Blockade of endogenous proinflammatory cytokines ameliorates endothelial dysfunction in obese Zucker rats.

To study the role of endogenous proinflammatory cytokines in endothelial dysfunction in diabetes, we administered semapimod, an inhibitor of proinflammatory cytokine production, to obese Zucker (OZ) rats, and examined its effect on endothelium-dependent vasorelaxation. Endothelium-dependent vasorelaxation induced by acetylcholine and adrenomedullin (AM) was significantly reduced in OZ rats compared to a control group of lean Zucker rats. Semapimod significantly restored endothelium-dependent vasorelaxation in OZ rats. This effect of semapimod was well correlated with the reduction in the serum concentrations of tumor necrosis factor-alpha (TNF-alpha), interleukin-6, and C-reactive protein, as well as with the recovery of AM-induced Akt phosphorylation and cGMP production. Furthermore, acute administration of TNF-alpha significantly suppressed endothelium-dependent vasorelaxation and AM-induced cGMP production. These results implicate endogenous proinflammatory cytokines, especially TNF-alpha, in endothelial dysfunction in diabetes, and indicate that blockade of these cytokines will be a promising strategy for inhibiting the progression of vascular inflammation.