Compensatory Role of EDHF in Type 2 Diabetes‐induced Endothelial Dysfunction

Endothelium‐derived hyperpolarizing factor (EDHF) is thought to play a major role in maintaining endothelial function when NO‐dependent function is reduced in diabetes. Thus, we assessed the role of EDHF in type 2 diabetic mice by evaluation of endothelial function of isolated and pressurized (60 cmH 2 O) coronary resistance vessels (40–100μm) of m Lepr db (normal) and Lepr db (advanced diabetic) mice (20–24 weeks) in a presence of NOS inhibitor N G ‐nitro‐L‐arginine‐methyl ester (L‐NAME, 10μM) and prostaglandin synthase inhibitor indomethacin (Indo, 10μM). Although dilation of vessels to the endothelium‐independent vasodilator, sodium nitroprusside (SNP) was not different between Lepr db and m Lepr db mice, dilation to the endothelium‐dependent agonist ACh was resistant to L‐NAME and Indo, and ACh‐induced EDHF‐dependent vasodilation was also impaired in Lepr db mice. Also, we evaluated the role of interleukin‐6 (IL‐6) in Lepr db mice. Interleukin assay analysis revealed elevations in circulating IL‐6 in Lepr db mice. Moreover, administration of IL‐6 (5 ng/ml) appeared to induce endothelial dysfunction in a similar manner as vasodilation in the presence of L‐NAME and Indo in m Lepr db mice. In conclusion, EDHF plays a pivotal role in maintaining some degree of endothelial function in advanced type 2 diabetes and an increase in circulating and/or local vascular IL‐6 induce endothelial dysfunction in Lepr db .