Differential effects of salvinorin A on endotoxin-induced hypermotility and neurogenic ion transport in mouse ileum.

BACKGROUND: Salvinorin A (SA) is the principal active ingredient of Salvia divinorum, with an established inhibitory action on gastrointestinal (GI) transit and colonic ion transport in mice. Under normal conditions, the effects of SA are mediated by kappa opioid (KOR) and cannabinoid (CB1 and CB2) receptors. However, the role of SA in pathophysiological conditions remains unresolved. The aim of this study was to characterize the in vitro and in vivo effects of SA on mouse ileum after endotoxin challenge. METHODS: Changes in GI motility were studied in vitro, using smooth muscle preparations from the mouse ileum. In vivo, the fecal pellet output and small intestinal fluid content were measured. Neurogenic ion transport and intestinal permeability were examined using Ussing chambers. In addition, Western blot analysis of mucosa was performed and plasma nitrite/nitrate levels were determined. KEY RESULTS: Salvinorin A inhibited endotoxin-induced ileal hypercontractility via KOR, CB1, and CB2 receptors. Neurogenic ion transport, which was significantly reduced after endotoxin challenge, was normalized by SA through a nitric oxide synthase (NOS)-dependent mechanism. Western blot analysis and plasma nitrite/nitrate level quantitation confirmed the involvement of NOS in the regulatory action of SA. CONCLUSIONS & INFERENCES: This is the first report showing differential effects of SA on motor and secretory activity in mouse GI during endotoxemia. The outcomes of our study imply possible novel applications of SA and its analogs in the treatment of GI disorders.

Lack of effects of acemetacin on signalling pathways for leukocyte adherence may explain its gastrointestinal safety.

BACKGROUND AND PURPOSE: Acemetacin is a non-steroidal anti-inflammatory drug which is rapidly bioconverted to indomethacin, but produces significantly less gastric damage than indomethacin. This study was performed to investigate several possible mechanisms that could account for the gastrointestinal tolerability of acemetacin. EXPERIMENTAL APPROACH: The gastric and intestinal damaging effects of acemetacin and indomethacin were examined in the rat. Effects of the drugs on blood levels of leukotriene B(4) and thromboxane B(2), on leukocyte-endothelial adherence in post-capillary mesenteric venules, and on gastric expression of tumour necrosis factor-alpha (TNF-alpha) were determined. The two drugs were also compared for gastric toxicity in rats pretreated with inhibitors of COX-2 and NOS. KEY RESULTS: Acemetacin induced significantly less gastric and intestinal damage than indomethacin, despite markedly suppressing COX activity. Indomethacin, but not acemetacin, significantly increased leukocyte adherence within mesenteric venules, and gastric expression of TNF-alpha. Pretreatment with L-nitro-arginine methyl ester or lumiracoxib increased the severity of indomethacin-induced gastric damage, but this was not the case with acemetacin. CONCLUSIONS AND IMPLICATIONS: The increased gastric and intestinal tolerability of acemetacin may be related to the lack of induction of leukocyte-endothelial adherence. This may be attributable to the reduced ability of acemetacin to elevate leukotriene-B(4) synthesis and TNF-alpha expression, compared to indomethacin, despite the fact that acemetacin is rapidly bioconverted to indomethacin after its absorption.

Mechanisms underlying the anti-inflammatory activity and gastric safety of acemetacin.

BACKGROUND AND PURPOSE: Acemetacin is regarded as a pro-drug of indomethacin and induces significantly less gastric damage but the reasons for this greater gastric safety of acemetacin are unclear. The anti-inflammatory effects of acemetacin have been attributed, at least in part, to its hepatic biotransformation to indomethacin. The aim of this study was to determine the effects of acemetacin and indomethacin in an in vivo model of acute inflammation and to examine the importance of biotransformation of acemetacin (to indomethacin) to its anti-inflammatory actions. EXPERIMENTAL APPROACH: The zymosan airpouch model was used in rats. Indomethacin or acemetacin (2.7-83.8 micromol kg(-1)) were administered orally or directly into the pouch. Leukocyte infiltration, prostaglandin (PG) E(2) and leukotriene (LT) B(4) levels in exudates, and whole blood thromboxane (TX) B(2) synthesis were measured. KEY RESULTS: Acemetacin was rapidly converted to indomethacin after its administration. Both acemetacin and indomethacin elicited comparable, dose-dependent reductions of leukocyte infiltration and of PGE(2) and TXB(2) synthesis. However, indomethacin induced more gastric damage than acemetacin and elevated LTB(4) production in the airpouch. CONCLUSIONS AND IMPLICATIONS: The similar effects of acemetacin and indomethacin on leukocyte infiltration and PG synthesis are consistent with rapid biotransformation of acemetacin to indomethacin. Some of this biotransformation may occur extra-hepatically, for instance in inflammatory exudates. Acemetacin probably exerts actions independent of conversion to indomethacin, given the different effects of these two drugs on LTB(4) production. Such differences may contribute to the relative gastric safety of acemetacin compared to indomethacin.

