oxide in modulating gastrointestinal mucosal defense and injury. We also highlight the potential therapeutic benefits that may be realized through modulation of tissue nitric oxide levels.
Animals↗
Cyclooxygenase 1 contributes to inflammatory responses in rats and mice: implications for gastrointestinal toxicity.
BACKGROUND & AIMS: Selective inhibitors of cyclooxygenase (COX)-2 are being developed as gastrointestinal-sparing anti-inflammatory drugs based on the premise that this isoform is solely responsible for prostaglandin synthesis at sites of inflammation, whereas COX-1 produces prostaglandins important for maintenance of mucosal integrity. We investigated the relationship between suppression of inflammation by COX-2 inhibitors (NS-398, nimesulide, DuP697, and etodolac) and their effects on gastric prostaglandin synthesis. METHODS: Effects of pretreatment of rats with drugs with a range of in vitro selectivity for COX-2 vs. COX-1 on carrageenan-induced paw inflammation were assessed, along with extent of suppression of COX-1 and COX-2. The role of COX-1 in inflammation was also assessed in COX-2-deficient mice. RESULTS: Significant anti-inflammatory effects were only observed at doses of the drugs that inhibited COX-1. At these doses, the drugs also significantly suppressed gastric prostaglandin synthesis and elicited gastric mucosal erosions. The degree of suppression of prostaglandin synthesis at the site of inflammation correlated significantly with inhibition of COX-1 but not COX-2. CONCLUSIONS: COX-1 makes an important contribution to inflammatory responses. To achieve desirable anti-inflammatory effects, COX-2 inhibitors needed to be given at doses in which selectivity was lost, leading to suppression of gastric prostaglandin synthesis and to mucosal injury.
Animals↗
Alendronate induces gastric injury and delays ulcer healing in rodents.
Gastric ulceration associated with the use of NSAIDs is most frequently observed in elderly women, the same sector of society most likely to be receiving therapy for osteoporosis. As some anti-osteoporosis medications have been suggested to irritate the upper gastrointestinal mucosa, we evaluated the ability of one such drug, alendronate, to damage the gastric mucosa and to influence the severity and healing of gastric ulcers in rodents. The effects of alendronate on indomethacin-induced antral ulceration was evaluated in the rabbit, while effects on ulcer healing and on the formation of gastric erosions was evaluated in the rat. Effects of alendronate on gastric acid secretion, blood flow and prostaglandin synthesis were also evaluated. Alendronate caused erosions in the rabbit stomach, but not antral ulceration. However, at the highest doses tested (80 mg) alendronate increased the incidence and size of indomethacin-induced antral ulcers. Alendronate also enhanced indomethacin-induced gastric damage in the rat, and delayed gastric ulcer healing. These effects of alendronate were not attributable to changes in gastric acid secretion, blood flow, prostaglandin synthesis or the pharmacokinetics of indomethacin. The damaging effects of alendronate on the stomach were due to topical irritant effects and could be observed at concentrations as low as 4 mg/ml within 30 min of oral administration or topical superfusion. These results support preliminary clinical evidence that alendronate can damage the gastric mucosa. While gastric injury may be a rare occurrence in patients taking this drug, concomitant use of alendronate and NSAIDs may increase the incidence or severity of ulceration.
Alendronate↗
Effect of a nitric oxide-releasing naproxen derivative on hypertension and gastric damage induced by chronic nitric oxide inhibition in the rat.
NSAIDs can elevate blood pressure through mechanisms such as renal vasoconstriction and sodium retention. These effects are particularly evident in hypertensive individuals. Nitric oxide-releasing NSAID derivatives have been shown to have greatly reduced toxicity in the gastrointestinal tract and kidney. We therefore evaluated the effects of a 4 week treatment with either naproxen or its nitric oxide-releasing derivative (NO-naproxen) on systemic arterial blood pressure and gastric damage in rats in which hypertension was induced by L-NAME. Rats received either L-NAME dissolved in the drinking water (400 mg/L) or tap water (control). Vehicle, naproxen (10 mg/kg) or an equimolar dose of NO-naproxen (14.5 mg/kg) were administered orally each day. After 4 weeks, blood pressure was measured, blood samples were taken for measurement of thromboxane synthesis, and gastric damage was evaluated by blind, macroscopic scoring. Both naproxen and NO-naproxen inhibited systemic cyclooxygenase activity by >90%. NO-naproxen-treated rats exhibited no significant gastric damage. The gastric damage produced by L-NAME alone was potentiated by naproxen but prevented by NO-naproxen. L-NAME treatment significantly increased blood pressure. In the absence of L-NAME, the naproxen group had significantly higher blood pressure than both the control and NO-naproxen groups. In rats receiving L-NAME, the same conclusions apply, but the concomitant administration of NO-naproxen was able to significantly reduce the blood pressure compared to L-NAME alone. Based on these results, we conclude that NO-naproxen may represent a safer alternative to standard NSAIDs in the treatment of inflammatory conditions in hypertensive patients.
