The ADP receptor P2Y1 mediates t-PA release in pigs during cardiac ischemia

Abstract

The endothelial ADP receptor P2Y(1) is responsible for a large part of the 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 could be mitigated through blocking the coronary endothelial P2Y(1) receptor. t-PA was measured in peripheral arterial blood and locally in the venous blood from the coronary sinus in a porcine model. The stable ADP analogue 2-MeSADP (10(-5) M), alone or as co-infusion with a selective P2Y(1) receptor blocker, MRS2179 (10(-3) M) was locally delivered in the left anterior descending artery through the tip of a coronary angioplasty balloon. In separate pigs the coronary artery was occluded with the balloon for 10 min. During the first and tenth minute of coronary ischemia, 2.5 ml of MRS2179 (10(-3) M) was delivered distal to the occlusion in 8 pigs, 10 pigs were used as controls. 2-MeSADP increased levels of t-PA in the coronary sinus, which could be significantly inhibited by co-infusion with MRS2179. During cardiac ischemia and reperfusion, t-PA increased significantly, an effect that could be significantly inhibited by MRS2179. Intra coronary administered MRS2179, a selective P2Y(1) receptor blocker, significantly reduces the increased levels of t-PA caused by both 2-MeSADP and cardiac ischemia in coronary arteries. Thus, ADP acting on the endothelial P2Y(1) receptor may mediate release of t-PA during ischemia and post-ischemic hyperemia, an effect that may counteract some of the platelet activating effects of ADP. Abbreviated Abstract We postulated that the release of t-PA during post ischemic reactive hyperemia could be mitigated through blocking the coronary endothelial P2Y(1) receptor in a porcine model. The ADP analogue 2-MeSADP (10(-5) M), alone or as co-infusion with a the P2Y(1) receptor blocker, MRS2179 (10(-3) M) was locally delivered in the left anterior descending artery. In separate pigs the coronary artery was occluded for ten min. During the first and tenth min of coronary ischemia, 2.5 ml of MRS2179 (10(-3) M) was delivered distal to the occlusion. t-PA was measured in peripheral arterial blood and also from the Coronary Sinus. We found that levels of t-PA in the blood from the coronary Sinus increased during infusion with 2-MeSADP as well as during ischemia and reperfusion. In pigs treated with MRS2179 levels of t-PA in the Coronary Sinus were significantly reduced during both coinfusion with 2-MeSADP and during ischemia/reperfusion. Thus, ADP acting on the endothelial P2Y(1) M receptor may mediate release of t-PA during ischemia and post-ischemic hyperemia, an effect that may counteract some of the platelet activating effects of ADP.