Endothelium-Dependent Vasodilation and Oxidative Stress in Chronic Renal Failure

Sammanfattning: Cardiovascular disease (CVD) is the major cause of death in patients with chronic renal failure (CRF). Endothelial function and oxidative stress (OS) have previously been shown to be important in the pathogenesis of CVD. In this thesis, the endothelium-dependent vasodilatation (EDV) and OS were investigated in the patients with CRF. Also the influence of L-arginine, erythropoietin and diclofenac on EDV were evaluated in patients with CRF. Patients with CRF were found to be characterized by a defect EDV even after correction for traditional cardiovascular risk factors. This impairment was related to the degree of renal failure. Measurement of OS markers in CRF patients demonstrated that these patients were in a state of OS compared to healthy controls. The most informative indices to evaluate the degree of OS in CRF were: oxidized glutathione (GSSG) level, ratio between oxidized and reduced glutathione (GSSG/GSH ratio), lag phase of lipoprotein fraction (LPF) and baseline diene conjugation level of LPF. Simultaneously investigated OS markers and EDV demonstrated a relationship between OS and EDV in patients with CRF. EDV was positively correlated with total antioxidative activity, reduced glutathione (GSH) and lag phase of LDL. Local infusion of L-arginine as a substrate for nitric oxide synthesis and diclofenac as an inhibitor of cyclooxygenase-derived vasoconstrictive agents augmented EDV in patients CRF. In contrast, the erythopoietin treatment (both acute and long-term) impaired EDV in CRF patients. In conclusion, patients with CRF have increased levels of OS markers and impaired endothelial vasodilatory function. These factors may be important with respect to the high morbidity and mortality of CVD found in patients with CRF. One possible mechanism to reduce CVD in patients with CRF is to improve endothelial function and eliminate OS. Locally administrated L-arginine and diclofenae improved EDV but erythropoietin administration impaired EDV in patients with CRF.