Animals↗
Cyclooxygenase-independent chemoprevention with an aspirin derivative in a rat model of colonic adenocarcinoma.
Aspirin decreases the risk of colorectal cancer, reportedly through suppression of cyclooxygenase (COX) activity. Using a rat model of colonic adenocarcinoma, we compared the chemopreventative effects of aspirin versus a nitric oxide-releasing derivative (NCX-4016) which does not inhibit COX. Beginning six weeks after intracolonic administration of trinitrobenzene sulfonic acid, the rats were given azoxymethane weekly (15 mg/kg i.p.) for 4 weeks. Over the same 4-week period, the rats were treated daily with vehicle, aspirin (10 mg/kg) or NCX-4016 (equimolar dose). Six weeks later, the number of aberrant crypt foci (an early preneoplastic lesion) were blindly counted by light microscopy. Effects of aspirin vs. NCX-4016 on COX-1 and COX-2 activity were compared, as was their analgesic activity. Rats receiving vehicle developed a mean of 856 +/- 260 aberrant crypt foci in the colon. Aspirin reduced the number of aberrant crypt foci by 64%, while NCX-4016 produced an 85% reduction. Aspirin, but not NCX-4016, markedly suppressed systemic COX-1 and COX-2 activity, and colonic prostaglandin synthesis. Despite not inhibiting COX, NCX-4016 exhibited comparable analgesic activity to aspirin. These results demonstrate that NCX-4016, a nitric oxide-releasing aspirin derivative, exhibited superior chemopreventative effects to aspirin in this model of colon cancer. This effect occurred independent of inhibition of COX-1 or COX-2.
Adenocarcinoma↗
Effect of intracolonic benzalkonium chloride on trinitrobenzene sulphonic acid-induced colitis in the rat.
BACKGROUND: We investigated the effects of benzalkonium chloride (BAC) on trinitrobenzene sulphonic acid (TNBS)-induced colitis in rats. METHODS: TNBS was administered intrarectally before and/or after BAC treatment. In the first study, the effects of treatment with BAC 6, 12 or 24 h after TNBS were examined. In the second study, animals were treated with BAC before, after or before and after TNBS, and were examined 7 days later. The severity of colitis was assessed by macroscopic and histological scoring of the colonic damage and by determination of colonic myeloperoxidase (MPO) activity. Macrophages and CD4+ and CD8+ T cells were examined by immunohistochemistry. RESULTS: When BAC was instilled into the colon 6, 12 or 24 h after TNBS, weight loss and macroscopic and histological features of the colon were similar to that of controls (TNBS alone). In contrast, MPO activity was significantly reduced in all three groups post-treated with BAC. In the groups examined 7 days after TNBS treatment, rats post-treated with BAC exhibited increased weight gain and significantly reduced macroscopic damage and MPO activity compared to the TNBS control group. Rats pre-treated with BAC exhibited less macroscopic damage of the colon than rats receiving only TNBS, but histological damage, MPO and weight gain were unchanged from TNBS controls. Immunohistochemistry revealed that BAC pre-treatment increased the numbers of macrophages and T cells in the colon. After TNBS treatment, macrophage accumulation was evident in the colon, but T cells were scarce. However, these cells were preserved or enhanced in the colonic mucosa in TNBS-treated rats that had been pre-treated with BAC. CONCLUSIONS: Treatment with BAC, particularly after induction of colitis, produces a significant reduction in the severity of tissue injury and inflammation through mechanisms that are not fully understood.
Animals↗
Selective inhibitors of cyclooxygenase-2: are they really effective, selective, and GI-safe?
