Endothelial cell hyperpolarization and EDHF: Local and regional influence of diabetes

Endothelial dysfunction is a major risk factor for the vascular complications of diabetes. Endothelium-derived hyperpolarizing factor (EDHF) is an important vasodilator mechanism in small arteries and arterioles and its actions are impaired in diabetes. Endothelial cell hyperpolarization is the initial step involved in the genesis of EDHF vasodilator activity. We investigated the mechanisms influencing EDHF function in mesenteric and hindlimb beds of rats with type I diabetes. Diabetes was induced in male Wistar rats with streptozotocin (60mg/kg) incitrate buffer and controls received buffer alone. Eight weeks after injection EDHF function was examined. In mesenteric arteries endothelial cell hyperpolarization and EDHF-mediated smoothmuscle hyperpolarization and relaxation were halved in diabetes. The contributions of both intermediate (IKCa) and small (SKCa)-conductance calcium activated potassium channels were reduced, with protein expression of the channels unaltered. The functional patency of myoendothelial gap junctions (MEGJs) was preserved. The role of calcium stores and TRPC3 in the generation of mesenteric endothelial cell hyperpolarization and the influence of diabetes was also examined. Local superoxide generation was upregulated in diabetic mesenteric arteries. In small femoral arteries where endothelial cells do not form MEGJs with smooth muscle cells, endothelialcell hyperpolarization was preserved, KCa channel protein expression was unchanged or increased. Local superoxide generation was unaltered in this region. In conclusion, diabetes has regional and differential effects on endothelial function. Impairment of mesenteric EDHF relaxation is due to impairment in the generation of endothelial cell hyperpolarization and not in the functional disruption of the MEGJ pathway