Inhibition of thrombosis by a novel platelet selective S-nitrosothiol compound without hemodynamic side effects

Vilahur, Gemma; Baldellou, María Isabel; Segales, E.; Salas, Eduardo; Badimon, Lina

doi:10.1016/j.cardiores.2003.11.034

Cited by 28 publications

(18 citation statements)

References 32 publications

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“…Furthermore, in a pig model, Vilahur et al could show that low doses of S-nitroso glutathione (GS-NO), slowly administered, significantly reduced blood pressure. 45 In accordance with our observations, in both studies, heart rates were not significantly affected, neither by an NO nor low-dose RS-NO injection. In this context, it should be noted that the systemic response of the vascular system depends on whether the given dose is administrated by bolus injection or gradually with slow infusion.…”

Section: Discussionsupporting

confidence: 92%

Whole Body UVA Irradiation Lowers Systemic Blood Pressure by Release of Nitric Oxide From Intracutaneous Photolabile Nitric Oxide Derivates

Opländer

Volkmar

Paunel-Görgülü

et al. 2009

Circulation Research

151

133

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Rationale: Human skin contains photolabile nitric oxide derivates like nitrite and S-nitroso thiols, which after UVA irradiation, decompose and lead to the formation of vasoactive NO. Objective: Here, we investigated whether whole body UVA irradiation influences the blood pressure of healthy volunteers because of cutaneous nonenzymatic NO formation. Methods and Results: As detected by chemoluminescence detection or by electron paramagnetic resonance spectroscopy in vitro with human skin specimens, UVA illumination (25 J/cm 2 ) significantly increased the intradermal levels of free NO. In addition, UVA enhanced dermal S-nitrosothiols 2.3-fold, and the subfraction of dermal S-nitrosoalbumin 2.9-fold. In vivo, in healthy volunteers creamed with a skin cream containing isotopically labeled 15 N-nitrite, whole body UVA irradiation (20 J/cm 2 ) induced significant levels of 15 N-labeled S-nitrosothiols in the blood plasma of light exposed subjects, as detected by cavity leak out spectroscopy. Furthermore, whole body UVA irradiation caused a rapid, significant decrease, lasting up to 60 minutes, in systolic and diastolic blood pressure of healthy volunteers by 11؎2% at 30 minutes after UVA exposure. The decrease in blood pressure strongly correlated (R

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Section: Discussionsupporting

confidence: 92%

Whole Body UVA Irradiation Lowers Systemic Blood Pressure by Release of Nitric Oxide From Intracutaneous Photolabile Nitric Oxide Derivates

Opländer

Volkmar

Paunel-Görgülü

et al. 2009

Circulation Research

151

133

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“…RhoA is a small guanosine triphosphatase involved in many cell functions, including cell-shape changes. 32 In accordance with our previous report, 24 NO donation with nitrosothiols decreased RhoA expression in its active form (membrane), confirming that NO regulates RhoA activation, subsequent cytoskeleton organization, and GPIIb/IIIa activation. Experimental studies are needed to further characterize the effects of LA816 on RhoA activity and the tissue factor pathway because our results suggest that the effects of LA816 on these signal pathways could partly explain its pharmacological activity.…”

Section: Discussionsupporting

confidence: 76%

“…11 In a previous study 24 we observed that GSNO given in equimolar doses caused a significant reduction in mean arterial pressure of 14 mm Hg (Ϸ30% reduction versus basal value) throughout the perfusion period. In contrast, LA816 intravenous treatment did not cause any significant variation in blood pressure throughout the experiment, indicating no concomitant negative hemodynamic effect.…”

Section: Discussionmentioning

confidence: 99%

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Effects of a Novel Platelet Nitric Oxide Donor (LA816), Aspirin, Clopidogrel, and Combined Therapy in Inhibiting Flow- and Lesion-Dependent Thrombosis in the Porcine Ex Vivo Model

et al. 2004

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Background-Acetylsalicylic acid (ASA), or aspirin, plus clopidogrel is becoming the standard antithrombotic treatment in people with coronary disease. Novel approaches such as the use of platelet-selective nitric oxide (NO) donors may provide additional protection against thrombosis. We evaluated the antithrombotic properties of a novel plateletselective NO donor (LA816) administered alone and in combination with ASA, clopidogrel, or ASAϩclopidogrel. Methods and Results-Thrombogenicity was measured in the porcine experimental model and assessed as plateletthrombus formation in the ex vivo Badimon perfusion chamber. Pigs were randomly divided into 4 groups: (1) placebo control, (2) clopidogrel, (3) ASA, and (4) ASAϩclopidogrel (ASA and clopidogrel were given orally, 10 mg · kgThe animals were anesthetized, heparinized, and catheterized, and the Badimon perfusion chamber was placed in an extracorporeal shunt. After baseline perfusions, all animal groups received the intravenous infusion of LA816 for 2 hours. Platelet aggregation, blood pressure, and heart rate also were evaluated during the experiments. LA816, clopidogrel, and ASAϩclopidogrel produced a reduction of Ϸ45% on thrombus mass versus placebo control perfusions (PϽ0.05). Combined treatment of oral ASAϩclopidogrel and intravenous LA816 produced a significant further reduction of 25% in platelet deposition (70% from placebo controls; PϽ0.0001). LA816 intravenous treatment did not modify blood pressure or heart rate. Conclusions-Acute NO donation with LA816, without modifying hemodynamic parameters, provides the same inhibitory effect as that obtained with chronic treatment with clopidogrelϩASA. Moreover, LA816 provides platelet inhibitory effects in addition to those of the combined blockade of cyclooxygenase and P2y(12) receptor.

