New Developments in Platelet Cyclic Nucleotide Signalling: Therapeutic Implications

Procter, Nathan E. K., Hurst, Nicola L., Nooney, Vivek B., Imam, Hasan, De Caterina, Raffaele, Chirkov, Yuliy Y. and Horowitz, John D. (2016) New Developments in Platelet Cyclic Nucleotide Signalling: Therapeutic Implications. Cardiovascular Drugs and Therapy, 30 (5). pp. 505-513. ISSN 0920-3206

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Abstract

Altered platelet physiology may contribute to the emergence of thrombosis in patients with many forms of cardiovascular disease. Excess platelet activation may reflect increased stimulation of pro-aggregatory pathways. There is, however, increasing evidence that excessive platelet response, due to impaired efficacy of anti-aggregatory autacoids such as nitric oxide (NO) and prostacyclin (PGI2), may be just as important. For example, diminished platelet response to NO has been documented in acute and chronic myocardial ischaemia, heart failure, aortic valve disease and in the presence of hyperglycaemia. This “NO resistance” has been shown to reflect both the scavenging of NO by reactive oxygen species and dysfunction of its intracellular “receptor”, soluble guanylate cyclase. Importantly, these abnormalities of NO signalling are potentially reversible through judicious application of pharmacotherapy. The analogous condition of impaired PGI2/adenylate cyclase (AC) signalling has received comparatively less attention to date. We have shown that platelet response to prostaglandin E1 (PGE1) is frequently impaired in patients with symptomatic myocardial ischaemia. Because the effects of ADP receptor antagonists such as clopidogrel and ticagrelor at the level of the P2Y12 receptor are coupled with changes in activity of AC, impaired response to PGE1 might imply both increased thrombotic risk and a reduced efficacy of anti-aggregatory drugs. Accordingly, patient response to treatment with clopidogrel is determined not only by variability of clopidogrel bio-activation, but also extensively by the integrity of platelet AC signalling. We here review these recent developments and their emerging therapeutic implications for thrombotic disorders.

Item Type: Article
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
Depositing User: LivePure Connector
Date Deposited: 20 Nov 2018 09:30
Last Modified: 22 Apr 2020 07:14
URI: https://ueaeprints.uea.ac.uk/id/eprint/68972
DOI: 10.1007/s10557-016-6671-4

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