Nitric oxide-mediated endothelial dysfunction--is there need to treat?
Before it gets to the development of manifest atherosclerotic lesions, all known risk factors primarily induce functional alterations in the vascular wall, namely in endothelial cells. Being termed endothelial dysfunction or endothelial activation, this condition is characterized by an altered availability of nitric oxide (NO). Under physiological conditions, NO is of unequivocal importance for the regulation of vascular homeostasis. Endothelium-derived NO released abluminally increases soluble guanylat cyclase activity in smooth muscle cells, thereby inducing relaxation and consequently vasodilatation. Intraluminally, NO inhibits the expression of adhesion molecules both on endothielial cells and neutrophils, thus preventing the adherence of cellular elements to the vascular wall. Furthermore, NO has antithrombotic effcts by inhibiting platelet aggregation and directly infuencing the synthesis of different factors involved in the coagulation cascade. Finally, in the long term, NO has been shown to exert antiproliferative properties. NO is generated intracellularly from L-arginine via NO-synthase with the help of several cofactors, including tetrahydobiopterin. Interestingly, it has recently become evident that under certain conditions, when there is a lack of tetrahydrobiopterin, NO-synthase produces reactive oxygen species instead of NO. Reactive oxygen species counteract the effects of NO and also scavenge NO resulting in the formation of peroxynitrite (ONOO). Peroxynitrite has been shown to have deleterious effects with respect to vascular function. The aim of the current review is to elucidate recent progress regarding the pathophysiological understanding of endothelial dysfunction. Furthermore, the significance of this condition for the evaluation and prognosis of patients is discussed. Finally, current therapeutical strategies in the treatment and improvement of endothelial dysfunction are highlighted.
Tiefenbacher
C P
CP
Department of Cardiology, University of Heidelberg, Germany. ctiefenbacher@med.uni-heidelberg.de
Kreuzer
J
J
D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D000818:Animals; D001120:Arginine / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D006710:Homocysteine / Q000037:antagonists & inhibitors / Q000097:blood; D020249:Hormone Replacement Therapy; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D009569:Nitric Oxide / Q000096:biosynthesis / Q000502:physiology*; D014652:Vascular Diseases / Q000188:drug therapy / Q000503:physiopathology
D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D006710:Homocysteine; D009569:Nitric Oxide; D001120:Arginine