Decreased nitric oxide synthase activity in platelets from IDDM and NIDDM patients

Rabini, R. A.; Staffolani, R.; Fumelli, P.; Mutus, Bülent; Curatola, G; Mazzanti, Laura

doi:10.1007/s001250050873

Cited by 69 publications

(46 citation statements)

References 18 publications

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“…In agreement with previous studies [11,12], we found that basal NOS activity in platelets from Type 2 diabetic patients was lower than in control subjects. The stimulation of βAR and increased cyclic AMP did not change NOS activity in comparison with basal in platelets from Type 2 diabetic patients.…”

Section: Discussionsupporting

confidence: 93%

“…A significant inverse correlation between HbA 1c values and basal platelet NOS activity has been found in Type 1 and Type 2 diabetic patients [12]. However, a similar study [11] failed to find any such correlation, while another study [10] reported no correlation between basal cyclic GMP and glycaemic control in people with Type 1 diabetes.…”

Section: Discussionmentioning

confidence: 95%

“…Re-cently we reported that the stimulation of β-adrenoceptors (βAR) through an increase of cyclic AMP generates NO in human platelets and that this plays a role in regulating platelet adhesion to vascular endothelium [6]. Impairment of the L-arginine/NO pathway in endothelium and/or platelets is common in many cardiovascular disorders, including diabetes mellitus [7,8,9,10,11,12]. It is, however, uncertain whether such impairment plays a central role in, or occurs as a result of vascular disease in these conditions.…”

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confidence: 99%

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Nitric oxide generation mediated by ?-adrenoceptors is impaired in platelets from patients with Type 2 diabetes mellitus

Queen

Goubareva

et al. 2003

Diabetologia

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Aims/hypothesis. Type 2 diabetic patients have been shown to have reduced basal platelet nitric oxide synthase activity, which is a possible contributor to the vascular complications seen in the disease. We investigated platelet nitric oxide generation stimulated by β-adrenoceptors and adenylyl cyclase in Type 2 diabetic patients and control subjects. Methods. Platelets isolated from blood taken from nine Type 2 diabetic patients and nine healthy control subjects of similar age were treated with isoproterenol 1 µmol/l, forskolin 1 µmol/l or vehicle. Platelet nitric oxide synthase activity was measured by L-[ 3 H]-arginine to L-[ 3 H]-citrulline conversion, cyclic GMP content by radioimmunoassay, and nitric oxide synthase type 3 expression by western blotting. Results. Basal platelet nitric oxide synthase activity was lower in diabetic patients than in control subjects (0.01±0.02 pmol L-citrulline/10 8 platelets, compared with 0.12±0.05; p<0.05), although no corresponding difference was seen in basal platelet cyclic GMP (0.61±0.39 and 0.13±0.22 pmol cyclic GMP/10 8 platelets respectively; p=0.37). In control subjects isoproterenol 1 µmol/l and forskolin 1 µmol/l increased platelet nitric oxide synthase activity (to 0.27±0.08 and 0.27±0.07 pmol L-citrulline/10 8 platelets respectively; p<0.05 for each in comparison with basal) and cyclic GMP (to 1.84±0.41 and 1.86±0.48; p<0.05 for each in comparison with basal). This effect was not achieved in diabetic patients. Isoproterenol-and forskolin-stimulated cyclic GMP correlated inversely with plasma glucose and HbA 1c . Platelet nitric oxide synthase type 3 expression was not different in control and diabetic subjects and was not changed by acute exposure of platelets to isoproterenol. Conclusions/interpretation. Nitric oxide generation stimulated by β-adrenoceptors and adenylyl cyclase is impaired in platelets of people with Type 2 diabetes mellitus, with no corresponding change in nitric oxide synthase type 3 expression. It is possible that this impairment contributes to the thrombotic and atherosclerotic complications of Type 2 diabetes. [Diabetologia (2003[Diabetologia ( ) 46:1474[Diabetologia ( -1482

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 95%

mentioning

confidence: 99%

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Nitric oxide generation mediated by ?-adrenoceptors is impaired in platelets from patients with Type 2 diabetes mellitus

Queen

Goubareva

et al. 2003

Diabetologia

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“…A previous work by our group described a decreased NO production in platelets from Type I and Type II diabetic patients, possibly related to the higher sensitivity of these cells to aggregating stimuli [16]. Moreover, a further mechanism causing platelet dysfunction in diabetes related to NO synthesis might be an imbalance between NO and superoxide production, leading to the formation of the powerful oxidant peroxynitrite.…”

