Evolution of streptozotocin-pancreatic damage in the rat:: Modulatory effect of endothelins on the nitridergic and prostanoid pathway

Many lines of evidence indicate that an increased pancreatic production of nitric oxide (NO) and prostaglandins (PGs) is found in the pancreas of streptozotocin-diabetic rats and that endothelins (ETs) are closely related to the nitridergic and prostanoid pathway in several tissues. In the present study the relationship between NO, ETs, and PGs has been explored in isolated pancreatic tissue from streptozotocin-diabetic rats. Pancreatic ET levels are higher in pancreatic tissues from diabetic (D) rats compared to control (C) animals. The addition of nitric oxide synthase (NOS) inhibitors (1 mM N-G-nitro-L-arginine methyl ester, 600 mu M N-G- monomethyl-L-arginine) in the incubating medium reduces and NO donors (SIN-1, 300 mu M spermine supress, NONOate 100 mu M) increases ET levels in pancreatic slices from C and D animals. PGE(2) (10(-7) M) increases and indomethacin (10(-6) M) decreases ET pancreatic production only in D but not in C tissues when added into the incubating bath. When tissues are incubated in the presence of endothelin 1 (ET-1) (10(-7) M), NOS activity is higher in C pancreas, while the ET-receptor antagonist bosentan (B) decreases NOS levels in D but not in C tissues. When pancreatic arachidonic acid (AA) conversion to prostaglandins was explored, ET-1 increased PGF(2 alpha), PGE(2) and TXB2 levels in C but not in D tissues. B abolishes TXB2 increment due to the diabetic state, but failed in modulating AA conversion to 6-keto PGF(1 alpha), PGF2(alpha) and PGE(2 i)n D pancreas. Our results show an alteration in AA metabolism, ET production, and NO increment associated with pancreatic damage due to streptozotocin. (C) 1999 Academic Press.