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

Background Recently, we demonstrated in vivo effects of acutely induced hyp erglycemia, diabetes and mannitol infusions on rat mesenteric microcirculat ion concerning leukocyte-endothelial-cell interaction (Schaffler et al. EJC I 28: 886-893, 1998). Design In this study we have investigated the possible involvement of the p rotein kinase C (PKC) and p38 MAP kinase cascade as signal transducing elem ents during hyperglycemic and osmotic stress in an in vivo rat model. Results Acutely induced hyperglycemia resulted in a significant increase in leukocyte adhesion. This effect could be mimicked by mannitol. Both PKC an d p38 MAP kinase were involved in the effects mediated by glucose and manni tol. Acutely induced hyperglycemia resulted in a significant increase in le ukocyte emigration. This effect could be imitated by mannitol. However, PKC and p38 MAP kinase were only involved under osmotic stimulation. The hyper glycemia-induced reduction in leukocyte rolling velocity seemed to be a glu cose-specific effect, since mannitol did not influence leukocyte rolling ve locity. This glucose effect on leukocyte rolling velocity was mediated by a n activation of the PKC/p38 MAP kinase cascade. Both hyperglycemia and osmo tic stimuli alone were able to reduce venular shear rate without recruitmen t 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 th e PKC system. Conclusion The observed effects of glucose on adhesion, emigration and shea r rate are due to osmotic effects. The PKC/MAP kinase cascade is involved a s a signal transducing component. The reduction of leukocyte rolling veloci ty is a glucose-specific effect, mediated by the activation of both the PKC and the p38 MAP kinase cascade. Venular shear rate and leukocyte emigratio n can be influenced by glucose and mannitol due to different regulation mec hanisms. It is concluded, that isoform-specific inhibitors of PKC and speci fic MAP kinase inhibitors represent a potential drug target for preventing microvascular dysfunction in diabetes.