Effect of N-epsilon-(carboxymethyl)lysine on coronary vasoconstriction in isolated perfused hearts from control and streptozotocin-induced diabetic rats.

Advanced glycation end products (AGEs) derived from glucose are implicated in the pathogenesis of diabetic vascular disease. However, their direct modulatory effects on coronary vascular tone remain unclear. We previously reported that coronary vasoconstriction was induced by acetylcholine (ACh) infusion of the isolated perfused rat heart and that sensitivity was greater in perfused hearts from streptozotocin (STZ)-induced diabetic rats than in those from age-matched controls (Kamata et al., 2008). Here, we investigated the effect of N(epsilon)-(carboxymethyl)lysine (CML), which has one of the main AGE structures, on ACh-induced vasoconstriction in perfused hearts isolated from control and diabetic rats. ACh-induced vasoconstriction was significantly greater in the STZ-induced diabetic group than in the age-matched controls. CML enhanced the ACh-induced vasoconstriction in coronary arteries from control rats, but not in those from STZ-induced diabetic rats. In the controls, the vasoconstriction induced by the calcium-channel activator Bay K 8644 was also enhanced by CML. These CML-mediated enhancements of the vasoconstrictions induced by ACh and Bay K 8644 were significantly suppressed by tempol, a superoxide dismutase mimetic. The plasma CML and glucose levels were each significantly elevated in STZ-induced diabetic rats. These findings suggest (a) that CML augments ACh-induced coronary vasoconstriction, an effect that may be attributable to increased superoxide and to activation of voltage-gated Ca(2+) channels and (b) that this modulating effect may be desensitized in the STZ-induced diabetic heart.