Endothelial dysfunction in the streptozotocin‐induced diabetic apoE‐deficient mouse

Endothelial dysfunction plays a role in the development of atherosclerosis and diabetes‐associated vascular disease and, in the streptozotocin (STZ)‐induced apoE‐deficient diabetic mouse, we report that, when compared to the citrate (CIT)‐treated nondiabetic apoE‐deficient control, acetylcholine (Ach)‐mediated endothelium‐dependent relaxation was reduced in the small mesenteric arteries (SMA) and the plaque‐prone regions of the aorta from the STZ‐diabetic mouse. In the SMA the component of Ach‐mediated relaxation that was attributed to nitric oxide (NO) from STZ‐treated diabetic apoE‐deficient mice was enhanced; however, the endothelium‐derived hyperpolarizing factor (EDHF)‐mediated component was reduced. The EDHF component was assessed by determining the component of the Ach‐mediated response that was resistant to the combination of the NO synthase (NOS) inhibitor N ‐nitro‐ L ‐arginine methyl ester, cyclooxygenase inhibitor, indomethacin, and soluble guanylate cyclase inhibitor, ODQ, and inhibited by the combination of the intermediate conductance K Ca (IK Ca ) inhibitor TRAM‐34 and the small‐conductance K Ca (SK Ca ) inhibitor apamin. Endothelial NOS was increased but SK2, SK3 and connexin (Cx) 37 mRNA expressions were significantly ( P <0.05) decreased in the SMA from STZ‐treated apoE‐deficient mice compared to the CIT‐treated controls. There was no difference in the IK Ca expression or in Cx 40, 43 and 45 mRNA levels between STZ‐ and CIT‐treated mice. The microvasculature of STZ‐induced apoE‐deficient mice developed endothelial dysfunction, which may be linked to a decrease in the contribution of the EDHF component due to a decrease in SK2 and 3 and Cx 37 expression.British Journal of Pharmacology (2005) 146 , 1110–1118. doi: 10.1038/sj.bjp.0706417