Long-term treatment in vivo with NOX-101, a scavenger of nitric oxide, prevents diabetes-induced endothelial dysfunction

Pieper, Galen M.; Dembny, Ken; Siebeneich, Wolfgang

doi:10.1007/s001250051055

Cited by 40 publications

(30 citation statements)

References 60 publications

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“…Endothelial dysfunction in OSA is reversible with antioxidants (22)(23)(24), suggesting a role for oxidant overproduction in the decreased NO availability in OSA. This provides parallels to other cardiovascular diseases in which oxidative stress-induced endothelial dysfunction is important (25,26).…”

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confidence: 67%

Endothelial Dysfunction in the Microcirculation of Patients with Obstructive Sleep Apnea

Patt¹,

Jarjoura²,

Haddad³

et al. 2010

Am J Respir Crit Care Med

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Rationale: Obstructive sleep apnea (OSA) is a risk factor for cardiovascular disease. We hypothesized that patients with OSA and no cardiovascular disease have oxidant-related microcirculatory endothelial dysfunction. Objectives: To evaluate the microcirculation in OSA. Methods: This study included seven patients with OSA and seven ageand weight-matched control subjects (mean age, 38 yr; mean body mass index, 32.5 kg/m 2 ). All participants were free of cardiovascular risk factors. Participants received measurement of brachial artery flow-mediated dilation and forearm subcutaneous biopsy. Patients underwent repeated tests 12 weeks after treatment. Microcirculatory endothelial cells were isolated, and immunohistochemistry staining for peroxynitrite in the microcirculation was performed. Measurements and Main Results: Flow-mediated dilation was lower in patients than in control subjects at baseline (mean 6 SEM: 5.7 6 0.5 vs. 9.5 6 0.6; P 5 0.02) and increased after treatment (5.7-7.3; change, 1.7 6 0.6; P 5 0.04). Microcirculatory peroxynitrite deposit was higher in patients compared with control subjects (44.0 6 1.6 vs. 21.8 6 1.9 stain density units; P , 0.001) and decreased after treatment from 44.0 to 30.5 stain density units (change, 213.5 6 2.9; P 5 0.009). In patients, transcription of endothelial nitric oxide synthase decreased from 5.2 to 21.3 after treatment (change, 6.5 6 2.5; P 5 0.05), and transcription of superoxide dismutase1 decreased from 24.0 to 212.3 after treatment (change, 28.3 6 2.1; P 5 0.01). These changes persisted after adjustment for weight and underlying severity of OSA. Conclusions: This is the first direct evaluation of the microcirculation in OSA. Patients with OSA with low cardiovascular risk status had increased oxidant production in the microcirculation and endothelial dysfunction, both of which improved with treatment. Endothelial nitric oxide synthase transcription decreased with treatment.

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mentioning

confidence: 67%

Endothelial Dysfunction in the Microcirculation of Patients with Obstructive Sleep Apnea

Patt¹,

Jarjoura²,

Haddad³

et al. 2010

Am J Respir Crit Care Med

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“…Indeed, in the cardiovascular system, NO scavengers have been shown to protect against endothelial dysfunction during diabetes (47). In the kidney, a NOS inhibitor or treatment with insulin has been shown to prevent development of glomerular hyperfiltration in diabetic animals (48).…”

Section: Discussionmentioning

confidence: 99%

Two Phases of Nitrergic Neuropathy in Streptozotocin-Induced Diabetic Rats

2003

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The distinction between metabolic and structural changes occurring in autonomic neurons during diabetes has not been fully clarified. Here we demonstrate that nitric oxide synthase-containing (nitrergic) neurons innervating the penis and gastric pylorus of streptozotocin-induced diabetic rats undergo a selective degenerative process in two phases. In the first phase, nitrergic nerve fibers lose some of their neuronal nitric oxide synthase content and function. In the second phase, nitrergic degeneration takes place in the cell bodies in the ganglia, leading to complete loss of nitrergic function. The changes in the first phase are reversible with insulin replacement; however, the neurodegeneration in the second phase is irreversible. Neurodegeneration is due to apoptotic cell death in the ganglia, which is selective for the nitrergic neurones. Diabetes 52:2353-2362, 2003 D iabetes is a common disorder that leads to complications affecting the retina, kidney, vascular, gastrointestinal, peripheral, and autonomic nervous systems. The mechanism through which diabetic complications develop is unclear. The generally accepted view for most diabetic complications is that the disease is accompanied by metabolic changes in the affected organ that, in the long term, result in structural alterations. Thus, if insulin replacement is started before the structural lesions occur, then it should reverse the metabolic changes and prevent the development of the complication. Once the structural lesions occur, however, the process should become less reversible with insulin replacement. Although from early studies in vivo "a point of no return" had been suggested during the course of diabetic peripheral neuropathy, cardiomyopathy, and nephropathy (1-3), most of the subsequent work has concentrated either on cellular dysfunction or on cell death without addressing the distinction between metabolic and structural alterations.Nitric oxide (NO) is a well-characterized neurotransmitter in the central and peripheral nervous systems. In many tissues of the urogenital and gastrointestinal tract, NO mediates nonadrenergic noncholinergic (NANC) relaxant responses (4). Nerves that release NO are now known as nitrergic (5). NO is generated in these nerves by activation of the neuronal NO synthase (nNOS) and diffuses into the smooth muscle to activate the soluble guanylyl cyclase (sGC), producing an increase in the intracellular cyclic guanosine-3Ј, 5Ј-monophosphate concentration, leading to relaxation (6).Impaired nitrergic transmission has been shown to be responsible for erectile dysfunction and gastropathy in diabetes (7-12). To investigate the mechanisms by which the metabolic changes lead to structural disturbances in autonomic neuropathy, we studied the structure and function of nitrergic nerve fibers and neuronal cell bodies in the gastric pylorus, penis, and major pelvic ganglia in streptozotocin (STZ)-induced diabetic rats. In addition, we investigated the effect of different schedules of insulin treatment on this process. RESEARCH DE...