Selective inhibitors of the "inducible" isoform of cyclooxygenase (COX-2) have been suggested to be effective analgesic and anti-inflammatory drugs while sparing the gastrointestinal (GI) tract of injury. There is some experimental and early clinical evidence to support this hypothesis. However, some important questions remain regarding the utility of selective COX-2 inhibitors. For example, estimates of the selectivity of COX-2 inhibitors based on in vitro studies are likely to be poor predictors of selectivity in vivo. Efficacy with selective blockade of COX-2 may be inferior to that achieved with combined inhibition of COX-1 and COX-2. Furthermore, in situations in which there is inflammation or ulceration in the GI tract, COX-2 produces prostaglandins that are essential for repair. In these circumstances, inhibition of COX-2 leads to delay of ulcer healing and exacerbation of inflammation. Some caution should therefore be exercised before the theory is fully accepted that selective COX-2 inhibitors are effective anti-inflammatory drugs that spare the GI tract of injury.
Analgesics↗
Reduction of acute and reactivated colitis in rats by an inhibitor of neutrophil activation.
Neutrophils have been implicated as major contributors to tissue injury in inflammatory bowel disease. In this study, we have assessed the effects of an inhibitor of neutrophil activation and adherence, NPC-18915 (4-¿2-[2-(2-benzofuranyl)phenyl]-(E)-ethenyl¿benzoic acid sodium salt), in models of both acute and reactivated colitis. Acute colitis was induced by intracolonic administration of a hapten. In other rats, colitis was reactivated 6 wk after a bout of acute colitis by subcutaneous administration of the hapten. NPC-18915 given during the first 4 days after induction of acute colitis significantly reduced tissue injury and the incidence of diarrhea and adhesions. When treatment of NPC-18915 was initiated after colitis was firmly established (48 h posthapten), it did not produce a significant effect. NPC-18915 was effective at significantly reducing colonic injury and granulocyte infiltration in the reactivated colitis model, and a similar effect could be observed in rats treated with antineutrophil serum. These results demonstrate that an inhibitor of neutrophil activation is effective in both acute and reactivated colitis, although in the former case, effectiveness is only seen when the drug is given before full establishment of colitis. These results also suggest that neutrophils, are a critical effector cell of hapten-induced colitis in the rat, particularly in the case of reactivated colitis.
Acute Disease↗
Bacteria rapidly colonize and modulate healing of gastric ulcers in rats.
The stomach is generally regarded as an environment that is not conducive to bacterial colonization. In this study, we examined the possibility that this changes significantly when an ulcer has formed and that colonization of ulcers interferes with the normal healing process. Gastric ulcers were induced by serosal application of acetic acid. The relationship between ulcer healing and bacterial colonization was examined. The effects of antibiotics, induction of Lactobacillus colonization, and selective colonization with an antibiotic resistant strain of Escherichia coli on ulcer healing were examined. Within 6-12 h of their induction, gastric ulcers were colonized by a variety of bacteria, with gram-negative bacteria predominating. Suppression of colonization with antibiotics resulted in marked acceleration of healing. Induction of Lactobacillus colonization also accelerated ulcer healing. The beneficial effects of antibiotics were reversed through selective colonization with antibiotic-resistant E. coli. Bacterial colonization occurred irrespective of the method used to induce the ulcer. This study demonstrates that colonization of gastric ulcers in rats occurs rapidly and significantly impairs ulcer healing. This effect appeared to be primarily attributable to gram-negative bacteria.
Acetic Acid↗
Nonsteroidal anti-inflammatory drug-induced gastrointestinal toxicity: new insights into an old problem.
Nonsteroidal anti-inflammatory drugs are widely used for the treatment of chronic arthropathies, but their gastrointestinal damage remains a significant limitation to their use. In this review, the pathogenic mechanisms through which these drugs are believed to cause gastrointestinal damage are outlined. A better understanding of the pathogenesis of gastric and intestinal injury has resulted in novel strategies that are being employed to develop nonsteroidal anti-inflammatory drugs that do not have significant adverse effects on the gastrointestinal tract.
Anti-Inflammatory Agents, Non-Steroidal↗
Induction of cyclooxygenase 1 and 2 in the rat stomach during endotoxemia: role in resistance to damage.
