Abstract 18649: Vascular Prostanoids Paradoxically Amplify Vasoconstriction During Platelet Activation

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Introduction: Platelet activation is associated with release of vasoactive factors which drive vasoconstriction, vasospasm and promote tissue hypoperfusion. These include the monoamine 5-HT and the prostanoid thromboxane (TX)A2 which represent validated clinical targets in the treatment of peripheral artery disease and thrombosis. Endothelial cells, which line the lumen of vessels, are typically thought to oppose this by the release of dilatory prostanoids and NO. However, the vessel wall can also produce contractile prostanoids. This raises the possibility that vascular as well as platelet prostanoids contribute to constrictor responses during thrombosis revealing the endothelium as a novel therapeutic target in thrombotic or vasospastic disease.

Hypothesis: Blood vessels produce prostanoid mediators that contribute and amplify vasoconstrictor responses during platelet activation.

Methods: Vasoconstrictor responses were monitored in mouse aorta using wire myography in the presence of specific agonists, inhibitors and/or addition of TRAP-6 activated human whole blood.

Results: Addition of activated human blood produced constriction of isolated aorta, which was partly driven by the prostanoid receptors TP (reduced 18±14% by terutroban) and EP3 (reduced 33±17 by L798106). Selectively blocking prostanoid production in vessels (but not blood) by pre-treatment with diclofenac reduced the contraction produced by activated blood (Fig A). Diclofenac also reduced the sensitivity of aorta to contraction induced by the TXA2 mimetic U46619 (Fig B) and 5HT (Fig C).

Conclusions: Prostanoids produced by the vascular wall sensitise vessels to contractile substances released from activated platelets. This contrasts with the established view that vascular prostanoids are purely protective in thrombosis and raises the possibility that drugs targeting vascular TP/EP3 receptors might synergise with anti-platelet agents to reduce thrombosis or vasospasm.

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