Abd-Elfattah A S, Jessen M E, Wechsler A S
Department of Surgery, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298-0532.
J Thorac Cardiovasc Surg. 1994 Aug;108(2):269-78.
A previous study has shown that endogenous adenosine trapping during ischemia (by blocking adenine nucleoside transport and inhibiting adenosine breakdown) prevents myocardial stunning. In this study, we tested the hypothesis that delay of administration of inhibitors until reperfusion would similarly prevent myocardial stunning in the absence of entrapped adenosine. In both studies, a selective nucleoside transport blocker, p-nitrobenzyl-thioinosine, was used in combination with a potent adenosine deaminase inhibitor, erythro-9-(2-hydroxy-3-nonyl)adenine, to entrap adenosine (preischemic treatment) or inosine (postischemic treatment) in an in vivo canine model of reversible global ischemia. Twenty-five anesthetized adult dogs were instrumented (by sonomicrometry) to monitor left ventricular performance from the relationship between stroke work and end-diastolic length as a sensitive and load-independent index of contractility. Hearts of animals supported by cardiopulmonary bypass were subjected to 30 minutes of normothermic global ischemia and 60 minutes of reperfusion. Saline solution containing the pharmacologic agents were infused into the bypass circuit before ischemia (group 1) or during reperfusion (group 2). Control group (group 3) received saline before and after ischemia. Myocardial biopsy specimens were obtained before, during, and after ischemia, and levels of adenine nucleotides, nucleosides, oxypurines, and the oxidized form of nicotinamide-adenine dinucleotide were determined. Left ventricular contractility fully recovered within 30 minutes of reperfusion in the groups treated with erythro-9-(2-hydroxy-3-nonyl)adenine and p-nitrobenzyl-thioinosine (p < 0.05 versus control group). Myocardial adenosine triphosphate was depleted by 50% in all groups at the end of ischemia. Adenosine triphosphate recovered during reperfusion only in the group that was treated with inhibitors before ischemia (group 1). At the end of ischemia, adenosine levels were low (< 10% of total nucleosides) in the control group (group 3) and in the group treated only after ischemia (group 2). A high level of adenosine (> 90% of total nucleosides) was present in group 1. We infer that selective pharmacologic blockade of nucleoside transport, only after ischemic injury, accelerated functional recovery during reperfusion, even without trapping of endogenous adenosine during ischemia and without adenosine triphosphate recovery during reperfusion. Recovery of myocardial adenosine triphosphate required preischemic treatment and adenosine entrapment during ischemia and reperfusion. Therefore, nucleoside trapping may be used to prevent reperfusion-mediated injury after reversible ischemic injury.
先前的一项研究表明，缺血期间内源性腺苷捕获（通过阻断腺嘌呤核苷转运和抑制腺苷分解）可预防心肌顿抑。在本研究中，我们检验了这样一个假设：在没有捕获腺苷的情况下，将抑制剂的给药延迟至再灌注时同样可预防心肌顿抑。在这两项研究中，一种选择性核苷转运阻滞剂对硝基苄基硫代肌苷与一种强效腺苷脱氨酶抑制剂赤藓红-9-（2-羟基-3-壬基）腺嘌呤联合使用，在犬可逆性全脑缺血的体内模型中捕获腺苷（缺血前治疗）或次黄嘌呤核苷（缺血后治疗）。25只麻醉的成年犬通过超声心动图进行监测，以通过每搏功与舒张末期长度之间的关系来监测左心室功能，作为收缩性的敏感且与负荷无关的指标。接受体外循环支持的动物心脏经历30分钟的常温全脑缺血和60分钟的再灌注。在缺血前（第1组）或再灌注期间（第2组）将含有药物制剂的盐溶液注入体外循环回路。对照组（第3组）在缺血前后均接受生理盐水。在缺血前、缺血期间和缺血后获取心肌活检标本，并测定腺嘌呤核苷酸、核苷、氧嘌呤和烟酰胺腺嘌呤二核苷酸氧化形式的水平。在用赤藓红-9-（2-羟基-3-壬基）腺嘌呤和对硝基苄基硫代肌苷治疗的组中，左心室收缩性在再灌注后30分钟内完全恢复（与对照组相比，P<0.05）。在缺血结束时，所有组的心肌三磷酸腺苷均消耗了50%。仅在缺血前用抑制剂治疗的组（第1组）中，三磷酸腺苷在再灌注期间恢复。在缺血结束时，对照组（第3组）和仅在缺血后治疗的组（第2组）中的腺苷水平较低（<总核苷的10%）。第1组中存在高水平的腺苷（>总核苷的90%）。我们推断，仅在缺血性损伤后对核苷转运进行选择性药理阻断，可加速再灌注期间的功能恢复，即使在缺血期间没有捕获内源性腺苷且在再灌注期间没有三磷酸腺苷恢复的情况下也是如此。心肌三磷酸腺苷的恢复需要缺血前治疗以及缺血和再灌注期间的腺苷捕获。因此，核苷捕获可用于预防可逆性缺血性损伤后的再灌注介导的损伤。
