Endogenous Nitric Oxide Inhibits Human Platelet Adhesion to Vascular Endothelium

Radomski, Marek W.; Palmer, Richard; Moncada, Salvador

doi:10.1016/s0140-6736(87)91481-4

Cited by 1,344 publications

(640 citation statements)

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“…Another important role of NO in the vasculature is its antiatherogenic effects by scavenging superoxide radicals and suppression of platelet aggregation, leukocyte adhesion and smooth muscle cell proliferation [38][39][40]. In this study we assessed IMT as an index of early atherosclerosis.…”

Section: Discussionmentioning

confidence: 99%

Association of - 786T-C mutation of endothelial nitric oxide synthase gene with insulin resistance

et al. 2002

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Aims/hypothesis. Endothelial derived nitric oxide synthase (eNOS) gene polymorphisms affect eNOS activity and are associated with abnormal vasomotility and impaired local blood flow. A decrease in local blood flow has been reported to cause insulin resistance. The aim of this study was to examine a possible association of two eNOS polymorphisms, Glu298Asp (G894T) in exon 7 and -786T-C mutation with insulin resistance. Methods. Genotypes of both Glu298Asp and -786T-C mutation were examined by the PCR-RFLP method. Plasma nitrate and nitrite concentrations were also measured. Results. The allele frequencies of both polymorphisms showed no considerable differences in 233 non-diabetic subjects and 301 patients with Type II (non-insulin-dependent) diabetes mellitus. Non-diabetic subjects with the -786C allele had (p<0.05) higher fasting plasma insulin and homeostasis model assessment of insulin resistance than those with the -786T/ -786T genotype. Diabetic subjects with -786C allele showed higher HbA 1c than those with the -786T/ -786T genotype. A euglycaemic hyperinsulinemic clamp study done on 71 of the 301 patients showed a lower glucose infusion rate in diabetic patients with the -786C allele than those without it. In diabetic patients with the -786C allele, plasma nitrate and nitrite concentrations were lower than in subjects without it (p=0.026). No differences were observed between mutant carriers of Glu298Asp and non-carriers among both nondiabetic subjects and Type II diabetic patients. Conclusions/interpretation. The -786T-C mutation of the eNOS gene is associated with insulin resistance in both Japanese non-diabetic subjects and Type II diabetic patients. [Diabetologia (2002[Diabetologia ( ) 45:1594[Diabetologia ( -1601 Keywords Endothelial nitric oxide synthase, polymorphism, glucose infusion rate, homeostasis model assessment of insulin resistance insulin resistance, intima-media thickness. Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Suita City, Japan a key role in the regulation of vascular tone. Skeletal muscle glucose uptake is enhanced by insulin-mediated vasodilation and the decrease in local blood flow can result in insulin resistance [1][2][3][4][5]. However, several reports deny a major role of endothelial NO production in determining insulin sensitivity [6,7].Recently eNOS knockout mice have been reported to be insulin resistant [8]. These mice have also shown a decrease in whole-body and muscle-glucose uptake as well as the simultaneous decrease in the local blood flow [9]. Two major polymorphisms have been found in the human eNOS gene: Glu298Asp (G894T) in exon 7 and -786T-C mutation in the 5′-flanking region. Glu298Asp causes a structural change of the eNOS Endothelial derived nitric oxide (NO), synthesized from L-arginine by the endothelium isoform of NO synthase (eNOS), mediates local vasodilation and plays

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Section: Discussionmentioning

confidence: 99%

Association of - 786T-C mutation of endothelial nitric oxide synthase gene with insulin resistance

et al. 2002

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“…Superoxide radicals react rapidly with nitric oxide to form deleterious peroxynitrite [39,40], which may for example initiate peroxidation of LDL [41]. This reaction also reduces potential physiological protective effects of nitric oxide, such as platelet inhibition [42], deactivation of leukocytes [43], vasodilatation [44,45], and termination of lipid peroxidation [46]. Moreover, superoxide radicals can by formed by endothelial cells [47], smooth muscle cells [37] and leukocytes participating in the inflammatory component of the atherosclerotic process [48].…”

Section: Discussionmentioning

confidence: 99%

Two variants of extracellular‐superoxide dismutase: relationship to cardiovascular risk factors in an unselected middle‐aged population

