Vascular protective actions of a nitric oxide aspirin analog in both in vitro and in vivo models of diabetes mellitus

Pieper, Galen M.; Siebeneich, Wolfgang; Olds, Cara; Felix, Christopher C.; Soldato, Piero Del

doi:10.1016/s0891-5849(02)00832-8

Cited by 34 publications

(25 citation statements)

References 66 publications

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Section: Discussionmentioning

confidence: 99%

“…17,27 However, other studies reported that aspirin could not enhance NO availability in endothelial cells or prevent endothelial dysfunction. 12,28,29 Therefore, it has remained unclear whether aspirin has beneficial effects on endothelial function, particularly cerebrovascular function.The current study showed that cilostazol could maintain eNOS phosphorylation and reduce infarct size in SHR. Dipyridamole, a phosphodiesterase-5 inhibitor, has been shown to decrease the cerebral infarct size, and the combination of subtherapeutic doses of statin and dipyridamole increased eNOS activity and cerebral blood flow and reduced infarct volume.…”

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confidence: 99%

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Cilostazol, Not Aspirin, Reduces Ischemic Brain Injury via Endothelial Protection in Spontaneously Hypertensive Rats

Oyama

Yagita

Kawamura

et al. 2011

Stroke

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Background and Purpose-It is well-established that hypertension leads to endothelial dysfunction in the cerebral artery.Recently, cilostazol has been used for the secondary prevention of ischemic stroke. Among antiplatelet drugs, phosphodiesterase inhibitors including cilostazol have been shown to have protective effects on endothelial cells. The aim of the present study is to investigate the effects of cilostazol and aspirin on endothelial nitric oxide synthase (eNOS) phosphorylation in the cerebral cortex, endothelial function, and infarct size after brain ischemia in spontaneously hypertensive rats (SHR). Methods-Five-week-old male SHR received a 5-week regimen of chow containing 0.1% aspirin, 0.1% cilostazol, 0.3% cilostazol, or the vehicle control. The levels of total and Ser 1177 -phosphorylated eNOS protein in the cerebral cortex were evaluated by Western blot. To assess the contribution of eNOS in maintaining cerebral blood flow, we monitored cerebral blood flow by laser-Doppler flowmetry after L-N 5 -(1-iminoethyl)ornithine infusion. Additionally, we evaluated residual microperfusion using fluorescence-labeled serum protein and infarct size after transient focal brain ischemia. Results-In SHR, the blood pressure and heart rate were similar among the groups. Cilostazol-treated SHR had a significantly higher ratio of phospho-eNOS/total eNOS protein than vehicle-treated and aspirin-treated SHR. Treating with cilostazol, but not aspirin, significantly improved cerebral blood flow response to L-N 5 -(1-iminoethyl)ornithine. Cilostazol also increased residual perfusion of the microcirculation and reduced brain damage after ischemia compared to vehicle control and aspirin. Conclusions-These findings indicate that cilostazol, but not aspirin, can attenuate ischemic brain injury by maintaining endothelial function in the cerebral cortex of SHR. (Stroke. 2011;42:2571-2577.)Key Words: brain ischemia Ⅲ endothelial function Ⅲ hypertension Ⅲ phosphodiesterase-3 inhibitor H ypertension is one of the most important risk factors for cerebrovascular disease and is closely associated with endothelial dysfunction. Some studies observed endothelial dysfunction in patients with hypertension or cerebrovascular disease. 1,2 In hypertensive animal models, hypertension impairs endothelium-dependent vasodilatation, cerebrovascular autoregulation, and cerebral blood flow (CBF) responses, and it exacerbates ischemic brain damage. [3][4][5][6] Endothelial dysfunction is often characterized by a decrease in the bioavailability of endothelium-derived nitric oxide (NO). In endothelial cells, NO is produced by endothelial nitric oxide synthase (eNOS), and eNOS activity is regulated primarily by calcium-calmodulin activation and multisite phosphorylation of specific serine or threonine residues. Most importantly, phosphorylation of eNOS-Ser 1177 is thought to play a crucial role in eNOS activation. In a cerebral ischemia model, modification of the eNOS-Ser 1177 phosphorylation state modulated CBF and the outcome of ischemic injury. 7 Th...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Cilostazol, Not Aspirin, Reduces Ischemic Brain Injury via Endothelial Protection in Spontaneously Hypertensive Rats

