INFLUENCE OF CHRONIC EXPOSURE TO HIGH-CONCENTRATIONS OF D-GLUCOSE ANDLONG-TERM BETA-BLOCKER TREATMENT ON INTRACELLULAR CALCIUM CONCENTRATIONS OF PORCINE AORTIC ENDOTHELIAL-CELLS

Clinical observations indicate that diabetes leads to micro-and macroa ngiopathy involving endothelial dysfunction. Because recent studies in dicate an antiangiopathic effect of celiprolol, but not of metoprolol, in type 1 diabetes, we investigated the direct influence of exposure to high D-glucose concentrations on endothelial cells and the possible effects of both beta-blockers. Nine different chronic treatments were carried out on cultured porcine aortic endothelial cells: 1) 5 mmol/l D-glucose (''normoglycemic'' cells), 2)5 mmol/l D-glucose plus 15 mmo l/l L-glucose (osmotic control), 3)5 mmol/l D-glucose plus 0.5 mu mol/ l celiprolol, 4)5 mmol/l D-glucose plus 0.05 mu mol/l metoprolol, 5) 5 mmol/l D-glucose plus 0.5 mu mol/l celiprolol plus 5 mu mol/l propran olol, 6) 20 mmol/l D-glucose (''hyperglycemic'' cells), 7) 20 mmol/l D -glucose plus 0.5 mu mol/l celiprolol, 8) 20 mmol/l D-glucose plus 0.0 5 mu mol/l metoprolol, and 9) 20 mmol/l D-glucose plus 0.5 mu mol/l ce liprolol plus 5 mu mol/l propranolol. Using the Fura-2 technique, appl ication of either 1 nmol/l bradykinin or 1 mu mol/l ATP to the normogl ycemic endothelial cells led to a significant increase in intracellula r calcium, whereas the hyperglycemic cells showed significantly less r eactivity to both agents. Exposure of endothelial cells to L-glucose d id not show any difference to normoglycemia: controls. Coadministratio n of 20 mmol/l. glucose and celiprolol demonstrated that the alteratio n of the calcium signal induced by high D-glucose concentrations could be significantly antagonized with celiprolol. In contrast, coincubati on with metoprolol failed to normalize the calcium signal. This effect of celiprolol was completely abolished in the presence of propranolol . In normoglycemic cells, none of the beta-blockers influenced the int racellular calcium response to bradykinin or ATP. These results indica te that chronic treatment with high D-glucose concentrations leads to an impairment of calcium signaling, which might be ameliorated by celi prolol.