Abstract 842: Release of Tissue Plasminogen Activator (t-PA) in Response to Ischemia and Reactive Hyperemia is Mediated by P2Y1 Receptors
Background: The endothelial P2Y1 receptor is responsible for a large part of reactive hyperemia following cardiac ischemia. Tissue plasminogen activator (t-PA) increases during reactive hyperemia. We postulated that the release of t-PA during reactive hyperemia is mitigated through blocking the coronary endothelial P2Y1 receptor for ADP.
Methods: t-PA was measured in peripheral arterial blood and locally in the venous blood from the coronary sinus (CS) in a porcine model. 2-MeSADP (10−5M), alone or as co-infusion with a selective P2Y1 receptor blocker, MRS 2179 (10−3M) was locally delivered in the left anterior descending artery (LAD) through the tip of a coronary angioplasty balloon. In separate pigs the coronary artery was occluded with the balloon for ten min. During the first and tenth min of coronary ischemia, 2.5 ml of MRS 2179 (10−3M) was delivered distal to the occlusion in 8 pigs, 10 pigs were used as controls.
Results: The ADP analogue,2-MeSADP increased levels of t-PA in the CS, which could be significantly inhibited by co-infusion with MRS 2179. During cardiac ischemia and reperfusion, t-PA increased significantly, an effect that could be significantly inhibited by MRS 2179 ( 2.27 ± 0.72 vs. 0.92 ± 0.38 ).
Conclusions: Intra coronary administered MRS 2179, a selective P2Y1 receptor blocker, significantly reduces the increased levels of t-PA caused by both 2-MeSADP and cardiac ischemia + reperfusion in coronary arteries. Thus, ADP acting on the endothelial P2Y1receptor may play a major role in the release of t-PA during ischemia and post-ischemic hyperemia.