Amelioration of hyperglycemic and hyperosmotic induced vascular dysfunction by in vivo inhibition of protein kinase C and p38 MAP kinase pathway in the rat mesenteric microcirculation.

BackgroundRecently, we demonstrated in vivo effects of acutely induced hyperglycemia, diabetes and mannitol infusions on rat mesenteric microcirculation concerning leukocyte–endothelial-cell interaction (Schäffler et al. EJCI 28: 886–893, 1998). DesignIn this study we have investigated the possible involvement of the protein kinase C (PKC) and p38 MAP kinase cascade as signal transducing elements during hyperglycemic and osmotic stress in an in vivo rat model. ResultsAcutely induced hyperglycemia resulted in a significant increase in leukocyte adhesion. This effect could be mimicked by mannitol. Both PKC and p38 MAP kinase were involved in the effects mediated by glucose and mannitol. Acutely induced hyperglycemia resulted in a significant increase in leukocyte emigration. This effect could be imitated by mannitol. However, PKC and p38 MAP kinase were only involved under osmotic stimulation. The hyperglycemia-induced reduction in leukocyte rolling velocity seemed to be a glucose-specific effect, since mannitol did not influence leukocyte rolling velocity. This glucose effect on leukocyte rolling velocity was mediated by an activation of the PKC/p38 MAP kinase cascade. Both hyperglycemia and osmotic stimuli alone were able to reduce venular shear rate without recruitment of the p38 MAP kinase cascade. The observed reduction of shear rate seems to be mediated only by the osmotic effects of glucose via activation of the PKC system. ConclusionThe observed effects of glucose on adhesion, emigration and shear rate are due to osmotic effects. The PKC/MAP kinase cascade is involved as a signal transducing component. The reduction of leukocyte rolling velocity is a glucose-specific effect, mediated by the activation of both the PKC and the p38 MAP kinase cascade. Venular shear rate and leukocyte emigration can be influenced by glucose and mannitol due to different regulation mechanisms. It is concluded, that isoform-specific inhibitors of PKC and... [ABSTRACT FROM AUTHOR]