Oyama

Yagita

Kawamura

et al. 2011

Stroke

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“…Pieper et al (30) showed that this NO-aspirin derivative caused a significant reduction of plasma isoprostanes in diabetic animals that is negatively linked to NO synthesis and ROS formation. Napoli et al (26) showed that chronic treatment with NCX-4016 reduced oxidative stress in hypercholesterolemic mice.…”

Section: Discussionmentioning

confidence: 99%

Antioxidant activity of nitro derivative of aspirin against ischemia-reperfusion in hamster cheek pouch microcirculation

Bertuglia¹,

Giusti²,

Soldato³

2004

American Journal of Physiology-Gastrointestinal and Liver Physi

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oxidant activity of nitro derivative of aspirin against ischemia-reperfusion in hamster cheek pouch microcirculation. Am J Physiol Gastrointest Liver Physiol 286: G437-G443, 2004. First published October 16, 2003 10.1152/ajpgi.00339.2003.-Aspirin that has been chemically combined with a nitric oxide (NO) donor (NCX-4016) has been shown to inhibit cyclooxygenase and prostaglandin generation while maintaining the inhibitory effects of aspirin. The possible role of reactive oxygen species (ROS) in the action of NCX-4016 in ischemia-reperfusion (I/R) has not been studied. Furthermore, we were interested in comparing the effects of a conventional NO donor [2,2Ј-hydroxynitrosohydrazino-bis-etanamine (DETA/NO)] and NCX-4016 at the microvascular level in the hamster cheek pouch visualized by using an intravital fluorescent microscopy technique. Microvascular injury was assessed by measuring diameter change, the perfused capillary length (PCL), and leukocyte adhesion. Animals were treated with NCX-4016 (100 mg/kg or 30 mg⅐kg Ϫ1 ⅐day Ϫ1 for 5 days po) or DETA-NO (0.5 mg/kg). Mean arterial blood pressure increased slightly but significantly after NCX-4016 treatment. During 5-and 15-min reperfusion, lipid peroxides in the systemic blood increased by 72 and 89% vs. baseline, respectively, and were still higher than in basal conditions after 30-min reperfusion in the I/R group. Pretreatment with NCX-4016 maintained ROS at normal levels; increased arteriolar diameter, blood flow, and PCL; and decreased leukocyte adhesion (P Ͻ 0.05). DETA-NO decreased ROS during 30-min reperfusion; however, later there was a significant increase during reperfusion. DETA-NO decreased leukocyte adhesion (P Ͻ 0.05) but microvascular permeability increased after 30 min of reperfusion. In conclusion, NCX-4016 attenuates oxidative stress and prevents arteriolar constriction during I/R, whereas DETA-NO increases lipid peroxides in the systemic blood and permeability after reperfusion. oxidative stress; nitric oxide-aspirin; microcirculation; lipid peroxides RECENTLY, A NEW CLASS of anti-inflammatory drugs has been developed by adding nitric oxide (NO) moiety to aspirin . NO released from these compounds has been shown to suppress prostanoid synthesis and to inhibit pathogenetic events during endotoxic shock (22,27,38,39). NCX-4016 has a more pronounced anti-thrombotic activity than aspirin (25, 37) as shown by the fact that it protected mice from pulmonary embolism, whereas in rabbits it reduced platelet accumulation induced by thrombin in the pulmonary vasculature (22, 32). NCX-4016 reduced infarct size and suppressed arrhythmias after myocardial ischemia-reperfusion (I/R) in pigs (38) and rats (40). NCX-4016, but not aspirin alone, was found to reduce brain damage induced by focal cerebral ischemia in spontaneously hypertensive rats (11).On restoration of blood flow during I/R, the production of reactive oxygen species (ROS) increases and is strongly implicated in microvascular dysfunction in experimental conditions, as well as in patients with acu...

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“…NCX 4016, an NO-releasing aspirin derivative initially designed to overcome the side effects of nonsteroidal anti-inflammatory drugs on the gastrointestinal mucosa, proved to exert greater cardiovascular protection than the parent compound, apparently caused by improved antithrombotic and anti-inflammatory activity. [11][12][13][14][15][16][17][18] We considered the possibility that NCX 4016, besides providing a better way to prevent thrombotic events, could also ameliorate the reparative angiogenesis response that naturally occurs after arterial occlusion. Here, we document for the first time that NCX 4016 accelerates the rate of hemodynamic recovery of ischemic limbs.…”

