The Section of Cardiology, Department of Medicine, Baylor College of Medicine, 7200 Cambridge Street, Houston, TX, 77030, USA.
University of Texas at Austin, Austin, TX, USA.
Cardiovasc Drugs Ther. 2023 Aug;37(4):625-646. doi: 10.1007/s10557-022-07329-9. Epub 2022 Feb 22.
Recombinant apyrase (AZD3366) increases adenosine production and ticagrelor inhibits adenosine reuptake. We investigated whether intravenous AZD3366 before reperfusion reduces myocardial infarct size (IS) and whether AZD3366 and ticagrelor have additive effects.
Sprague-Dawley rats underwent 30 min ischemia. At 25 min of ischemia, animals received intravenous AZD3366 or vehicle. Additional animals received intravenous CGS15943 (an adenosine receptor blocker) or intraperitoneal ticagrelor. At 24 h reperfusion, IS was assessed by triphenyltetrazolium chloride. Other rats were subjected to 30 min ischemia followed by 1 h or 24 h reperfusion. Myocardial samples were assessed for adenosine levels, RT-PCR, and immunoblotting.
AZD3366 and ticagrelor reduced IS. The protective effect was blocked by CGS15943. The effect of AZD3366 + ticagrelor was significantly greater than AZD3366. One hour after infarction, myocardial adenosine levels significantly increased with AZD3366, but not with ticagrelor. In contrast, 24 h after infarction, adenosine levels were equally increased by AZD3366 and ticagrelor, and levels were higher in the AZD3366 + ticagrelor group. One hour after reperfusion, AZD3366 and ticagrelor equally attenuated the increase in interleukin-15 (an early inflammatory marker after ischemic cell death) levels, and their combined effects were additive. AZD3366, but not ticagrelor, significantly attenuated the increase in RIP1, RIP3, and P-MLKL (markers of necroptosis) 1 h after reperfusion. AZD3366, but not ticagrelor, significantly attenuated the increase in IL-6 and GSDMD-N (markers of pyroptosis) 1 h after reperfusion. At 24 h of reperfusion, both agents equally attenuated the increase in these markers, and their effects were additive.
AZD3366 attenuated inflammation, necrosis, necroptosis, and pyroptosis and limited IS. The effects of AZD3366 and ticagrelor were additive.
重组 apyrase（AZD3366）可增加腺苷的产生，替格瑞洛可抑制腺苷再摄取。我们研究了再灌注前静脉内给予 AZD3366 是否可以减少心肌梗死面积（IS），以及 AZD3366 和替格瑞洛是否具有相加作用。
Sprague-Dawley 大鼠进行 30 分钟缺血。在缺血 25 分钟时，动物接受静脉内 AZD3366 或载体。其他动物接受静脉内 CGS15943（一种腺苷受体阻滞剂）或腹腔内替格瑞洛。在再灌注 24 小时时，通过三苯基四氮唑氯化物评估 IS。其他大鼠进行 30 分钟缺血，随后进行 1 小时或 24 小时再灌注。评估心肌样本中的腺苷水平、RT-PCR 和免疫印迹。
AZD3366 和替格瑞洛降低了 IS。CGS15943 阻断了保护作用。AZD3366 + 替格瑞洛的作用明显大于 AZD3366。梗塞后 1 小时，AZD3366 可显著增加心肌腺苷水平，但替格瑞洛则不能。相反，梗塞后 24 小时，AZD3366 和替格瑞洛均可同等增加腺苷水平，并且 AZD3366 + 替格瑞洛组的水平更高。再灌注后 1 小时，AZD3366 和替格瑞洛同样减弱了白细胞介素-15（缺血性细胞死亡后早期炎症标志物）水平的升高，且其联合作用具有加和性。AZD3366 可显著减弱再灌注后 1 小时 RIP1、RIP3 和 P-MLKL（坏死性凋亡标志物）的升高，但替格瑞洛则不能。AZD3366 可显著减弱再灌注后 1 小时 IL-6 和 GSDMD-N（细胞焦亡标志物）的升高，但替格瑞洛则不能。再灌注 24 小时时，两种药物均可同等减弱这些标志物的升高，且其作用具有加和性。
AZD3366 可减轻炎症、坏死、坏死性凋亡和细胞焦亡，并限制 IS。AZD3366 和替格瑞洛的作用具有加和性。
