Kaminski P M, Proctor K G
Department of Physiology, University of Tennessee Health Science Center, Memphis 38163.
Circ Res. 1992 Sep;71(3):720-31. doi: 10.1161/01.res.71.3.720.
By using pharmacological tools, the biological actions of adenosine (ADO) were manipulated in rat intestine that had been rendered ischemic for 5 or 15 minutes and reperfused for 1 or 24 hours. With 100 microM ADO topically administered for 30 minutes after ischemia and then washed out, intestinal arteriolar blood flow (BF) and tissue ATP were restored to preocclusion levels, and histological damage was minimal after 1 hour of reperfusion. For comparison, with vehicle treatment after ischemia, BF was reduced by 50%, tissue ATP was reduced by 50%, myeloperoxidase levels in the intestine and lung were increased at least twofold, and mucosal villi were shortened and thickened after 1 hour of reperfusion. Furthermore, with vehicle treatment, both baseline BF and reactivity to endothelium-dependent (acetylcholine) and endothelium-independent (2-chloroadenosine) vasodilators were significantly depressed after 24 hours of reperfusion. In contrast, with ADO, baseline BF remained near normal, and vascular reactivity to 2-chloroadenosine and acetylcholine was preserved after 24 hours. The salutary effect of ADO on BF was reduced by simultaneous application of the antagonist 8-phenyltheophylline or the cellular uptake inhibitor dipyridamole. The nonmetabolized agonist 2-chloroadenosine, the purine precursor aminoimidazole carboxamide riboside, or dipyridamole alone all had favorable effects relative to the vehicle, but all were less potent than ADO. The conclusions are as follows: 1) Endogenous ADO modulates the inflammatory response evoked by intestinal reperfusion because aminoimidazole carboxamide riboside or dipyridamole, which increases its availability, generally had favorable effects, whereas 8-phenyltheophylline tended to have opposite effects. 2) Exogenous ADO arrests most of the inflammatory changes associated with reperfusion by mechanisms that include both extracellular (e.g., receptor-mediated vasodilation and granulocyte inhibition) and intracellular (e.g., restoration of ATP) actions. 3) The effectiveness of ADO-related compounds even when administered after ischemia attests to the practicality of salvaging ischemic bowel, at least in some conditions.
运用药理学手段，对缺血5分钟或15分钟并再灌注1小时或24小时的大鼠肠道中腺苷（ADO）的生物学作用进行调控。缺血后局部给予100微摩尔的ADO，持续30分钟，随后冲洗掉，肠道小动脉血流量（BF）和组织ATP恢复到阻断前水平，再灌注1小时后组织学损伤最小。作为对照，缺血后给予赋形剂处理，再灌注1小时后，BF降低50%，组织ATP降低50%，肠道和肺中的髓过氧化物酶水平至少升高两倍，黏膜绒毛缩短变厚。此外，给予赋形剂处理后，再灌注24小时后，基础BF以及对内皮依赖性（乙酰胆碱）和内皮非依赖性（2-氯腺苷）血管舒张剂的反应性均显著降低。相比之下，给予ADO后，基础BF仍接近正常水平，再灌注24小时后对2-氯腺苷和乙酰胆碱的血管反应性得以保留。同时应用拮抗剂8-苯基茶碱或细胞摄取抑制剂双嘧达莫可降低ADO对BF的有益作用。非代谢性激动剂2-氯腺苷、嘌呤前体氨基咪唑甲酰胺核苷或单独使用双嘧达莫相对于赋形剂均有有利作用，但效力均低于ADO。结论如下：1）内源性ADO调节肠道再灌注引发的炎症反应，因为增加其可用性的氨基咪唑甲酰胺核苷或双嘧达莫通常有有利作用，而8-苯基茶碱往往有相反作用。2）外源性ADO通过包括细胞外（如受体介导的血管舒张和粒细胞抑制）和细胞内（如ATP恢复）作用在内的机制阻止与再灌注相关的大多数炎症变化。3）即使在缺血后给予，ADO相关化合物的有效性证明了挽救缺血肠段的可行性，至少在某些情况下是如此。
