The impaired renal vasodilator response attributed to endothelium-derived hyperpolarizing factor in streptozotocin-induced diabetic rats is restored by 5-methyltetrahydrofolate

Aims/hypothesis. Endothelial dysfunction contributes to the development of diabetic vascular complications. A better understanding of the pathophysiol ogy of endothelial dysfunction in diabetes could lead to new approaches to prevent microvascular disease. Methods. Endothelium-dependent and endothelium-independent vasodilator resp onses were investigated in the renal microcirculation of streptozotocin-ind uced diabetic rats. We measured renal blood flow changes with an electromag netic flow probe. In addition, the responses of the different segments of t he renal microcirculation were evaluated with videomicroscopy using the hyd ronephrotic kidney technique. Because endothelial cells release different r elaxing factors (nitric oxide, prostacyclin and an unidentified endothelium -derived hyperpolarizing factor), responses to acetylcholine were measured before and after treatment with the nitric oxide synthase inhibitor L-NG-ni troarginine methylester HCI (L-NAME) and the cyclooxygenase inhibitor indom ethacin, We evaluated with the effect of 5-methyltetrahydrofolate, the acti ve form of folate, on the responses. Results. The L-NAME- and indomethacin-resistant vasodilation to intra-renal acetylcholine was significantly reduced in the diabetic compared with cont rol rats, suggesting impaired endothelium-derived hyperpolarizing factor-me dieted vasodilation. The responses to the nitric oxide donor (Z)-1-[-2-(am inoethyl)-N-(2-ammonioethyl) amino]diazen-1-ium-1,2-diolate (DETA-NONOate) and to the K+-channel opener pinacidil were similar in diabetics and contro ls, indicating intact: endothelium-independent vasodilator mechanisms. The contribution of endothelium-derived hyperpolarizing factor to vasodilation induced by acetylcholine was greatest in the smallest arterioles. In diabet ic rats, the response to acetylcholine was increasingly impared as vessel s ize decreased. Defective vasodilation in diabetic kidneys was rapidly norma lized by 5-methyltetrahydrofolate. Conclusion-interpretation. Endothelium-derived hyperpolarizing factor-media ted vasodilation is impaired in the renal microcirculation of diabetic rats , in particular in the smallest arteries. Treatment with folate restores th e impaired endothelial function in diabetes.