Role of prostanoids in experimental duodenal ulcer in rat

Abstract

The purposes of this study were to determine whether inhibition of cyclooxygenase is a mechanism by which cysteamine and mepirizole produce duodenal ulcers, identify qualitative or quantitative differences in prostanoid production between gastric mucosa and duodenum, and determine whether differences in cyclooxygenase sensitivity to inhibition by aspirin exist between these two tissues. In fed female rats, gastric mucosal prostaglandin E₂ (PGE₂) and prostacyclin (PGI₂) generation was 235±25 and 832±40 ng/g/min, respectively, whereas full-thickness duodenal PGE₂ and PGI₂ generation was 665±46 and 662±49 ng/g/min, respectively. Over an intraperitoneal dose range of 0– 25 mg/kg, aspirin-induced cyclooxygenase inhibition was dose-dependent and similar for the two tissues. Duodenal ulceration (16.7 mm²) produced by cysteamine, 425 mg/kg, was associated with a 46% reduction in duodenal PGE₂ generation, while having no effect on PGI₂ generation; however, cysteamine, 213 mg/kg, produced no visible duodenal mucosa injury yet reduced duodenal PGE₂ generation 39% compared to control values. In fed male rats, gastric mucosal PGE₂ and PGI₂ generation was 179± 18 and 813± 61 ng/g/min, respectivley, whereas duodenal PGE₂ and PGI₂ generation was 321± 27 and 454± 38 ng/g/min, respectively. Duodenal ulceration (7.7 ± 2.3 mm²) produced by oral mepirizole was associated with a 63% reduction in duodenal PGE₂ generation compared to control values, while having no effect on PGI₂ generation. Subcutaneous aspirin, 100 mg/kg, which reduced duodenal PGE₂ generation to a greater degree than either ulcerogen, given in conjunction with pentagastrin, did not produce visible duodenal ulceration. It therefore seems unlikely that reduced PGE₂ generation within the duodenum is the primary mechanism of gross injury associated with these two ulcerogens.