Previous studies have demonstrated that the gastric mucosa of diabetic rats is highly vulnerable to acute injury but the influence of nonsteroidal anti-inflammatory drugs (
NSAID) and their new
nitric oxide (NO) releasing derivatives of
aspirin (
NO-ASA) on the
ulcer healing under diabetic conditions has been little studied. In this study
streptozocin (STZ, 70 mg/kg injected intraperitoneally) was used to induce
diabetes mellitus in rats. Four weeks after STZ injection,
gastric ulcers were induced using the
acetic acid method and rats with
gastric ulcers received the treatment with 1)
aspirin (ASA, 30 mg/kg-d i.g.), 2)
NO-ASA applied in equimolar dose of 50 mg/kg-d i.g., 3)
rofecoxib (5 mg/kg-d i.g.), the selective
cyclooxygenase-(
COX)-2 inhibitor and 4) SNAP (5 mg/kg-d i.g.), a donor of NO, combined with ASA (30 mg/kg-d i.g.). Ten days after the induction of the
ulcers, the healing rate and the gastric blood flow (GBF) were measured by planimetry and
hydrogen (H(2))-gas clearance method, respectively and the plasma
cytokine such as IL-1beta,
TNF-alpha and IL-10 were determined. In addition, the effect of
insulin (4 IU/day/rat i.p.) with or without the blockade of
NO-synthase by L-NNA (20 mg/kg-d i.p.) on the
ulcer healing and the GBF in non-diabetic and diabetic rats was determined. In the diabetic rats, a significant delay in
ulcer healing (approximately by 300%) was observed with an accompanied decrease in the GBF at
ulcer margin. The prolongation of the healing in diabetic animals was associated with an increase in the plasma
cytokine (IL-1beta,
TNF-alpha and IL-10) levels. ASA and
rofecoxib, that significantly suppressed the mucosal
prostaglandin (PG) E(2) generation in
ulcer area, delayed significantly the rate of
ulcer healing and decreased the GBF at
ulcer margin, while elevating plasma IL-1beta,
TNF-alpha and IL-10 concentrations in non-diabetic rats and these alterations were significantly augmented in diabetic animals. In contrast to ASA, the treatment with
NO-ASA failed to influence both, the
ulcer healing and GBF at
ulcer margin and significantly attenuated the plasma levels of IL-1beta,
TNF-alpha and IL-10 as compared to those recorded in ASA- or
rofecoxib-treated animals. Co-treatment of SNAP with native ASA abolished the deleterious effect of ASA on
ulcer healing, GBF at
ulcer margin and
luminal NO release in diabetic rats. Administration of
insulin in rats with diabetes, opposed the delay in
ulcer healing, and the fall in the GBF at
ulcer margin and these effects were counteracted by the concurrent treatment with L-NNA. We conclude that: 1)
ulcer healing is dramatically impaired in experimental diabetes and this effect involves the fall in the gastric microcirculation at the
ulcer margin and increased release of proinflammatory
cytokines; 2) classic
NSAID such as ASA and selective
COX-2 inhibitors such as
rofecoxib, prolong
ulcer healing under diabetic conditions probably due to suppression of endogenous PG and the fall in the GBF at the
ulcer margin suggesting that both COX
isoforms, namely, COX-1 and COX-2, are important sources of PG during
ulcer healing in diabetes; and 3)
NO-ASA counteracts the impairment of
ulcer healing in diabetic rats induced by ASA, mainly due to the release of NO that compensates for PG deficiency resulting in enhancement in the GBF at
ulcer margin and suppression of
cytokine release in the
ulcer area.