title: Mechanisms of endothelial dysfunction in resistance arteries from patients with end-stage renal disease.
abstract: The study focuses on the mechanisms of endothelial dysfunction in the uremic milieu. Subcutaneous resistance arteries from 35 end-stage renal disease (ESRD) patients and 28 matched controls were studied ex-vivo. Basal and receptor-dependent effects of endothelium-derived factors, expression of endothelial NO synthase (eNOS), prerequisites for myoendothelial gap junctions (MEGJ), and associations between endothelium-dependent responses and plasma levels of endothelial dysfunction markers were assessed. The contribution of endothelium-derived hyperpolarizing factor (EDHF) to endothelium-dependent relaxation was impaired in uremic arteries after stimulation with bradykinin, but not acetylcholine, reflecting the agonist-specific differences. Diminished vasodilator influences of the endothelium on basal tone and enhanced plasma levels of asymmetrical dimethyl L-arginine (ADMA) suggest impairment in NO-mediated regulation of uremic arteries. eNOS expression and contribution of MEGJs to EDHF type responses were unaltered. Plasma levels of ADMA were negatively associated with endothelium-dependent responses in uremic arteries. Preserved responses of smooth muscle to pinacidil and NO-donor indicate alterations within the endothelium and tolerance of vasodilator mechanisms to the uremic retention products at the level of smooth muscle. We conclude that both EDHF and NO pathways that control resistance artery tone are impaired in the uremic milieu. For the first time, we validate the alterations in EDHF type responses linked to kinin receptors in ESRD patients. The association between plasma ADMA concentrations and endothelial function in uremic resistance vasculature may have diagnostic and future therapeutic implications.
authors.affiliation: Division of Obstetrics & Gynecology, Karolinska Institutet, Karolinska University Hospital, Department of Clinical Science, Intervention & Technology, Stockholm, Sweden.
authors.forename: Leanid
authors.initials: L
authors.lastname: Luksha
authors.forename: Peter
authors.initials: P
authors.lastname: Stenvinkel
authors.forename: Folke
authors.initials: F
authors.lastname: Hammarqvist
authors.forename: Juan Jesús
authors.initials: JJ
authors.lastname: Carrero
authors.forename: Sandra T
authors.initials: ST
authors.lastname: Davidge
authors.forename: Karolina
authors.initials: K
authors.lastname: Kublickiene
mesh_terms: D000328:Adult; D000368:Aged; D001120:Arginine / Q000031:analogs & derivatives / Q000097:blood; D001158:Arteries / Q000187:drug effects* / Q000473:pathology; D001685:Biological Factors / Q000378:metabolism; D001920:Bradykinin / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D017629:Gap Junctions / Q000378:metabolism; D006801:Humans; D007676:Kidney Failure, Chronic / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D001685:Biological Factors; D014665:Vasodilator Agents; C487735:dimethylarginine; C067410:endothelium-dependent hyperpolarization factor; D001120:Arginine; D052250:Nitric Oxide Synthase Type III; D001920:Bradykinin