Effects of In Vivo Nitroglycerin Treatment on Activity and Expression of the Guanylyl Cyclase and cGMP-Dependent Protein Kinase and Their Downstream Target Vasodilator-Stimulated Phosphoprotein in Aorta

Mülsch, Alexander; Oelze, Matthias; Klöss, Stefan; Mollnau, Hanke; Töpfer, Andrea; Smolenski, Albert; Walter, Ulrich; Stasch, Johannes‐Peter; Warnholtz, Ascan; Hink, Ulrich; Meinertz, Thomas; Münzel, Thomas

doi:10.1161/01.cir.103.17.2188

Cited by 126 publications

(102 citation statements)

References 30 publications

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“…24 In line with the hypothesis that increased oxidative stress is causally associated with decreased NMD, vitamin C has been shown to protect against nitrate tolerance, possibly by decreasing O 2Ϫ formation. 25 Oxidized LDL was not associated with FMD in the present study, although one would assume that if NO produced by GTN bioconversion is inactivated by oxidized LDL, the same would occur when NO is released from the endothelium. The reason for this controversy remains unclear, although it may be thought that other risk factors than oxidized LDL might be more potent in the development of endothelial dysfunction in children.…”

Section: Järvisalo Et Al Arterial Nitrate-mediated Dilatation In Chilmentioning

confidence: 49%

Determinants of Arterial Nitrate-Mediated Dilatation in Children

2004

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Background-Impaired arterial dilatation response to nitroglycerin has been observed in adults with risk factors for atherosclerosis and in patients with established atherosclerotic disease. This defect parallels changes in vascular endothelial function and may be attributed to increased oxidative stress. Because atherosclerosis begins in childhood, we examined the correlates of nitrate-mediated dilatation (NMD) in children, including brachial artery endothelial function, oxidized LDL, and carotid artery intima-media thickness (IMT). Methods and Results-Brachial artery flow-mediated endothelium-dependent dilatation (FMD) Key Words: arteries Ⅲ diabetes mellitus Ⅲ endothelium Ⅲ nitroglycerin Ⅲ pediatrics E ndothelial dysfunction is currently considered a key early event in the atherosclerotic process already evident in children with cardiovascular risk factors, such as hypercholesterolemia 1 and diabetes. 2 The brachial artery ultrasound test for flow-mediated endothelial-dependent vasodilatory function (FMD), described by Celermajer et al, 1 includes administration of sublingual nitrates to examine the vasodilating effect of an exogenous source of nitric oxide (NO). NO acts directly at the level of the arterial smooth muscle cells and produces an endothelium-independent dilatation response. Nitrate-mediated dilatation (NMD) has therefore been used as a control test for the FMD measurement to ensure that a decreased FMD capacity observed is truly a consequence of endothelial dysfunction and not a reflection of underlying smooth muscle dysfunction.Recent evidence indicates that in addition to influencing endothelial function, atherosclerosis may also induce changes in arterial dilatation responses to exogenous NO. 3,4 Adult patients with coronary artery disease show impaired brachial NMD compared with healthy control subjects. 4 Attenuated NMD is associated with serum cholesterol concentration independently of endothelial function in apparently healthy adults. 3 In most previous studies in children, the NMD responses have actually been mildly reduced in high-risk individuals, although the difference has not reached statistical significance, possibly because of limited sample size. 1,2,5 Increased oxidative stress and oxidized LDL have been implicated as risk factors for atherosclerosis 6 and shown to potently quench NO 7 and decrease its production 8 in experimental studies. Recent studies have associated oxidative stress with nitrate tolerance. 9 Because the atherosclerotic process begins in childhood, 10 we examined the correlates of NMD in children, including brachial artery endothelial function, oxidized LDL, and carotid artery intima-media thickness (IMT). Methods SubjectsWe studied 142 children (83 boys; mean age, 11 years; range, 8 to 17 years), including 41 children with diabetes and 14 children with familial hypercholesterolemia (FH). All subjects were nonsmokers.Received December 8, 2003; revision received February 27, 2004; accepted March 4, 2004. Children with diabetes were consecutively recruited fro...

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Section: Järvisalo Et Al Arterial Nitrate-mediated Dilatation In Chilmentioning

confidence: 49%

Determinants of Arterial Nitrate-Mediated Dilatation in Children

2004

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“…Nitrate tolerance or tachyphylaxis is characterized by a reduction in the nitrate-induced cyclic GMP-mediated pathway [4]. Proposed mechanisms of tolerance include: (1) depletion of critical sulfhydryl groups [5], (2) desensitization of guanylyl cyclase [6], (3) impaired bioconversion of nitrates leading to diminished NO-release [7], (4) reduced generation of NO from nitrates [8], (5) increased activity of the cyclic GMP phosphodiesterase, which decreases cyclic GMP levels [9] and (6) a free radical hypothesis proposing increased oxidant stress [10,11]. Nitroglycerininduced reactive oxygen species also inhibit the activation of nitroglycerin by thiol oxidation of mitochondrial aldehyde dehydrogenase which might explain why nitroglycerin elicits mitochondrial superoxide formation and nitrate tolerance [12].…”

Section: Introductionmentioning

confidence: 99%

Chronic nitrates blunt the effects of not only nitric oxide but also natriuretic peptides in cardiac myocytes

