Aging enhances susceptibility of diclofenac-treated rats to gastric ulceration, while attenuating enteropathy

Although clinical reports note aging and gender as risk factors for NSAID t herapy associated gastroenteropathy, neither variable has been examined in an animal model. We addressed this unknown by comparing the responses of yo ung (4 months) and old (22 months) rats of both genders to oral treatment w ith diclofenac (10 or 50 mg/kg). Diclofenac produced gastric ulcers only in old rats, with markedly larger lesions in females. In contrast, the small intestines in old rats of both genders given the 50 mg/kg dosage had >30% f ewer ulcers and a fourfold decrease in area of ulceration compared to young rats. The small intestine was the only site of lesions after the 10 mg/kg dosage and showed one gender influence, namely, a transiently faster time c ourse of ulcer development in females. Old and young rats given 50 mg/kg sh owed similar declines in serum levels of the vascular permeability indices- total protein and albumin-despite reduced intestinal damage in the old anim als, which suggests additive vascular leakage across the gastric lesions th at were evident only in old animals. Serum biochemistry showed no evidence of hepatotoxicity or dysfunction, consonant with small intestine as the pri mary target for diclofenac toxicity in rats. We provide the first experimen tal evidence for an aging influence on the gastrointestinal target site of a nonaspirin NSAID.