Chronic Treatment With Ticagrelor Limits Myocardial Infarct Size: An Adenosine and Cyclooxygenase-2–Dependent Effect

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 34; no. 9; pp. 2078 - 2085
• Main Authors: Nanhwan, Manjyot K, Ling, Shukuan, Kodakandla, Monica, Nylander, Sven, Ye, Yumei, Birnbaum, Yochai
• Format: Journal Article
• Language: English
• Published: United States American Heart Association, Inc 01.09.2014
• Subjects: 6-Ketoprostaglandin F1 alpha - metabolism; Adenosine - analogs & derivatives; Adenosine - pharmacology; Adenosine - physiology; Adenosine - therapeutic use; Adenosine A1 Receptor Antagonists - pharmacology; Adenosine A2 Receptor Antagonists - pharmacology; Animals; Aspirin - pharmacology; Cardiotonic Agents - pharmacology; Cardiotonic Agents - therapeutic use; Cyclooxygenase 2 - biosynthesis; Cyclooxygenase 2 - genetics; Cyclooxygenase 2 - physiology; Cyclooxygenase 2 Inhibitors - pharmacology; Drug Evaluation, Preclinical; Enzyme Induction - drug effects; Lipoxins - metabolism; Male; Myocardial Infarction - drug therapy; Myocardial Infarction - pathology; Myocardial Reperfusion Injury - drug therapy; Myocardial Reperfusion Injury - pathology; Myocardial Reperfusion Injury - prevention & control; Nitric Oxide Synthase Type III - biosynthesis; Nitric Oxide Synthase Type III - genetics; Nitric Oxide Synthase Type III - physiology; Pyrazoles - pharmacology; Quinazolines - pharmacology; Rats; Rats, Sprague-Dawley; Receptor, Adenosine A1 - physiology; Receptor, Adenosine A2A - physiology; Ticlopidine - analogs & derivatives; Ticlopidine - therapeutic use; Triazoles - pharmacology; Up-Regulation - drug effects; adenosine; aspirin; cyclooxygenase; platelet aggregation inhibitors
• ISSN: 1079-5642; 1524-4636
• DOI: 10.1161/ATVBAHA.114.304002

OBJECTIVE—In a phase III clinical trial (PLATelet inhibition and patient Outcomes, PLATO), ticagrelor provided better clinical outcomes than clopidogrel in patients with acute coronary syndromes. In addition to P2Y12-receptor antagonism, ticagrelor prevents cell uptake of adenosine and has proven able to augment adenosine effects. Adenosine protects the heart against ischemia–reperfusion injury. We compared the effects of clopidogrel and ticagrelor on myocardial infarct size (IS). APPROACH AND RESULTS—Rats received oral ticagrelor (0, 75, 150, or 300 mg/kg/d) or clopidogrel (30 or 90 mg/kg/d) for 7 days and underwent 30-minute coronary artery ligation and 24-hour reperfusion. Area at risk was assessed by blue dye and IS by 2,3,5-triphenyl-tetrazolium-chloride. Cyclooxygenase-2 (COX2) enzyme activity was assessed by ELISA and expression by real-time polymerase chain reaction. Mechanism responsible was explored using adenosine-receptor antagonist (CGS15943, an A2A/A1 antagonist) or cyclooxygenase inhibition by either aspirin (5, 10, or 25 mg/kg) or specific cyclooxygenase-1 (SC560) or COX2 (SC5815) inhibitors. Ticagrelor, dose-dependently, reduced IS, whereas clopidogrel had no effect. Adenosine-receptor antagonism blocked the ticagrelor effect and COX2 inhibition by SC5815, or high-dose aspirin attenuated the IS-limiting effect of ticagrelor, whereas cyclooxygenase-1 inhibition or low-dose aspirin had no effect. Ticagrelor, but not clopidogrel, upregulated COX2 expression and activity. Also this effect was blocked by adenosine-receptor antagonism. Ticagrelor, but not clopidogrel, increased Akt and endothelial nitric oxide synthase phosphorylation. CONCLUSIONS—Ticagrelor, but not clopidogrel, reduces myocardial IS. The protective effect of ticagrelor was dependent on adenosine-receptor activation with downstream upregulation of endothelial nitric oxide synthase and COX2 activity.