Section: Discussionmentioning

confidence: 99%

“…[11][12][13] The compound also exerts greater protective effects than aspirin in focal cerebral ischemia, 14 myocardial infarction, 15 arterial restenosis, 16 and diabetes-induced endothelial dysfunction. 17 The vasoprotective action of NCX 4016 extends beyond thrombosis to include local vasodilation, 18 reduction of oxidative stress, 19 and inflammation 20 (via inhibition of cytokine release and downregulation of iNOS and tissue factor expression), 21,22 and modulation of vascular cell proliferation and survival. 20,23 The present study was conducted in a murine model of unilateral limb ischemia to explore the therapeutic potential of NCX 4016 on reparative angiogenesis.…”

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confidence: 99%

Nitric Oxide–Releasing Aspirin Derivative, NCX 4016, Promotes Reparative Angiogenesis and Prevents Apoptosis and Oxidative Stress in a Mouse Model of Peripheral Ischemia

Emanueli

Linthout

Salis

et al. 2004

ATVB

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Background-Recently, nitric oxide (NO) donors have been developed that mimic the physiological intracellular release of NO. We evaluated whether one of these new compounds, consisting of aspirin coupled to an NO-releasing moiety (NCX 4016), would protect limbs from supervening arterial occlusion. Methods and Results-Mice were assigned to receive regular chow or chow containing NCX 4016 or aspirin (both at 300 mol/kg body weight, daily) throughout the 3-week experimental period. One week after randomization, they underwent surgical excision of the left femoral artery. Key Words: angiogenesis Ⅲ ischemia Ⅲ peripheral vascular disease Ⅲ apoptosis Ⅲ endothelial cell A ngiogenesis is essential for the repair of wounds and tissues damaged by ischemia. The regenerative process is tightly regulated by master angiogenic factors, cytokines, and the downstream mediator nitric oxide (NO). 1,2 In addition, modulators of vascular growth, such as COX-2-generated prostanoids, contribute to the process by stabilizing the hypoxia-inducible factor 3 and by stimulating the expression of vascular endothelial growth factor (VEGF). 4 The physiological overlapping of NO and prostaglandins implies that they can compensate reciprocally in maintaining vascular endothelium integrity. Conversely, postischemic healing could be severely compromised under conditions in which both systems are functionally impaired. 5,6 For instance, elderly patients taking nonsteroidal anti-inflammatory drugs may fail to mount an efficient reparative angiogenesis because of the concomitant aging-related loss of NO biologic activity and/or biosynthesis. In a therapeutic perspective, delivery of NO could represent a way for counterbalancing the endogenous deficit and simultaneously surrogate the lack of angiogenic prostaglandins.Among the many attempts made to improve the profile of nonsteroidal anti-inflammatory drugs, the approach based on grafting an NO-releasing moiety has provided results of therapeutic interest. 7,8 A modified version of aspirin that releases NO surpasses its parent compound in terms of improved cardiovascular protection and reduced gastrointestinal side effects (see Wallace and Del Soldato for review). 7 NCX 4016, 2-(acetyloxy)benzoic acid 3-(nitrooxymethyl)phenyl ester, consists of acetylsalicylic acid, to which a nitrate group has been covalently linked through a spacer. In contrast to conventional 19 and inflammation 20 (via inhibition of cytokine release and downregulation of iNOS and tissue factor expression), 21,22 and modulation of vascular cell proliferation and survival. 20,23 The present study was conducted in a murine model of unilateral limb ischemia to explore the therapeutic potential of NCX 4016 on reparative angiogenesis. Results indicate that NO-releasing aspirin improves vascular regeneration, prevents endothelial apoptosis, and reduces oxidative stress. Thus, this new drug may have clinical value for the treatment of peripheral vascular disease. MethodsAll procedures complied with the standards stated in the Guide for t...

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Vascular protective actions of a nitric oxide aspirin analog in both in vitro and in vivo models of diabetes mellitus

Cited by 34 publications

References 66 publications

Cilostazol, Not Aspirin, Reduces Ischemic Brain Injury via Endothelial Protection in Spontaneously Hypertensive Rats

Cilostazol, Not Aspirin, Reduces Ischemic Brain Injury via Endothelial Protection in Spontaneously Hypertensive Rats

Antioxidant activity of nitro derivative of aspirin against ischemia-reperfusion in hamster cheek pouch microcirculation

Nitric Oxide–Releasing Aspirin Derivative, NCX 4016, Promotes Reparative Angiogenesis and Prevents Apoptosis and Oxidative Stress in a Mouse Model of Peripheral Ischemia

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