BACKGROUND & AIMS: Prostaglandins and nitric oxide are key mediators of gastric mucosal defense. Endotoxemia alters gastric resistance to damage, but little is known of the effects of chronic endotoxemia on the expression of prostaglandin and nitric oxide synthases (NOSs). The effects of short- vs. long-term administration of endotoxin on gastric resistance to damage and on expression of NOS and prostaglandin synthesis were compared. METHODS: Rats were treated with short- or long-term bacterial endotoxin, after which susceptibility to ethanol-induced damage was assessed. The effects of various inhibitors of prostaglandin and NOS were examined. Expression of gastric NOS and cyclooxygenase (COX) messenger RNA (mRNA) were examined. RESULTS: Repeated administration of endotoxin increased gastric resistance to ethanol- but not indomethacin-induced injury. Indomethacin, but not a highly selective COX-2 inhibitor or an inducible NOS inhibitor, abolished long-term endotoxin-induced gastric resistance to injury. Expression of mRNA for both COX-1 and -2, but not for endothelial or inducible NOS, were significantly increased after long-term endotoxin administration. CONCLUSIONS: Repeated exposure to endotoxin resulted in increased resistance of the gastric mucosa to injury through a prostaglandin-dependent pathway. These prostaglandins were produced via COX-1, which like COX-2, is induced by endotoxin administration.
Animals↗
Nonsteroidal anti-inflammatory drug enteropathy in rats: role of permeability, bacteria, and enterohepatic circulation.
BACKGROUND & AIMS: The pathogenesis of nonsteroidal anti-inflammatory drug (NSAID)-induced small intestinal damage remains poorly understood. The aim of this study was to examine the relative importance of the three suggested components of the pathogenesis of NSAID enteropathy, namely, epithelial permeability, enteric bacterial numbers, and enterohepatic recirculation, using an NSAID derivative (nitrofenac) that does not cause small intestinal damage. METHODS: Rats were given diclofenac or nitrofenac at 12-hour intervals. Epithelial permeability to [51Cr]-ethylenediaminetetraacetic acid and enteric bacterial numbers were determined after 1-4 doses of the drugs. Serum levels and biliary excretion of the two drugs were determined by high-performance liquid chromatography. RESULTS: Diclofenac caused a progressive increase in epithelial permeability, marked increases in enteric gram-negative bacterial numbers, and frank intestinal ulceration. Nitrofenac caused similar changes in intestinal permeability after a single dose but no further increase with repeated administration. Moreover, nitrofenac had no effect on enteric bacterial numbers and did not cause frank ulceration. Unlike diclofenac, nitrofenac did not undergo extensive enterohepatic recirculation. Two other NSAIDs that do not undergo enterohepatic recirculation (nabumetone and aspirin) also did not modify enteric bacterial numbers or cause intestinal ulceration. CONCLUSIONS: Enterohepatic recirculation of NSAIDs is of paramount importance in the pathogenesis of enteropathy caused by these drugs, whereas suppression of prostaglandin synthesis is relatively unimportant.
Animals↗
TNF-alpha facilitates inflammation-induced glucocorticoid secretion in rats with biliary obstruction.
AIMS: We investigated the role of TNF-alpha in inflammation-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis in rats with cholestasis due to bile duct resection. METHODS: Acute inflammation was induced in bile duct or sham resected rats by subcutaneous injection of carrageenan and HPA axis activation was determined by measuring plasma ACTH and corticosterone levels in the absence or presence of TNF-alpha inhibition. RESULTS: Bile duct resected rats had a 2.4-fold elevation in basal circulating TNF-alpha levels compared to sham resected and unoperated controls. Acute inflammation induced by carrageenan injection resulted in a significant increase in plasma ACTH and corticosterone levels in bile duct resected and control rats in the absence of significant changes in plasma TNF-alpha levels. However, bile duct resected rats demonstrated blunted ACTH release coupled with augmented corticosterone secretion in response to carrageenan administration compared to control rats. Inhibition of TNF-alpha activity by pretreating rats with a specific TNF-antiserum or pentoxifylline did not alter inflammation-induced ACTH secretion in bile duct resected or control rats, or corticosterone secretion in control rats. However, anti-TNF treatments significantly attenuated the inflammation-induced rise in plasma corticosterone in bile duct resected rats. CONCLUSIONS: These results indicate that inflammation in rats with biliary obstruction is associated with blunted ACTH release coupled with augmented glucocorticoid secretion facilitated by TNF-alpha. Furthermore, these results suggest that what have been previously considered as low level elevations in circulating TNF-alpha levels can facilitate adrenal glucocorticoid secretion during the inflammatory response.
Adrenocorticotropic Hormone↗