Diethyldithiocarbamate, a Superoxide Dismutase Inhibitor, Reduces Indomethacin-lnduced Gastric Lesions in Rats

Abstract

We examined the effect of diethyldithiocarbamate (DDC), the superoxide dismutase (SOD) inhibitor, on the development of gastric lesions induced by indomethacin in rats. Indomethacin (25 mg/kg) was given subcutaneously, and gastric acid secretion, motility, lipid peroxidation, vascular permeability, and myeloperoxidase as well as gastric lesions were measured. Indomethacin produced high-amplitude contractions of the stomach and caused hemorrhagic lesions in the corpus mucosa with significant increase in neutrophil-related processes such as myeloperoxidase activity, vascular permeability and lipid peroxidation. These changes caused by indomethacin were all significantly inhibited by prior administration of atropine (3 mg/kg s.c). Pretreatment of the animals with DDC (75-1,000 mg/kg s.c.) prevented these lesions induced by indomethacin in the corpus mucosa in a dose-dependent manner ( > 100 mg/kg), though at high doses ( > 750 mg/kg) some damage was found in both the antrum and duodenum. DDC showed a significant inhibition against the gastric mucosal SOD activity ( > 400 mg/kg), yet potently suppressed the increase of lipid peroxidation, vascular permeability, and myeloperoxidase activity caused by indomethacin. DDC dose-dependently ( > 75 mg/kg) inhibited the enhancement of gastric motility caused by indomethacin and showed a weak antisecretory effect at high doses ( > 750 mg/kg). These results showed that DDC reduced indomethacin-induced gastric lesions by suppressing gastric motility, despite inhibiting SOD activity. This study also indicates the prime importance of gastric hypercontraction in the pathogenesis of this lesion model and suggests that other events including the neutrophil-related processes may be secondary to gastric hypercontraction caused by indomethacin.

Green Coffee Bean Extract and Its Metabolites Have a Hypotensive Effect in Spontaneously Hypertensive Rats

“…SBP and heart rate were measured 1 h after oral administration of FA using the tail-cuff method. The dosage of atropine was the same as those reported previously (36,37).…”

Decreased gastric tone and delayed gastric emptying precede neutrophil infiltration and mucosal lesion formation in indomethacin-induced gastric damage in rats

“…The mechanism of NSAIDinduced gastric damage is generally believed to be related to the ability of these agents to inhibit gastric prostaglandin generation (1). However, evidence has been recently produced that leukocyte adherence to the vascu-lar endothelium (2)(3)(4), microcirculatory disturbances, superoxide radicals and protease liberation may be relevant pathogenic mechanisms in NSAID gastropathy (5,6).…”

“…Several studies have shown that NSAIDs are associated with altered gastroduodenal motility (6)(7)(8)(9)(10). Some data indicate that the administration of NSAIDs is followed by either increased gastric contractility, which correlates with gastric damage (6-9) or decreased intestinal spiking amplitude and disruption of migrating motor complexes (10), with no correlation with gastric damage.…”

“…In spite of a number of studies showing different effects of NSAIDs on antral motor activity (6)(7)(8)(9)11), the motor function of the proximal stomach and the gastric emptying of liquid meals in indomethacin-induced gastropathy have not been studied extensively. In the present study we determined whether changes in gastric tone and emptying of nutrient or non-nutrient meals correlate with mucosal lesions and neutrophil infiltration in indomethacin-induced gastric damage in rats.…”

Hind limb ischemic preconditioning induces an anti-inflammatory response by remote organs in rats

“…The main side effect of NSAIDs is gastric injury, the mechanism of which is generally believed to be related to the ability of these agents to inhibit gastric prostaglandin (PG) generation (34). However, recently published evidence suggests that leukocyte adherence to the vascular endothelium (35), microcirculatory disturbances, superoxide radicals, and protease release play a relevant pathogenic role in NSAIDinduced gastropathy (36). In the present study, hind limb rIPC significantly reduced mucosal lesions and neutrophil infiltration in INDO-induced gastric injury in rats.…”