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  • Review Article
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Potential cardioprotective actions of no-releasing aspirin

Nature Reviews Drug Discovery volume 1, pages 375–382 (2002)Cite this article

Key Points

  • Aspirin remains one of the most commonly used drugs for the treatment of pain, fever and inflammation, and is increasingly used to reduce the risk of heart attacks and strokes.

  • A major drawback to the use of aspirin is its ability to cause ulcers in the stomach.

  • A new type of aspirin has been developed that consists of aspirin linked to a nitric oxide (NO)-releasing moiety — NO-aspirin.

  • In human and experimental studies, NO-aspirin does not cause damage in the stomach or intestine, in contrast to aspirin. However, NO-aspirin can still suppress inflammation and platelet aggregation.

  • NO-aspirin has been shown to have beneficial effects, often superseding those of aspirin, in experimental models of myocardial infarction (heart attack), cardiac ischaemia–reperfusion and coronary restenosis.

  • NO-aspirin has been shown to reduce blood pressure in experimental models of hypertension (high blood pressure), in contrast to conventional nonsteroidal anti-inflammatory drugs and selective cyclooxygenase-2 inhibitors.

  • NO-aspirin, unlike the parent drug, is able to potently suppress the production of several pro-inflammatory cytokines.

  • NO-aspirin produces its effects through various mechanisms, not all of which are related to its ability to inhibit cyclooxygenase activity and release nitric oxide.

  • NO-aspirin could represent an important advance in the prevention of serious cardiovascular events, such as heart attacks and stroke, being safer and more potent than aspirin.

Abstract

The use of low doses of aspirin on a daily basis has increased greatly in the past 20 years, based on observations that it can significantly reduce the risk of heart attacks and strokes. However, aspirin can also cause severe damage to the stomach. A modified version of aspirin that releases nitric oxide has been developed that seems to offer important advantages over its 103-year-old parent — namely, improved protection for the heart without the unwanted effects on the stomach.

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Figure 1: Structures of aspirin and NCX4016.
Figure 2: Metabolism of NO-NSAIDs.
Figure 3: Intracellular formation of nitric oxide (NO) from NO-aspirin.
Figure 4: Inhibition of cell proliferation by nitric oxide.
Figure 5: Inhibition of cytokine synthesis by NO-aspirin.
Figure 6: Anti-apoptotic effects of NO-aspirin.

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Acknowledgements

J.L.W. is an Alberta Heritage Foundation for Medical Research Senior Scientist.

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Authors and Affiliations

  1. Department of Pharmacology & Therapeutics, University of Calgary, Calgary, T2N 4N1, Alberta, Canada

    John L. Wallace

  2. Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, 90121, California, USA

    Louis J. Ignarro

  3. Department of Clinical and Experimental Medicine, University of Perugia, Perugia, 06100, Italy

    Stefano Fiorucci

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  1. John L. Wallace
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  2. Louis J. Ignarro
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  3. Stefano Fiorucci
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Corresponding author

Correspondence to John L. Wallace.

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caspase-1

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caspase-5

caspase-6

caspase-7

caspase-8

caspase-9

caspase-10

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IL-12

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Glossary

PROPHYLAXIS

Preventative treatment against a disease.

ISCHAEMIA–REPERFUSION

A local reduction of blood flow, usually due to an obstruction, which is followed by a restoration of blood flow.

NORMOTENSIVE

A state of normal blood pressure.

VASOCONSTRICTOR

A substance that causes a narrowing of blood vessels, such that there is a slowing of the flow of blood.

ATHEROSCLEROSIS

Hardening of the arteries, which is caused by irregularly distributed fat deposits on the inner lining of these blood vessels (particularly in medium and large arteries).

ATHEROGENESIS

The formation of fat deposits on the inner lining of blood vessels.

PERCUTANEOUS TRANSLUMINAL ANGIOPLASTY

An operation for enlarging a narrowed artery by introducing, through the skin, a balloon-tipped catheter into the artery, and dilating the lumen of the artery on withdrawal of the inflated catheter tip.

RESTENOSIS

Recurrence of a narrowing of a blood vessel after corrective surgery or angioplasty has been performed.

NEOINTIMA

A newly formed inner lining of a blood vessel (such as that which is formed after angioplasty has been performed).

HYPERPLASIA

An increase in the number of cells in a tissue, such that the bulk of the tissue is increased.

ANGIOPLASTY

A procedure to reconstruct a blood vessel (often referring to the physical removal of atherosclerotic plaques (fat deposits) from the inner lining of blood vessels).

MESENTERIC VENULES

Small veins in the abdomen that carry blood from the digestive tract to the portal vein, and, through that vessel, to the liver.

PROSTACYCLIN

A chemical that is produced by various cells, including those on the inner lining of blood vessels, which can cause a widening of blood vessels (thereby increasing the flow of blood) and prevent platelets from sticking to one another.

ENDOPROTEASE

An enzyme that digests proteins by cleaving peptide bonds (between neighbouring amino acids) other than those at either end of the protein.

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Wallace, J., Ignarro, L. & Fiorucci, S. Potential cardioprotective actions of no-releasing aspirin. Nat Rev Drug Discov 1, 375–382 (2002). https://doi.org/10.1038/nrd794

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