title: Endothelial dysfunction in acute renal failure: role of circulating and tissue endothelin-1.
abstract: The kidney is an important target and source of the potent vasoconstrictor and mitogen endothelin-1 (ET-1). However, its exact role in acute renal failure (ARF) remains to be determined. ARF was induced in male Wistar-Kyoto rats (n = 7) in a 2-kidney, 2-clip model of 30-min clamping. Twenty-four hours after clamp release, contractions to angiotensin I (Angl) and II, ET-1, and big ET-1 were studied in isolated aortic and renal artery rings. Endothelium-dependent and -independent relaxations were assessed by acetylcholine and sodium nitroprusside. ET-1 clearance, tissue uptake, plasma levels, and vascular and kidney content were investigated. In addition, ET(A) and Et(B) receptor mRNA expression was determined. Sham-operated animals served as controls (n = 7). In ARF, ET-1 plasma levels and tissue content of the renal artery, the aorta, and the kidney markedly increased (P<0.01). Plasma half-life of radiolabeled 125I-ET-1 was markedly prolonged, whereas 125I-ET-1 tissue uptake decreased in the kidney in ARF. Contractions to AngI and AngII were blunted (P<0.05) and those to KCl were unchanged, whereas vascular responses to big ET-1 and ET-1 were enhanced in the renal artery and also in the aorta in ARF (P<0.05 to 0.001). Correspondingly, ET(A) and Et(B) receptor mRNA expression significantly increased in both vascular beds. In addition, endothelium-dependent relaxation to acetylcholine was diminished and inversely correlated with vascular ET-1 protein levels in the renal artery (r = -0.827, P<0.001) and the aorta (r = -0.812, P<0.001). In conclusion, the present study demonstrates that increase of circulating and tissue ET-1 protein levels and ET(A) and Et(B) receptor gene expression occurs, which induces endothelial dysfunction and enhanced vasoconstriction in different vascular beds in ARF.
authors.affiliation: Department of Cardiology, University Hospital Zürich, Institute of Physiology, University of Zürich-Irchel, Switzerland.
authors.forename: F
authors.initials: F
authors.lastname: Ruschitzka
authors.forename: S
authors.initials: S
authors.lastname: Shaw
authors.forename: D
authors.initials: D
authors.lastname: Gygi
authors.forename: G
authors.initials: G
authors.lastname: Noll
authors.forename: M
authors.initials: M
authors.lastname: Barton
authors.forename: T F
authors.initials: TF
authors.lastname: Lüscher
mesh_terms: D058186:Acute Kidney Injury / Q000378:metabolism / Q000503:physiopathology*; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D019332:Endothelin-1 / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology / Q000502:physiology*; D016232:Endothelins / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000503:physiopathology*; D066298:In Vitro Techniques; D008297:Male; D011498:Protein Precursors / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011921:Rats, Inbred WKY; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000235:genetics; D012077:Renal Artery / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D014661:Vasoconstriction / Q000502:physiology; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D019332:Endothelin-1; D016232:Endothelins; D011498:Protein Precursors; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D014662:Vasoconstrictor Agents