Nilsson

Israelsson

et al. 1997

Journal of Internal Medicine

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Abstract. Marklund SL, Nilsson P, Israelsson K, Schampi I, Peltonen M, Asplund K (University Hospital, Umeå, Sweden). Two variants of extracellular-superoxide dismutase: relationship to cardiovascular risk factors in an unselected middle-aged population. J Intern Med 1997; 242: 5-14.Objective. Description of the distribution of plasma levels of two variants of extracellular-superoxide dismutase (EC-SOD) and their relationship to cardiovascular risk factors in the general population. Design. A cross-sectional study. Setting. Norrbotten and Västerbotten counties in northern Sweden. Subjects. Four thousand, nine hundred 25-74-yearold randomly selected subjects. Main outcome measures. Plasma levels of EC-SOD.Genotyping by an allele-specific PCR method. Results. Plasma EC-SOD levels showed a distinct bimodal distribution with the smaller group (3.8%) having a variant of the enzyme with about eight-fold-higher plasma levels. Genotyping was performed in 65 individuals with the high-level variant. All but one were found to carry the same mutation, Arg213Gly, affecting the heparin-binding domain of EC-SOD. Subjects with the high-level variant of EC-SOD had modestly higher body mass index and higher levels of serum cholesterol, serum triglycerides and plasma fibrinogen than those with the common EC-SOD phenotype. Within the population with common EC-SOD, the plasma levels were lower in men than in women and increased with age. Low levels of common phenotype EC-SOD were associated with smoking, high plasma levels of fibrinogen and low activity of tissue plasminogen activator in both univariate and multivariate analyses. Obesity and total serum cholesterol were associated with high common phenotype EC-SOD levels. Conclusions. A high-level variant of EC-SOD caused by one and the same mutation and with low tissue binding and high plasma levels is present in approximately four per cent of an unselected middle-aged population in northern Sweden. Plasma levels of EC-SOD may be modulated by lifestyle factors such as smoking and show a complex covariation with many of the conventional cardiovascular risk factors.

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“…Hydrogen peroxide was purchased from J.T. Baker (Deventer, Holland); [2,3,4,5] The macrophage cell line, NR8383 was kindly provided by R.J. Helmke, (Dept of Pediatrics, University of Texas Health Science Center, San Antonio, Texas, USA). Klebsiella Pneumoniae were a kind gift from J. van Amsterdam (Rijksinstituut voor Volksgezondheid en Milieu, Bilthoven, the Netherlands).…”

Section: Chemicalsmentioning

confidence: 99%

“…Nitric oxide (NO) is a free radical that is known to have an important function as mediator in several biological processes amongst which, vasorelaxation [1,2], cellmediated immune responses [3,4], inhibition of platelet aggregation [5] and neurotransmission [6] are extensively investigated. The formation of NO has been described in many mammalian cell types and can be ascribed to three isoforms of nitric oxide synthase (NOS), all of which oxidize L-arginine to L-citrulline.…”

mentioning

confidence: 99%

Inhibition of nitric oxide synthase by nasal decongestants

Westerveld¹,

Voss²,

Hee³

et al. 2000

Eur Respir J

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The nasal decongestants oxymetazoline and xylometazoline are frequently used in the topical treatment of rhinitis and sinusitis. As nitric oxide (NO) is thought to play a role in inflammation of the upper respiratory tract, the aim of this study was to examine the in vitro effects of these compounds on the activity and the expression of NO producing enzymes, including the inducible form of NO synthase (iNOS) and the constitutive isoform of NO synthase (cNOS).Experiments concerning the effects of both compounds on enzymatic activity and enzyme induction of iNOS were performed in a lipopolysaccharide (LPS) induced rat alveolar macrophage cell line (NR8383) using the Griess assay and the 3 H-citrulline assay respectively. The effects on cNOS were examined in fresh rat synaptosomes using the 3 H-citrulline assay. The direct scavenging properties of both compounds were investigated using a amperometric NO sensor.Oxymetazoline and xylometazoline were shown to have a dose dependent inhibitory effect on total iNOS activity indicated by nitrite/nitrate formation in the Griess assay. This effect was found to be due to an inhibition of induction of the enzyme rather than inhibition of the enzyme activity, as was investigated in two separate experiments using the 3 H-citrulline assay. Inhibition of cNOS was moderate and in the same order of magnitude as the inhibition of enzymatic iNOS activity. Direct scavenging of NO could not be detected.As constitutive nitric oxide synthase activity is thought to serve beneficial physiological functions, and exaggerated inducible nitric oxide synthase activity may cause exacerbation of the inflammatory process, pharmacological treatment influencing the nitric oxide generating system should focus on inhibition of inducible nitric oxide synthase alone. The specific characteristics of these decongestants in vitro suggests suitability for this application and may indicate an additional beneficial effect in the treatment of upper respiratory tract inflammation. Eur Respir J 2000; 16: 437±444.

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Endogenous Nitric Oxide Inhibits Human Platelet Adhesion to Vascular Endothelium

Cited by 1,344 publications

References 9 publications

Association of - 786T-C mutation of endothelial nitric oxide synthase gene with insulin resistance

Association of - 786T-C mutation of endothelial nitric oxide synthase gene with insulin resistance

Two variants of extracellular‐superoxide dismutase: relationship to cardiovascular risk factors in an unselected middle‐aged population

Inhibition of nitric oxide synthase by nasal decongestants

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