ICSM 3rd Annual Scientific Meeting Plenary Lectures

Alterations of vascular smooth muscle function have been implicated in the development of vascular complications and circulatory dysfunction in diabetes mellitus. However, little is known on changes in smooth muscle contractility and the intracellular mechanisms contributing to such altered responsiveness in blood vessels from diabetic patients. Thus, smooth muscle reactivity to increased K + , norepinephrine (NE) and phenylephrine (PE) and acetylcholine-induced endothelium-dependent relaxation were assessed in uterine arteries from control individuals (CI) and diabetic patients (DM). Smooth muscle sensitivity to K + , NE and PE was enhanced by 1.4, 2.3-and 9.7-fold and relaxation was reduced by 64% in vessels from DM. In addition, in freshly isolated smooth muscle cells from DM an increased perinuclear Ca 2+ signaling to K + (30 mmol/l: +73%; 30 mmol/l: +68%) and NE (300 nmol/l +86%; 10  mol/l +67%) was found, which promotes smooth muscle contraction. In contrast, subplasmalemmal Ca 2+ response, which favors smooth muscle relaxation due to activation of Ca 2+ -activated K + channels, was reduced by 38% in DM, indicating a significant change in the subcellular Ca 2+ distribution in vascular smooth muscle cells during diabetes. In contrast to the altered Ca 2+ signaling found in freshly isolated cells from DM, in cultured smooth muscle cells isolated from CI and DM no further difference in the Ca 2+ signaling to stimulation with either K + or NE was found. Hence, production of superoxide anions (ïO 2) in intact and endothelium-denuded arteries from DM was increased by 150 and 136%, respectively. Incubation of freshly isolated smooth muscle cells from CI with