Decreased Modulation by Lipopolysaccharide of Aortic Smooth Muscle Contractility in Streptozotocin-Induced Hyperglycemic Rats

Abstract

Infection is a major complication of patients with diabetes, and endotoxemic shock is a serious complication during sepsis. The purpose of this study was to determine whether the action of bacterial lipopolysaccharide (LPS) on vasocontractility is altered in diabetic vessels. Diabetes was induced in 10-week-old Wistar rats by an intraperitoneal injection of streptozotocin. LPS-induced increase in cGMP (cyclic guanosine 3',5'-monophosphate) level was lower in aortae from streptozotocin-induced hyperglycemic (diabetic) rats than in those from vehicle-injected control rats, while LPS-induced nitric oxide production was not different in the diabetic and control aortae. Phenylephrine-induced contraction of diabetic aortae was lower than that of the control aortae. LPS treatment resulted in depression of contractile response to phenylephrine in both diabetic and control aortae, and the degree of depression was much lower in diabetic aortae. Treatment with N monomethyl l-arginine (l-NMMA) prevented diminution of phenylephrine-induced contraction of the aortae after LPS stimulation, and the degree of the preventive effect by l-NMMA was significantly lower in diabetic aortae than in the control aortae. Protein expression of inducible nitric oxide synthase detected by Western blot analysis was not different in the diabetic and control aortae. The decrease in cGMP production after LPS stimulation in diabetic aortae was not prevented by treatment of the aortae with superoxide dismutase but was partially prevented by that with Tiron (4,5-dihydroxy-1,3-benzene disulfonic acid), a cell-permeable scavenger of reactive oxygen species. These results suggest that LPS-induced depression of vasocontractility is attenuated in diabetic aortae due to a decrease in nitric oxide-stimulated cGMP production, probably resulting from increased inactivation of inducible nitric oxide by excessive intracellular oxidative stress. It is concluded that contractility of aortae from streptozotocin-induced hyperglycemic rats may be less affected by LPS during endotoxemia.