sq-29548 and 1-3-dimethylthiourea

The vasoactive responses of renal arteries from diabetic and control rats were compared in vitro in arteriograph assemblies. Diabetes was established by an iv injection of streptozotocin (55 mg/kg) in Wistar-Kyoto 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 produce 50% relaxation of norepinephrine preconstriction were 3.2 and 25 microM for arteries from diabetic rats and 0.4 microM in control arteries, representing 8- and 62-fold decreases in sensitivity to the endothelium-dependent vasodilator in the diabetic arteries. After 6 wk of diabetes, renal arteries also became 20-fold less sensitive to relaxation induced by histamine, another agonist that induces EDNO-mediated relaxations. The inhibition of EDNO production with L-NG-nitroarginine produced greater impairments in acetylcholine relaxations in arteries from diabetic rats than from control rats. Relaxations in response to acetylcholine were impaired in arteries from diabetic rats because of increased production of factors that opposed the vasorelaxant effects of EDNO, rather than from decreased production of EDNO. Pretreatment of the diabetic arteries with the hydroxyl radical scavenger dimethylthiourea normalized relaxations in response to acetylcholine. The blockade of prostaglandin H2-thromboxane A2 receptors with SQ 29548 also improved relaxations in response to acetylcholine in diabetic arteries. These data indicate that endothelial dysfunction in the renal arteries of diabetic rats may be mediated by the increased production of free radicals and of prostaglandin endoperoxides, which oppose the vasorelaxant effects of EDNO.

Topics: Animals; Arginine; Arterioles; Bridged Bicyclo Compounds, Heterocyclic; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Endothelium, Vascular; Fatty Acids, Unsaturated; Free Radical Scavengers; Free Radicals; Hydrazines; In Vitro Techniques; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Prostaglandin Endoperoxides; Rats; Rats, Inbred WKY; Receptors, Thromboxane; Renal Artery; Superoxide Dismutase; Thiourea; Vasodilation