Li B, Roth S
Department of Anesthesia and Critical Care, University of Chicago, Illinois 60637, USA.
Invest Ophthalmol Vis Sci. 1999 May;40(6):1200-16.
A brief period of ischemia can induce a remarkably complete state of ischemic tolerance in the retina, a phenomenon known as ischemic preconditioning (IPC). The mechanisms of IPC were studied in the rat retina by examining the role of adenosine as a possible mediator and determining whether IPC protection could be induced more than once in the same rat.
Retinal ischemia was produced for 60 minutes in ketamine-xylazine-anesthetized Sprague-Dawley rats, and recovery was measured using electroretinography. Twenty-four hours earlier, the IPC stimulus of 5 minutes of ischemia was applied. To test the role of adenosine as a mediator of IPC, the selective adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; 0.45 mg/kg, 2.25 mg/kg, or 4.5 mg/kg), the A2a antagonist 8-(3-chlorostyryl)caffeine (CSC; 0.1 mg/kg or 1.0 mg/kg), or their cyclodextrin vehicle were administered 15 minutes before IPC. To examine whether exogenous adenosine administration could mimic IPC, animals received intravitreal injections of the adenosine A1 receptor stimulant adenosine amine congener (ADAC) or the A2a stimulant CGS21680, followed by ischemia 24 hours later. To test the hypothesis that IPC could be induced repeatedly without loss of protection, rats were divided to receive IPC or sham IPC, followed 10 days later by IPC or a sham procedure, and 24 hours later by 60 minutes of ischemia.
Adenosine A1 receptor blockade with 4.5 mg/kg DPCPX administered intraperitoneally (IP) before or immediately after 5 minutes of ischemia completely blocked IPC protection, whereas lower doses resulted in partial blockade. CSC at the lowest dose (0.1 mg/kg) had no significant effect on IPC's protective effect, whereas partial blockade was found with 1.0 mg/kg CSC. A1 or A2a receptor stimulation produced partial but significant mimicking of IPC protection, effects that were antagonized by DPCPX or CSC. Ischemic preconditioning applied twice, separated by 10 days, and followed by 60 minutes of ischemia 24 hours after the second IPC stimulus, resulted in nearly identical recovery of function after ischemia compared with IPC performed one time.
Adenosine, acting through the A1 and A2a receptors, is a critical component in the induction of ischemic tolerance after preconditioning in the retina. The neuroprotective effects of IPC in the retina are lost over time but may be reinduced by subsequent application of the IPC stimulus.
短暂的缺血可在视网膜中诱导出一种显著的完全缺血耐受状态,这一现象被称为缺血预处理(IPC)。通过研究腺苷作为可能的介质所起的作用,并确定在同一只大鼠中是否能多次诱导出IPC保护作用,对大鼠视网膜中IPC的机制进行了研究。
在氯胺酮-赛拉嗪麻醉的斯普拉格-道利大鼠中造成60分钟的视网膜缺血,并使用视网膜电图测量恢复情况。在24小时前施加5分钟缺血的IPC刺激。为了测试腺苷作为IPC介质的作用,在IPC前15分钟腹腔注射选择性腺苷A1受体拮抗剂8-环戊基-1,3-二丙基黄嘌呤(DPCPX;0.45毫克/千克、2.25毫克/千克或4.5毫克/千克)、A2a拮抗剂8-(3-氯苯乙烯基)咖啡因(CSC;0.1毫克/千克或1.0毫克/千克)或它们的环糊精载体。为了检查外源性腺苷给药是否能模拟IPC,动物接受玻璃体内注射腺苷A1受体激动剂腺苷胺类似物(ADAC)或A2a激动剂CGS21680,24小时后进行缺血。为了测试IPC可重复诱导且不丧失保护作用的假设,将大鼠分为接受IPC或假IPC组,10天后再接受IPC或假手术,24小时后进行60分钟的缺血。
在5分钟缺血前或缺血后立即腹腔注射4.5毫克/千克DPCPX阻断腺苷A1受体,完全阻断了IPC保护作用,而较低剂量导致部分阻断。最低剂量(0.1毫克/千克)的CSC对IPC的保护作用无显著影响,而1.0毫克/千克CSC则出现部分阻断。A1或A2a受体刺激产生了部分但显著的IPC保护模拟作用,这些作用被DPCPX或CSC拮抗。缺血预处理分两次进行,间隔10天,在第二次IPC刺激后24小时进行60分钟缺血,与单次进行IPC相比,缺血后功能恢复情况几乎相同。
腺苷通过A1和A2a受体发挥作用,是视网膜预处理后诱导缺血耐受的关键成分。视网膜中IPC的神经保护作用会随着时间的推移而丧失,但后续施加IPC刺激可能会再次诱导出这种作用。