In vitro study of the anti-aggregating activity of two nitroderivatives of acetylsalicylic acid

Lechi, C.; Gaino, Stefania; Tommasoli, Rosamaria; Zuliani, Valeria; Bonapace, Stefano; Fontana, Luigi; Degan, Maurizio; Lechi, Alessandro; Minuz, P.

doi:10.1097/00001721-199603000-00024

Cited by 26 publications

(16 citation statements)

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“…NCX-4016 was more efficient than aspirin at inhibiting platelet activation (aggregation and adhesion) induced by thrombin, and it also inhibited the thrombin-induced aggregation of platelets pretreated with acetylsalicylic acid in a dose-dependent manner. 56,57 This effect was reversed by oxyhemoglobin and methylene blue, further implicating NO as the active moiety. The antithrombotic activity of this nitroaspirin was also studied in vivo in a rodent model of thrombosis.…”

Section: Nitroaspirinsmentioning

confidence: 94%

Nitric Oxide Donors and Cardiovascular Agents Modulating the Bioactivity of Nitric Oxide

Ignarro

Napoli

Loscalzo

2002

Circulation Research

438

335

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Abstract-Nitric oxide (NO) mediates multiple physiological and pathophysiological processes in the cardiovascular system. Pharmacological compounds that release NO have been useful tools for evaluating the pivotal role of NO in cardiovascular physiology and therapeutics. These agents constitute two broad classes of compounds, those that release NO or one of its redox congeners spontaneously and those that require enzymatic metabolism to generate NO. In addition, several commonly used cardiovascular drugs exert their beneficial action, in part, by modulating the NO pathway. Here, we review these classes of agents, summarizing their fundamental chemistry and pharmacology, and provide an overview of their cardiovascular mechanisms of action. ysfunction of the normally protective endothelium is found in several cardiovascular diseases, including atherosclerosis, hypertension, heart failure, coronary heart disease, arterial thrombotic disorders, and stroke. [1][2][3][4][5][6] Endothelial dysfunction leads to nitric oxide (NO) deficiency, 1,6 -11 which has been implicated in the underlying pathobiology of many of these disorders (NO insufficiency states). (For a detailed overview of the role of NO in cardiovascular biology and pathobiology, the reader is referred to Loscalzo and Vita. 3 ) NO insufficiency may reflect an absolute deficit of NO (synthesis), impaired availability of bioactive NO, or enhanced NO inactivation. Whatever its biochemical basis, NO insufficiency limits NO-mediated signal transduction of normal or protective physiological processes. In light of this pathobiology, replacement or augmentation of endogenous NO by exogenously administered NO donors has provided the foundation for a broad field of pharmacotherapeutics in cardiovascular medicine.Organic nitrate and nitrite esters represent a time-honored class of NO-donating agents used in cardiovascular therapeutics since the 19th century. These agents have direct vasoactive effects that have been used to treat ischemic heart disease, heart failure, and hypertension for many years. Treatment with conventional nitrate preparations is limited by their therapeutic half-life, systemic absorption with potentially adverse hemodynamic effects, and drug tolerance. 1,6 To overcome these limitations, novel NO donors that offer selective effects, a prolonged half-life, and a reduced incidence of drug tolerance have been developed. NO donors are pharmacologically active substances that spontaneously release, or are metabolized to, NO or its redox congeners. In the present article, we review our current understanding of NO-donating compounds and of cardiovascular drugs that modulate the bioactivity of endogenously produced NO. NO DonorsBecause of the limited utility of authentic NO gas in many experimental systems and the short half-life of NO in vivo, compounds that have the capacity to release NO have been widely used as therapeutic agents and as pharmacological tools to investigate the role of NO in cardiovascular physiology and pathophysiology. Several NO do...

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Section: Nitroaspirinsmentioning

confidence: 94%

Nitric Oxide Donors and Cardiovascular Agents Modulating the Bioactivity of Nitric Oxide

Ignarro

Napoli

Loscalzo

2002

Circulation Research

438

335

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“…Incubation periods exceeding 30 rnin resulted in a reduced anti-aggregatory effect. In comparison, NCX 4016 proved more potent than NCX 4215 (20).…”

Section: Platelet Aggregatiorimentioning

confidence: 85%

“…In these experiments, the inhibitory activity of NCX 4215 (0.1 moU1) on platelet aggregation was largely prevented (42). The anti-aggregating effects of NCX 42 IS (1 mmol/l) were only partially (although significantly) prevented by oxyhemoglobin (10 pmol/l) (20,42). In addition, preincubation of platelets with methylene blue, an inhibitor of guanylyl cyclase and a generator of oxygen free radicals (9), significantly attenuated the inhibitory effects of NCX 42 15 on thrombin-induced platelet aggregation (26).…”