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“…One of the earliest systems was one designed by Badimon et al [251]. Their system could generate physiologic arterial levels of shear stress and shear rate and was used to assess thrombogenicity related endpoints [251][252][253][254][255]. Other systems have been reported which were designed without the ability to accurately simulate the higher frequency content of the physiologic arterial pressure or flowrate waveforms.…”

Section: The Concept Of Ex Vivo Perfusion Was Originally Investigatedmentioning

confidence: 99%

In Situ Bioengineering of Arterial Vein Grafts

El-Kurdi

Morelli

Hong

et al. 2008

ASME 2008 Summer Bioengineering Conference, Parts a and B

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The autogenous saphenous vein remains the graft of choice for both coronary (500,000 annually in the US) and peripheral (80,000 annually) arterial bypass procedures. Failure of arterial vein grafts (AVGs) remains a major problem, and patients with failed grafts will die or require reoperation. Intimal hyperplasia (IH) accounts for 20% to 40% of all AVG failures. It is believed that this adverse pathological response by AVGs is largely due to their abrupt exposure to the significantly elevated circumferential wall stress (CWS) associated with the arterial system. We believe that if an AVG is given an ample opportunity to adapt and remodel to the stresses of its new environment, cellular injury may be reduced, thus limiting the initiating mechanisms of IH.The goal of this work was to develop a new mechanical conditioning paradigm, in the form of a peri-adventitially placed, biodegradable polymer wrap, to safely and functionally "arterialize" AVGs in situ. The polymer wrap was tuned so that as it degraded over a desired period of time, the mechanical support offered by it was reduced and the vein was exposed to gradually increasing levels of CWS in situ.To investigate the effects of mechanical conditioning on AVGs, we utilized both our well established, validated ex vivo vascular perfusion system (EVPS) as well as an appropriate preclinical animal model. The "engineering" component of this bioengineering study was to enhance our EVPS capabilities. Enhancements were made in the form of rigorous mathematical modeling, via subspace system identification, and automatic feedback control, via proportional iv integral and derivative control, of the arterial CWS and shear stress waveform generation capabilities of the EVPS. Pairs of freshly harvested porcine internal jugular veins (PIJVs) were perfused ex vivo under several biomechanical conditions. The acute hyperplastic response of PIJVs abruptly exposed to arterial hemodynamic conditions was compared to PIJVs perfused under normal venous conditions. In an attempt to attenuate this acute hyperplastic response, an ex vivo mechanical conditioning paradigm was imposed onto the PIJVs both via manual adjustment of EVPS parameters and via an adventitially placed tuned electrospun biodegradable polymer wrap. Early markers of IH were evaluated post-perfusion, and they included vascular smooth muscle cell apoptosis, proliferation, and phenotypic modulation. Quantification of these markers via immunohistochemical techniques provided the foundation for the final stage of this work. To assess the efficacy of the tuned electrospun biodegradable polymer wrap in attenuating the development of intimal hyperplasia in AVGs, a series of preclinical studies was performed in a pig model. PIJVs abruptly exposed to arterial levels of CWS showed a significant increase in apoptosis and in the number of synthetic smooth muscle cells, as well as a decrease in proliferation. Mechanical conditioning, via both manual adjustment of the EVPS parameters and placement of the biodegradable adventitial wra...

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Inhibition of thrombosis by a novel platelet selective S-nitrosothiol compound without hemodynamic side effects

Abstract: This new anti-ischemic NO-donor (NOd) LA810 that inhibits platelet function without hypotensive side-effects seems a highly efficacious strategy to reduce acute thrombosis triggered by coronary artery disease.

Cited by 28 publications

References 32 publications

Whole Body UVA Irradiation Lowers Systemic Blood Pressure by Release of Nitric Oxide From Intracutaneous Photolabile Nitric Oxide Derivates

Whole Body UVA Irradiation Lowers Systemic Blood Pressure by Release of Nitric Oxide From Intracutaneous Photolabile Nitric Oxide Derivates

Effects of a Novel Platelet Nitric Oxide Donor (LA816), Aspirin, Clopidogrel, and Combined Therapy in Inhibiting Flow- and Lesion-Dependent Thrombosis in the Porcine Ex Vivo Model

In Situ Bioengineering of Arterial Vein Grafts

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