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“…There is compelling evidence to suggest that diabetes-associated endothelial dysfunction results, in part, from a paradoxical increase of NO production from iNOS. In fact, studies have demonstrated an improvement in endothelial function in diabetic arteries using NO scavengers and iNOS inhibitors (10,33). A recent study demonstrated that iNOS knock-out mice are resistant to endothelial dysfunction when made diabetic (16).…”

Section: Discussionmentioning

confidence: 99%

Increased expression of iNOS is associated with endothelial dysfunction and impaired pressor responsiveness in streptozotocin-induced diabetes

Nagareddy¹,

Xia²,

McNeill³

et al. 2005

American Journal of Physiology-Heart and Circulatory Physiology

138

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(MABP) and heart rate (HR), endothelial dysfunction, and attenuated pressor responses to vasoactive agents. We investigated whether these abnormalities are due to diabetes-associated activation of inducible nitric oxide synthase (iNOS). In addition, the effect of the duration of diabetes on these abnormalities was also evaluated. Diabetes was induced by administration of 60 mg/kg STZ via the tail vein. One, 3, 9, or 12 wk after STZ injection, MABP, HR, and endothelial function were measured in conscious unrestrained rats. Pressor response curves to bolus doses of methoxamine (MTX) and angiotensin II (ANG II) were constructed in the presence of N- [3(aminomethyl)benzyl]-acetamidine, dihydrochloride (1400W), a specific inhibitor of iNOS. Depressed MABP and HR and impairment of endothelial function were observed as early as 3 wk after induction of diabetes. Acute inhibition of iNOS with 1400W (3 mg/kg iv) restored the attenuated pressor responses to both MTX and ANG II without affecting the basal MABP and HR. Immunohistochemical and Western analysis blot studies in cardiovascular tissues revealed decreased expression of endothelial nitric oxide synthase (eNOS) concomitant with increased expression of iNOS and nitrotyrosine with the progression of diabetes. Our findings suggest that induction of iNOS in cardiovascular tissues is dependent on the duration of diabetes and contributes significantly to the depressed pressor responses to vasoactive agents and potentially to endothelial dysfunction. inducible nitric oxide synthase; nitric oxide; cardiovascular abnormalities CHRONIC HYPERGLYCEMIA has been shown to directly affect the composition and structure of cardiac, vascular, and renal tissues, the progressive modification of which results in a deranged cardiovascular homeostasis (8). Cardiovascular depression, characterized by depressed mean arterial blood pressure (MABP), heart rate (HR), and attenuated pressor responses to vasoactive agents is one of the most notable manifestations of this derangement, particularly in animal models of Type 1 diabetes. Although the exact mechanisms by which diabetes contributes to cardiovascular depression are currently unknown, it is likely that hyperglycemia may initiate this abnormality through the activation of protein kinase C, increased activity of the polyol pathway, formation of nonenzymatic advanced glycosylation end products, oxidative stress, and/or possibly by induction of nitric oxide (NO) synthase (NOS) (19,42).The role of NO in the regulation of hemodynamics under hyperglycemic conditions has been controversial. Despite an impairment of endothelial function and reduced bioavailability of endothelium-derived NO, streptozotocin (STZ)-induced diabetic rats are not hypertensive but instead are normotensive or hypotensive (9,14,18,20,23,31,39,44). In addition, an increased dependence on a functional NO system at the onset of diabetes has been reported to prevent the development of hypertension in STZ diabetic rats (12). It has been suggested that increased NO synthesis m...

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Long-term treatment in vivo with NOX-101, a scavenger of nitric oxide, prevents diabetes-induced endothelial dysfunction

Cited by 40 publications

References 60 publications

Endothelial Dysfunction in the Microcirculation of Patients with Obstructive Sleep Apnea

Endothelial Dysfunction in the Microcirculation of Patients with Obstructive Sleep Apnea

Two Phases of Nitrergic Neuropathy in Streptozotocin-Induced Diabetic Rats

Increased expression of iNOS is associated with endothelial dysfunction and impaired pressor responsiveness in streptozotocin-induced diabetes

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