Atherosclerosis and the Two Faces of Endothelial Nitric Oxide Synthase

Wever, Robert; Lüscher, Thomas F.; Cosentino, Francesco; Rabelink, Ton J.

doi:10.1161/01.cir.97.1.108

Cited by 254 publications

(176 citation statements)

References 68 publications

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“…Moreover, SOD did not further modify the response to Ach in the presence of L-arginine and BH 4 . This ®nding indicates that BH 4 did not undergo autooxidation with subsequent production of superoxide, which has been reported to occur in vitro (Wever et al, 1998).…”

Section: Discussionsupporting

confidence: 65%

“…Therefore, the impaired response to Ach re¯ects reduced bioavailability of endothelium-derived NO. It has been suggested that supplementation with the substrate L-arginine may enhance NO production and restore endothelial function in hypercholesterolemia and atherosclerosis (see Wever et al, 1998;Drexler, 1997). In the present study, preincubation with Larginine (1 mM) did not a ect the response to Ach, however, indicating that lack of substrate was not a primary cause of endothelial dysfunction.…”

Section: Discussionmentioning

confidence: 99%

“…Another important action of BH 4 may be that it seems to co-operate with L-arginine. Thus, binding of L-arginine to NO synthase is enhanced by BH 4 (Wever et al, 1998). Accordingly, an altered K M of NO synthase for L-arginine has been observed in mice with BH 4 de®ciency (Brand et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

“…NO reacts very rapidly with superoxide to produce peroxynitrite (Beckman & Koppenol, 1996). Since the generation of superoxide is increased in atherosclerotic lesions (see Wever et al, 1998) the catabolism of NO by its reaction with superoxide may be of importance in atherosclerosis. However, administration of SOD, at a concentration which has been demonstrated to improve endothelial function during stimulated superoxide production in rabbit aortic rings (Abrahamsson et al, 1992) and in aortic rings from spontaneously hypertensive rats , did not modify the Ach-induced relaxations in the present study.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, administration of L-arginine has been shown to enhance endothelium-dependent vasodilation (Creager et al, 1992) and to prevent development of atherosclerosis in low density lipoprotein (LDL) receptor knockout mice (Aji et al, 1997). However, the role of L-arginine as a ratelimiting factor in NO synthesis is controversial based on the high concentration of intracellular L-arginine and the ®nding that vascular e ects of L-arginine may be independent of NO synthesis (see Wever et al, 1998). Tetrahydrobiopterin (BH 4 ) is a co-factor for NO synthase in the production of NO from L-arginine (Cosentino & LuÈ scher, 1998;Marletta et al, 1998;Werner et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

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Endothelial dysfunction in atherosclerotic mice: improved relaxation by combined supplementation with L‐arginine‐tetrahydrobiopterin and enhanced vasoconstriction by endothelin

Jiang

Valen²,

Tokuno³

et al. 2000

British J Pharmacology

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1 Mice lacking the apolipoprotein E and low density lipoprotein receptor genes (E8xLDLR8) develop atherosclerosis and endothelial dysfunction. The aim of this study was to characterize the roles of L-arginine and tetrahydrobiopterin (BH 4 ) for endothelium-dependent relaxation and the changes in the vasoconstrictor response to endothelin-1 (ET-1) in thoracic aortic rings of E8xLDLR8 mice. 2 Histological examination revealed severe atherosclerosis of the thoracic aorta of E8xLDLR8 mice. Relaxations induced by acetylcholine (Ach), but not that to sodium nitroprusside, were signi®cantly impaired in E8xLDLR8 mice compared to control mice indicating attenuated endothelium-dependent relaxations. 3 Preincubation with the nitric oxide (NO) substrate L-arginine did not a ect, whereas the cofactor for NO synthase, BH 4 , slightly improved the relaxations induced by Ach. Combined preincubation with L-arginine and BH 4 induced a pronounced enhancement of Ach-induced relaxations in E8xLDLR8 mice. The relaxations induced by Ach in E8xLDLR8 mice in the presence of L-arginine and BH 4 were not di erent from those observed in control mice. 4 Preincubation with superoxide dismutase did not a ect Ach-induced relaxations in aorta from E8xLDLR8 mice. 5 The contractile response to ET-1 was enhanced in E8xLDLR8 mouse aorta. The contractions were abolished by the ET A receptor antagonist LU 135252. The ET B receptor agonist sarafotoxin 6c did not induce contractions or relaxations. 6 It is concluded that endothelial dysfunction of E8xLDLR8 mouse aorta is reversed by combined administration of L-arginine and BH 4 . In addition, the ET A receptor-mediated vasoconstriction by ET-1 is enhanced in E8xLDLR8 mice.

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Section: Discussionsupporting

confidence: 65%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Endothelial dysfunction in atherosclerotic mice: improved relaxation by combined supplementation with L‐arginine‐tetrahydrobiopterin and enhanced vasoconstriction by endothelin

Jiang

Valen²,

Tokuno³

et al. 2000

British J Pharmacology

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Nitric oxide in the pathogenesis of vascular disease

Li¹,

2000

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Nitric oxide (NO) is synthesized by at least three distinct isoforms of NO synthase (NOS). Their substrate and cofactor requirements are very similar. All three isoforms have some implications, physiological or pathophysiological, in the cardiovascular system. The endothelial NOS III is physiologically important for vascular homeostasis, keeping the vasculature dilated, protecting the intima from platelet aggregates and leukocyte adhesion, and preventing smooth muscle proliferation. Central and peripheral neuronal NOS I may also contribute to blood pressure regulation. Vascular disease associated with hypercholesterolaemia, diabetes, and hypertension is characterized by endothelial dysfunction and reduced endothelium‐mediated vasodilation. Oxidative stress and the inactivation of NO by superoxide anions play an important role in these disease states. Supplementation of the NOS substrate L‐arginine can improve endothelial dysfunction in animals and man. Also, the addition of the NOS cofactor (6R)‐5,6,7,8‐tetrahydrobiopterin improves endothelium‐mediated vasodilation in certain disease states. In cerebrovascular stroke, neuronal NOS I and cytokine‐inducible NOS II play a key role in neurodegeneration, whereas endothelial NOS III is important for maintaining cerebral blood flow and preventing neuronal injury. In sepsis, NOS II is induced in the vascular wall by bacterial endotoxin and/or cytokines. NOS II produces large amounts of NO, which is an important mediator of endotoxin‐induced arteriolar vasodilatation, hypotension, and shock. Copyright © 2000 John Wiley & Sons, Ltd.

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