Section: Discussionmentioning

confidence: 85%

Evidence for iNOS-dependent peroxynitrite production in diabetic platelets

et al. 1999

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Nitric oxide (NO), an important mediator of both physiological and pathological processes [1], is derived from l-arginine by a family of enzymes termed NO synthases [2]. At least three isoforms of NO synthase (NOS) have been detected. Of these, endothelial (eNOS) and neuronal (nNOS) enzymes are constitutive and regulated by Ca 2+ /calmodulin. The inducible NOS (iNOS) originally detected in macrophages and in the endothelium is produced in response to cytokines and cellular debris of microbial origin. This inducible form can produce 10-to 50-fold more NO than the constitutive NOS. In addition, Diabetologia (1999) Abstract Aims/hypothesis. The aim of the present study was twofold. Firstly, to determine whether diabetic platelets produce more peroxynitrite than normal platelets and secondly to correlate the peroxynitrite production with the intraplatelet induction of the inducible isoform of nitric oxide-synthase. Methods. Intraplatelet peroxynitrite production was monitored with dichlorofluorescin acetate with a combination of confocal microscopy and steady-state fluorescence. The platelets were probed for the induction of the inducible-nitric oxide-synthase by western immunoblotting.Results. In the presence of extracellular l-arginine (100 mmol/l), platelets from subjects with Type I (insulin-dependent) diabetes displayed about 5 times higher fluorescence than those from control subjects. To determine whether inducible-nitric oxide-synthase was the source of peroxynitrite, dichlorofluorescein production was quantified as a function of larginine as well as nitric oxide-synthase inhibitors, in platelets from control subjects, subjects with Type I diabetes and subjects with Type II (non-insulin-dependent) diabetes mellitus. Platelets from subjects with Type I yielded about sevenfold and those from Type II about threefold larger amounts of l-arginine/nitric oxide-synthase-dependent dichlorofluorescein fluorescence than those from control subjects. The platelets were then immunologically probed for inducible-nitric oxide-synthase, which has previously been implicated in peroxynitrite production and detected in megakaryocytes of subjects with coronary heart disease. Western immunoblots of intraplatelet proteins indicated that the inducible-nitric oxide-synthase was absent in control subjects. Platelets from both Type I and Type II diabetic subjects, however, contained inducible-nitric oxide-synthase. Conclusion/interpretation. Inducible-nitric oxide-synthase-derived peroxynitrite is a source of platelet damage in diabetes. [Diabetologia (1999) 42: 539± 544]

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“…T he endothelial dysfunction observed in the insulin-resistant states of obesity and type 2 diabetes has been attributed to decreased nitric oxide (NO) availability (1,2), likely related to both impaired production and increased consumption (3,4). However, paracrine control of vascular tone depends on the balance of both vasodilating and vasoconstricting factors (5).…”

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confidence: 99%

Endothelin Contributes to Basal Vascular Tone and Endothelial Dysfunction in Human Obesity and Type 2 Diabetes

et al. 2002

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Endothelium-dependent vasodilation is impaired in clinical states of insulin resistance such as obesity and type 2 diabetes. Individuals who have hyperinsulinemic insulin resistance have relatively elevated circulating levels of endothelin (ET)-1, suggesting that ET-1 may be important in the endothelial dysfunction and alterations of vascular tone in these conditions. In 8 lean subjects, 12 nondiabetic obese subjects, and 8 subjects with type 2 diabetes, we measured basal and methacholine-stimulated rates of leg blood flow (LBF) and total serum nitrates (NOx) before and after the intrafemoral arterial administration of BQ123, a specific blocker of ET A receptors. BQ123 produced significant vasodilation in the obese and type 2 diabetic subjects (leg vascular resistance ‫؍‬ mean arterial pressure/LBF fell by 34 and 36%; P < 0.005) but not in the lean subjects (13%; P ‫؍‬ NS, P ‫؍‬ 0.018 comparing all groups). ET A blockade did not change basal NOx flux (NOx*LBF). This suggests increased basal ET-1 constrictor tone among obese and type 2 diabetic subjects. BQ123 corrected the baseline defect in endothelium-dependent vasodilation seen in obese and type 2 diabetic subjects, suggesting an important contribution of ET-1 to endothelial dysfunction in these subjects. In contrast to basal conditions, stimulated NOx flux was augmented by BQ123 in obese and type 2 diabetic subjects but not in L subjects (P ‫؍‬ 0.04), suggesting a combined effect of ET A blockade to reduce constrictor tone and augment dilator tone. Endothelin seems to contribute to endothelial dysfunction and the regulation of vascular tone in human obesity and type 2 diabetes. Diabetes 51: [3517][3518][3519][3520][3521][3522][3523] 2002 T he endothelial dysfunction observed in the insulin-resistant states of obesity and type 2 diabetes has been attributed to decreased nitric oxide (NO) availability (1,2), likely related to both impaired production and increased consumption (3,4). However, paracrine control of vascular tone depends on the balance of both vasodilating and vasoconstricting factors (5). Endothelin (ET)-1, produced directly by vascular endothelial cells, is the most important locally produced vasoconstrictor, acting principally through type A (ET A ) receptors on vascular smooth muscle cells (6). ET-1 and NO function as mutual antagonists in the determination of vascular tone but also have important direct interactions at the level of transcription and expression (7) and signal transduction (8), with each acting to limit the net production of the other. This mutual antagonism can serve to amplify any imbalances resulting from other factors, for example insulin resistance/hyperinsulinemia. Furthermore, both ET-1 and NO have effects beyond their contributions to the regulation of vascular tone, which act in net as antiatherosclerotic (NO) or proatherosclerotic (ET-1) factors through modulation of platelet activity, lipid oxidation, leukocyte chemotaxis, and local production of thrombotic factors as well as the growth and proliferation of vascul...

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Decreased nitric oxide synthase activity in platelets from IDDM and NIDDM patients

Cited by 69 publications

References 18 publications

Nitric oxide generation mediated by ?-adrenoceptors is impaired in platelets from patients with Type 2 diabetes mellitus

Nitric oxide generation mediated by ?-adrenoceptors is impaired in platelets from patients with Type 2 diabetes mellitus

Evidence for iNOS-dependent peroxynitrite production in diabetic platelets

Endothelin Contributes to Basal Vascular Tone and Endothelial Dysfunction in Human Obesity and Type 2 Diabetes

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