Schrier D J, Lesch M E, Wright C D, Gilbertsen R B
Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, MI 48105.
J Immunol. 1990 Sep 15;145(6):1874-9.
Adenosine and adenosine receptor agonists have a variety of inhibitory effects on the generation of inflammatory mediators by neutrophils and other cell types. In human neutrophils stimulated with the chemotactic peptide FMLP, adenosine agonists inhibit O2- generation and degranulation. Because these findings suggest that the agonists may have potential as antiinflammatory agents, several compounds were evaluated for effects on the exudative and cellular phases of carrageenan-induced pleural inflammation in rats. All of the agonists tested inhibited both parameters of the inflammatory response. Inhibition appeared to correlate better with binding to the A1 than to the A2 receptor and was reversible by a known adenosine receptor antagonist, 8-phenyltheophylline. In mechanistic studies, R-N-(1-methyl-2-phenylethyl)adenosine, a standard A1 selective agonist, reversed the drop in circulating neutrophil count that occurs after injection of carrageenan. These results suggest that the agonists may prevent cell emigration by inhibiting adhesion to the endothelium or diapedesis. In addition (R)-N-(1-methyl-2-phenylethyl)adenosine had weak inhibitory effects on superoxide production by FMLP-stimulated rat neutrophils. Control studies showed that the effects of the agonists were not the result of agonist-induced hypotension nor corticosterone production by the adrenal glands. These findings indicate that adenosine receptor agonists are effective new pharmacologic tools for the study of inflammatory processes.
腺苷及腺苷受体激动剂对中性粒细胞和其他细胞类型产生炎症介质具有多种抑制作用。在用趋化肽FMLP刺激的人中性粒细胞中，腺苷激动剂抑制超氧阴离子的产生和脱颗粒。由于这些发现表明激动剂可能具有作为抗炎剂的潜力，因此评估了几种化合物对大鼠角叉菜胶诱导的胸膜炎渗出期和细胞期的影响。所有测试的激动剂均抑制炎症反应的两个参数。抑制作用似乎与A1受体的结合比与A2受体的结合相关性更好，并且可被已知的腺苷受体拮抗剂8-苯基茶碱逆转。在机制研究中，标准的A1选择性激动剂R-N-（1-甲基-2-苯乙基）腺苷逆转了注射角叉菜胶后循环中性粒细胞计数的下降。这些结果表明，激动剂可能通过抑制与内皮的粘附或穿膜迁移来防止细胞移出。此外，（R）-N-（1-甲基-2-苯乙基）腺苷对FMLP刺激的大鼠中性粒细胞产生超氧化物具有微弱的抑制作用。对照研究表明，激动剂的作用不是激动剂诱导的低血压或肾上腺产生皮质酮的结果。这些发现表明，腺苷受体激动剂是研究炎症过程有效的新型药理学工具。
