Healing of chronic gastric ulcers in diabetic rats treated with native aspirin, nitric oxide (NO)-derivative of aspirin and cyclooxygenase (COX)-2 inhibitor.
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.
Brzozowska
I
I
Department of Physiology, Jagiellonian University Medical College, 31-531 Cracow, ul. Grzegorzecka 16, Poland. mpbrzozo@cyf-kr.edu.pl
Targosz
A
A
Sliwowski
Z
Z
Kwiecien
S
S
Drozdowicz
D
D
Pajdo
R
R
Konturek
P C
PC
Brzozowski
T
T
Pawlik
M
M
Konturek
S J
SJ
Pawlik
W W
WW
Hahn
E G
EG
D000818:Animals; D001241:Aspirin / Q000031:analogs & derivatives / Q000627:therapeutic use*; D002908:Chronic Disease; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use*; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D009569:Nitric Oxide / Q000031:analogs & derivatives / Q000627:therapeutic use*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013276:Stomach Ulcer / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D009569:Nitric Oxide; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D001241:Aspirin