Section: Effects Of Methjlene Blue and 0xyhernoglobin On The Antiplnmentioning

confidence: 92%

“…3). This inhibitory activity (19,20). A direct comparison showed that NCX 4016 was more potent than NCX 4215 (Fig.…”

Section: Platelet Aggregatiorimentioning

confidence: 94%

“…TXA, generation was assessed according to the method described by Patrono, by measuring TXBz concentration in serum obtained by leaving whole blood in glass tubes for 1 h at 37°C (30 In vitro experiments demonstrated that NCX 4016 was more effective than NCX 4215 in inhibiting thromboxane production as assessed by comparing the effects of each dose on TXB, generation (NCX 4215, 1 mmol/l: 69.2 k 7.9%; NCX 4016, 0.1 mmol/l: 91.2 f 2.1%; P < 0.05) (20). NCX 4016 and ASA effectively inhibited TXA, production by platelets during blood clotting, (84.5 2 13.4% inhibition with NCX 4016 0.1 mmoY1; 98.3 2 0.4% with equimolar ASA), the inhibitory effect being complete only with ASA (19,20). Inhibitory activity on TXB, generation was also observed when platelets were washed after the addition of NCX 4016 and subsequently tested with agonists a few hours later, demonstrating the irreversibility of this activity (19).…”

Section: Effects On Platelet Cyclooxygenasementioning

confidence: 99%

See 2 more Smart Citations

NO‐Aspirins: Antithrombotic Activity of Derivatives of Acetyl Salicylic Acid Releasing Nitric Oxide

Minuz

Lechi

Zuliani

et al. 1998

Cardiovascular Drug Reviews

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Medicinal Chemistry and Therapeutic Applications of the GasotransmittersNO,CO, andH₂Sand their Prodrugs

Szabó

2010

Burger's Medicinal Chemistry and Drug Discovery

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Nitric oxide ( NO ), carbon monoxide ( CO ), and hydrogen sulfide ( H 2 S ) are the main endogenous gasotransmitters. These gases are produced by the body by enzymatic reactions and serve physiological regulatory purposes including vasodilatation and anti‐inflammatory effects. Over the past decades, multiple approaches have been identified for the therapeutic exploitation of these three gasotransmitters, based on inhalation of the gases and/or the parenteral or enteral administration of various formulations of these molecules or their prodrugs. Here we overview the medicinal chemistry and the therapeutic applications of NO, CO, and H 2 S and their prodrugs. Inhaled NO is used clinically to selectively dilate the pulmonary vasculature in the therapy of the primary pulmonary hypertension of the newborn. Organic nitrates such as glyceryl trinitrate or nitroglycerin are used in the therapy of acute and chronic angina. Sodium nitroprusside is used to counteract acute hypertensive crisis. Another class of clinical‐stage NO donor drugs is the sydnonimines (molsidomine, linsidomine). Additional classes of NO donors include diazeniumdiolates (NONOates) and S ‐nitrosothiols, with beneficial effects in various preclinical models of disease. With respect to CO, the main therapeutic approaches are CO inhalation (currently in clinical trials for the experimental therapy of delayed graft function associated with kidney transplantation) and carbon monoxide releasing compounds of various classes (in preclinical stage). With respect to H 2 S, a parenteral injectable formulation of the gas is currently is Phase I trials. Several classes of H 2 S donor molecules have also been identified, which are used in preclinical studies.

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In vitro study of the anti-aggregating activity of two nitroderivatives of acetylsalicylic acid

Cited by 26 publications

References 0 publications

Nitric Oxide Donors and Cardiovascular Agents Modulating the Bioactivity of Nitric Oxide

Nitric Oxide Donors and Cardiovascular Agents Modulating the Bioactivity of Nitric Oxide

NO‐Aspirins: Antithrombotic Activity of Derivatives of Acetyl Salicylic Acid Releasing Nitric Oxide

Medicinal Chemistry and Therapeutic Applications of the GasotransmittersNO,CO, andH₂Sand their Prodrugs

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In vitro study of the anti-aggregating activity of two nitroderivatives of acetylsalicylic acid

Cited by 26 publications

References 0 publications

Nitric Oxide Donors and Cardiovascular Agents Modulating the Bioactivity of Nitric Oxide

Nitric Oxide Donors and Cardiovascular Agents Modulating the Bioactivity of Nitric Oxide

NO‐Aspirins: Antithrombotic Activity of Derivatives of Acetyl Salicylic Acid Releasing Nitric Oxide

Medicinal Chemistry and Therapeutic Applications of the GasotransmittersNO,CO, andH2Sand their Prodrugs

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Product

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Medicinal Chemistry and Therapeutic Applications of the GasotransmittersNO,CO, andH₂Sand their Prodrugs