DIABETES-INDUCED ENDOTHELIAL DYSFUNCTION IN STREPTOZOTOCIN-TREATED RATS - ROLE OF PROSTAGLANDIN ENDOPEROXIDES AND FREE-RADICALS

The vasoactive responses of renal arteries from diabetic and control r ats were compared in vitro in arteriograph assemblies. Diabetes was es tablished by an iv injection of streptozotocin (55 mg/kg) in Wistar-Ky oto rats. Endothelium-dependent relaxations mediated by nitric oxide ( EDNO) were impaired in arteries from the diabetic rats; the impairment in endothelial function increased with duration of the diabetic state . After 6 and 16 wk, the concentrations of acetylcholine required to p roduce 50% relaxation of norepinephrine preconstriction were 3.2 and 2 5 muM for arteries from diabetic rats and 0.4 muM in control arteries, representing 8- and 62-fold decreases in sensitivity to the endotheli um-dependent vasodilator in the diabetic arteries. After 6 wk of diabe tes, renal arteries also became 20-fold less sensitive to relaxation i nduced by histamine, another agonist that induces EDNO-mediated relaxa tions. The inhibition of EDNO production with L-N(G)-nitroarginine pro duced greater impairments in acetylcholine relaxations in arteries fro m diabetic rats than from control rats. Relaxations in response to ace tylcholine were impaired in arteries from diabetic rats because of inc reased production of factors that opposed the vasorelaxant effects of EDNO, rather than from decreased production of EDNO. Pretreatment of t he diabetic arteries with the hydroxyl radical scavenger dimethylthiou rea normalized relaxations in response to acetylcholine. The blockade of prostaglandin H-2-thromboxane A2 receptors with SQ 29548 also impro ved relaxations in response to acetylcholine in diabetic arteries. The se data indicate that endothelial dysfunction in the renal arteries of diabetic rats may be mediated by the increased production of tree rad icals and of prostaglandin endoperoxides, which oppose the vasorelaxan t effects of EDNO.