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The myogenic response and the endothelial function in small resistance arteries from rodent models of type 2 diabetes

 

Henrik Kold-Petersen

Summary

In this thesis I have shown that vascular dysfunctions in diabetes differ from one animal model to another. Small resistance arteries from three different animal models of type 2 diabetes have been investigated on the isobaric pressure myograph, and the isometric wire myograph. Simultaneously with the investigations of the mechanical properties of the arteries I have been measuring [Ca2+]i, either in whole wall preparations or in single endothelial cells.In the GK-rat model of type 2 diabetes, I found a decreased myogenic reactivity in the middle cerebral arteries and in the coronary septal arteries, consequent to a defect in the calcium sensitization pathway which is most likely due to a defect in the rho-kinase pathway. Also in the GK-rat model I found no evidence of an attenuated endothelium-dependent vasodilation.In the ZDF-rat model of type 2 diabetes I found an attenuation of the endothelium-dependent vasorelaxation in the mesenteric arteries. This decreased endothelium-dependent vasorelaxation was due to a decreased endothelium dependent hyperpolarizing factor (EDHF) response. I could restore the attenuated EDHF response by potentiating the function of the small and intermediate calcium activated potassium channels (SKCa and IKCa) in the endothelial cells by the substance NS309. Also, I showed that defect in the ACh mediated EDHF response is down-stream from Ca2+ signalling and it not due to a reduced expression of the IKCa 3.1 channels.In the db/db mouse model of type 2 diabetes I confirmed that the endothelium mediated vasodilation in the mesenteric arteries is severely attenuated due to a decreased function of the nitric oxide axis. I was, however, able to restore endothelium-dependent vsaodilation by treating the db/db mice with sulfaphenazole - a blocker of the CYP2C9 enzyme. I also showed that treatment with tempol - a superoxide dismutase mimetic and an antibody against the receptor of advanced glycation end-products was ineffective with respect to restoring the endothelium mediated vasodilation.The key findings in this thesis have given us a deeper insight into the complexity of vascular dysfunction in type 2 diabetes. The genetic background of the animals investigated, the blood glucose concentration, and the lipid concentrations are factors that play a major role for the characteristics of vascular dysfunction in type 2 diabetes.