Vasorelaxant effects of a nitric oxide-releasing aspirin derivative in normotensive and hypertensive rats.

1. Nonsteroidal anti-inflammatory drugs have been reported to exacerbate hypertension and to interfere with the effectiveness of some anti-hypertensive therapies. In this study, we tested the effects of a gastric-sparing, nitric oxide-releasing derivative of aspirin (NCX-4016) on hypertension in rats. 2. Hypertension was induced by administering L-NAME in the drinking water (400 mg l(-1)). Groups of rats were treated daily with aspirin, NCX-4016 or vehicle. 3. NCX-4016 significantly reduced blood pressure relative to the aspirin-treated group over the 2-week period of treatment. Aspirin and, to a lesser extent, NCX-4016 suppressed whole blood thromboxane synthesis. 4. In anaesthetized rats, acute intravenous administration of NCX-4016 caused a significant fall in mean arterial pressure in hypertensive rats, but was devoid of such effects in normotensive controls. 5. In vitro, NCX-4016 relaxed phenylephrine-pre-contracted aortic rings obtained from both normotensive and hypertensive rats, and significantly reduced their responsiveness to the contractile effects of phenylephrine. 6. These results suggest that NCX-4016 reduces blood pressure in hypertensive rats, not simply through the direct vasodilatory actions of the nitric oxide released by this compound, but also through possible interference with the effects of endogenous pressor agents. These properties, added to its anti-thrombotic effects, suggest that NCX-4016 may be a safer alternative to aspirin for use by hypertensive patients.

Role of cyclooxygenase-2 in modulating gastric acid secretion in the normal and inflamed rat stomach.

Nonsteroidal anti-inflammatory drugs elevate gastric acid secretion, possibly contributing to their ability to interfere with gastric ulcer healing. Inhibitors of cyclooxygenase-2 have been shown to delay experimental gastric ulcer healing. In the present study, we tested the hypothesis that cyclooxygenase-2-derived prostaglandins modulate gastric acid secretion. Studies were performed in normal rats and in rats with iodoacetamide-induced gastritis. Inflammation in the latter group was confirmed histologically and by a threefold increase in tissue levels of the granulocyte marker myeloperoxidase and was also associated with overexpression of cyclooxygenase-2 in the stomach. Basal acid secretion in both groups of rats was not affected by pretreatment with DuP-697, a selective inhibitor of cyclooxygenase-2. A nonselective cyclooxygenase inhibitor, indomethacin, had no effect on acid secretion in normal rats but caused a doubling of acid secretion in the rats with gastritis. DuP-697 had no effect on pentagastrin-induced secretion in either group of rats. Gastritis itself was associated with significantly increased pentagastrin-induced acid secretion, and this was further increased in rats pretreated with indomethacin. These results suggest that in a setting of gastric inflammation, prostaglandins derived from cyclooxygenase-1, not cyclooxygenase-2, exert inhibitory effects on acid secretion.

N-bisphosphonates cause gastric epithelial injury independent of effects on the microcirculation.

BACKGROUND: Nitrogen-containing bisphosphonates have been shown to be effective for the treatment of osteoporosis and Paget's disease of bone. Unfortunately, these drugs also have the capacity to irritate the upper gastrointestinal mucosa. In this study we investigated the ability of alendronate and pamidronate to directly damage the gastric epithelium and attempted to determine whether these drugs caused injury through gastric microcirculatory alterations. METHODS: An ex vivo gastric chamber model was used. Effects of topically applied alendronate and pamidronate on transmucosal potential difference and epithelial integrity (histology) were determined. Also, the effects of agents capable of preventing microvascular injury in the stomach (PGE2 and two nitric oxide donors) were examined for their ability to prevent gastric injury induced by the two N-bisphosphonates. RESULTS: Alendronate and pamidronate caused a concentration-dependent decrease in transmucosal potential difference, widespread epithelial injury and infiltration of neutrophils into the mucosa. PGE2 and the two nitric oxide donors did not prevent the changes in potential difference or the epithelial injury, but did reduce neutrophil infiltration. Significant release of PGE2 into the lumen was observed following application of the two bisphosphonates, but neither drug altered mucosal blood flow. CONCLUSIONS: These results suggest that these N-bis- phosphonates directly damage the gastric epithelium independent of actions on the microvasculature.