Tan¹,

Zhang²,

Anyadike³

et al. 2007

Pharmacological Research

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Abstractexposure to nitrates causes tachyphylaxis to nitric oxide (NO), which reduces the effects of the second messenger cyclic GMP. We tested the hypothesis that prolonged exposure to NO would also blunt the effects of natriuretic peptides. Cardiac myocytes were isolated from control (N=7) and chronic nitroglycerin (patched, N=7) rabbits. Patched animals received a transdermal nitroglycerin patch (0.3 mg/hr for 5 days). Myocyte function was determined at baseline, after CNP (C-type natriuretic peptide, 10 −8 and 10 −7 M) or BNP (Brain natriuretic peptide, 10 −8 and 10 −7 M) or SNAP (S-nitroso-N-acetyl-penicilliamine, a NO donor, 10 −6 and 10 −5 M) followed by KT5823 (a cyclic GMP protein kinase inhibitor, 10 −6 M). Soluble and particulate guanylyl cyclase activities were measured in vitro and phosphoprotein analysis was performed. In control animals, CNP 10 −8 M (5.14±0.5%) and 10 −7 M (4.4±0.7%) significantly reduced percentage shortening from baseline (6.1±1.6%). KT5823 restored percentage shortening to 4.9±0.8%. Similar data were obtained with BNP and SNAP. In patched animals, CNP, BNP, SNAP had no significant effects on percentage shortening. The data on maximal rate of shortening and relaxation were consistent with these results. Guanylyl cyclase activities were not different in the control and patched animals. The myocytes from control and patched animals had similar protein phosphorylation patterns. Our data suggested that in addition to NO, the responses to both natriuretic peptides were downregulated after chronic exposure to nitroglycerin, but these effects were not due to changes in either guanylyl cyclase or cyclic GMP protein kinase, suggesting an altered downstream pathway.

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“…In the vascular wall, phosphorylation of VASP at Ser-239 (24) (product denoted P Ser-239 -VASP) is regulated by NO and prostacyclin. Phosphorylation of VASP at Ser-239 is a sensitive monitor of defective vascular NO͞cGMP signaling (25,26), endothelial dysfunction (27,28), and vascular oxidative stress (29).…”

mentioning

confidence: 99%

Reduced cGMP signaling associated with neointimal proliferation and vascular dysfunction in late-stage atherosclerosis

Melichar¹

2004

Proceedings of the National Academy of Sciences

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Atherosclerosis is associated with alterations in nitric oxide (NO)͞ cGMP signaling. In early stages of the disease, inflammatory and possibly other cells produce reactive oxygen species that scavenge vasoprotective NO. In addition to the oxidative stress, expression and activity of enzymes downstream to NO formation may also be affected. Here, we show in the aortas of chronically hypercholesterolemic rabbits (a model of late-stage atherosclerosis), both subunits and specific activity of the NO receptor soluble guanylyl cyclase (sGC) were significantly reduced, whereas overall NO synthase activity was unaffected. These changes were most prominent in the neointimal layer, wherein cGMP-dependent protein kinase I (cGK) levels also were reduced. Additionally, a protein (p38 nt ) that was constitutively tyrosine-nitrated was detected, and its expression was significantly reduced in atherosclerotic aorta. Phosphorylation of the cGK substrate vasodilator-stimulated phosphoprotein (VASP) at Ser-239, an established biochemical endpoint of NO͞cGMP signaling, also was reduced. Thus, late-stage atherosclerosis is associated not only with enhanced NO breakdown but also with altered NO reception and cGMP signaling. Preferential downregulation in neointima suggests a direct connection of these changes to neointimal proliferation and vascular dysfunction and provides a rationale for future pharmacotherapy using classical and novel sGC activators.hypercholesterolemia ͉ soluble guanylyl cyclase ͉ vasodilator-stimulated phosphoprotein ͉ cGMP-dependent protein kinase A therosclerosis is major risk factor to cardiovascular diseases such as coronary heart disease and stroke. The pathophysiology of atherosclerosis is highly complex, multifactorial, and yet to be fully understood (1). A common feature observed is malperfusion of tissues as a result of luminally obstructive atherosclerotic plaques, augmented vascular tone, and reduced sensitivity to endothelium-dependent vasodilators in atherosclerotic arteries from humans (2) and cholesterol-fed animals (3).Nitric oxide (NO) is an important antiatherosclerotic autocoid, which exerts antiproliferative and vasodilatory effect on vasculature and antiaggregatory effect on platelets. Vascular dysfunction in atherosclerosis is partly attributed to reduced tetrahydrobiopterin-dependent (4-7) production or bioavailability of endothelium-derived NO (8), which is supported by the observation of reduced activity and expression of endothelial NO synthase III (NOS-III) (9) in atherosclerotic vessels (10, 11). Additionally, the tissue half-life of NO is further reduced by reactive oxygen species (superoxide, O 2 Ϫ ) that scavenge NO and thereby impair its vasoprotective activity (12). Therefore, formation of O 2 Ϫ , by NADPH oxidase (13, 14) or xanthine oxidase (15) or uncoupled endothelial NOS (16) and͞or its decomposition, by superoxide dismutase (SOD) (17)(18)(19), are thought to play important roles in the pathogenesis of atherosclerosis.Endothelium-derived NO stimulates the production of the se...

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Effects of In Vivo Nitroglycerin Treatment on Activity and Expression of the Guanylyl Cyclase and cGMP-Dependent Protein Kinase and Their Downstream Target Vasodilator-Stimulated Phosphoprotein in Aorta

Cited by 126 publications

References 30 publications

Determinants of Arterial Nitrate-Mediated Dilatation in Children

Determinants of Arterial Nitrate-Mediated Dilatation in Children

Chronic nitrates blunt the effects of not only nitric oxide but also natriuretic peptides in cardiac myocytes

Reduced cGMP signaling associated with neointimal proliferation and vascular dysfunction in late-stage atherosclerosis

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