ADP acting on P2Y12 receptors stimulates vasoconstriction in human internal mammary artery branches (Emax=21+/-1%) and small veins (Emax=48+/-9%), an effect blocked by AR-C67085 but not clopidogrel.
P2Y12 receptors are expressed in human vascular smooth muscle cells and mediate vasoconstriction, suggesting that stable P2Y12 antagonists may offer dual benefits by preventing both thrombosis and vasospasm.
OBJECTIVE: ADP plays an important role in platelet aggregation by activating P2Y12 receptors. We assessed the hypothesis that P2Y12 receptors are expressed in vascular smooth muscle cells (VSMC). METHODS AND RESULTS: P2Y12 receptor mRNA was found to have a high expression among the P2 receptors in human VSMC, significantly higher than the other 2 ADP receptors (P2Y1 and P2Y13, real-time polymerase chain reaction). Western blots gave a band of 50 kD, similar to that in platelets. To unmask a P2Y12 receptor-mediated vasoconstriction by simulating the in vivo situation, vessels were precontracted to a submaximal level. 2-MeSADP stimulated contractions in vessel segments from internal mammary artery (IM), IM branches and small veins (Emax=15+/-6% of 60 mmol/L K+ contraction, pEC50=5.6+/-0.6, Emax=21+/-1%, pEC50=6.8+/-0.1, and Emax=48+/-9%, pEC50=6.6+/-0.4). The selective P2Y12 antagonist AR-C67085 blocked 2-MeSADP contractions. The contraction was not reduced in patients using clopidogrel, a drug inhibiting ADP-induced platelet aggregation by blocking the P2Y12 receptor. This may be explained by the high instability of the active clopidogrel metabolite that never reaches the systemic circulation. CONCLUSIONS: ADP acting on P2Y12 receptors not only is important for platelet activation but also stimulates vasoconstriction. Stable drugs with antagonistic effects on P2Y12 receptors, affecting both platelets and VSMC, could be of double therapeutic benefit in their prevention of both thrombosis and vasospasm.
Wihlborg et al. (2004) studied this question. 2-MeSADP was evaluated on Vasoconstriction in vessel segments. ADP acting on P2Y12 receptors stimulates vasoconstriction in human internal mammary artery branches (Emax=21+/-1%) and small veins (Emax=48+/-9%), an effect blocked by AR-C67085 but not clopidogrel.