Effect of elevated extracellular glucose concentrations on transmembrane calcium ion fluxes in cultured rat VSMC

Abstract

Blood flow autoregulation is impaired in early diabetes mellitus, predisposing the renal microcirculation to injury. These hemodynamic changes have been strongly implicated in the development and progression of diabetic glomerulopathy. Blood flow autoregulation is predominantly a myogenic reflex which is strongly dependent on Ca2+ uptake by vascular smooth muscle cells (VSMC). Because impaired blood flow autoregulation may be responsive to glycemic control, the present study examined the effects of elevated extracellular glucose concentrations on basal, voltage sensitive and receptor operated Ca2+ uptake by VSMC. Confluent cultured rat VSMC were exposed to: (1) control medium (CM; 5 mM glucose); (2) high glucose medium (HGM; 10 to 30 mM glucose); or (3) osmotic control medium (OCM; glucose 5 mM + L-glucose 25 mM or mannitol 25 mM). A threshold glucose concentration of 15 mM markedly and maximally depressed basal Ca2+ uptake by VSMC (HGM 52% vs. CM). In addition, HGM significantly depressed voltage sensitive Ca2+ uptake by VSMC as determined by responses to BAY K 8644 (10(-7) M) or high extracellular [K+] (65 mM, HGM 50% vs. CM). HGM similarly depressed pressor hormone-stimulated Ca2+ uptake (AVP or Ang II 10(-7) M) by VSMC. The effects of HGM on Ca2+ uptake were time exposure dependent and reversible. Ca2+ uptake by VSMC in the presence of OCM did not differ from CM. Elevated extracellular glucose concentrations thus exert a direct and profound effect on basal, voltage sensitive and receptor operated Ca2+ uptake by VSMC. These observations may provide a biochemical basis for glucose-induced dysregulation of regional blood flow autoregulation in early diabetes mellitus.