Krieg Thomas, Liu Yanping, Rütz Thomas, Methner Carmen, Yang Xi-Ming, Dost Turhan, Felix Stephan B, Stasch Johannes-Peter, Cohen Michael V, Downey James M
Department of Cardiology, Ernst-Moritz-Arndt University, Loefflerstr. 23, 17487 Greifswald, Germany.
Eur Heart J. 2009 Jul;30(13):1607-13. doi: 10.1093/eurheartj/ehp143. Epub 2009 Apr 30.
BAY 58-2667 (BAY-58) directly activates soluble guanylyl cyclase without tolerance in a nitric oxide (NO)-independent manner, and its haemodynamic effect is similar to that of nitroglycerin. We tested whether BAY-58 could make both rabbit and rat hearts resistant to infarction when given at the end of an ischaemic insult.
All hearts were exposed to 30 min regional ischaemia followed by 120-(isolated hearts) or 180-(in situ hearts) min reperfusion. BAY-58 (1-50 nM) infused for 60 min starting 5 min before reperfusion significantly reduced infarction from 33.0 +/- 3.2% in control isolated rabbit hearts to 9.5-12.7% (P < 0.05). In a more clinically relevant in situ rabbit model, infarct size was similarly reduced with a loading dose of 53.6 microg/kg followed by a 60 min infusion of 1.25 microg/kg/min (41.1 +/- 3.1% infarction in control hearts to 16.0 +/- 4.4% in treated hearts, P < 0.05). BAY-58 similarly decreased infarction in the isolated rat heart, and protection was abolished by co-treatment with a protein kinase G (PKG) antagonist, or a mitochondrial K(ATP) channel antagonist. Conversely, N(omega)-nitro-L-arginine-methyl-ester-hydrochloride, a NO-synthase inhibitor, failed to block BAY-58's ability to decrease infarction, consistent with the latter's putative NO-independent activation of PKG. Finally, BAY-58 increased myocardial cGMP content in reperfused hearts while cAMP was unchanged.
When applied at reperfusion, BAY-58 is an effective cardioprotective agent with a mechanism similar to that of ischaemic pre-conditioning and, hence, should be a candidate for treatment of acute myocardial infarction in man.
BAY 58 - 2667（BAY - 58）能以不依赖一氧化氮（NO）的方式直接激活可溶性鸟苷酸环化酶且不会产生耐受性，其血流动力学效应与硝酸甘油相似。我们测试了在缺血损伤末期给予BAY - 58是否能使兔和大鼠心脏抵抗梗死。
所有心脏均经历30分钟的局部缺血，随后进行120分钟（离体心脏）或180分钟（原位心脏）的再灌注。在再灌注前5分钟开始输注BAY - 58（1 - 50 nM）60分钟，可使离体兔心脏梗死面积从对照的33.0±3.2%显著降低至9.5 - 12.7%（P < 0.05）。在更具临床相关性的原位兔模型中，给予53.6微克/千克的负荷剂量，随后以1.25微克/千克/分钟的速度输注60分钟，梗死面积同样减小（对照心脏梗死率为41.1±3.1%，治疗后心脏梗死率为16.0±4.4%，P < 0.05）。BAY - 58在离体大鼠心脏中同样减少梗死面积，且与蛋白激酶G（PKG）拮抗剂或线粒体ATP敏感性钾通道拮抗剂共同处理可消除这种保护作用。相反，一氧化氮合酶抑制剂盐酸N（ω）-硝基-L-精氨酸甲酯未能阻断BAY - 58降低梗死面积的能力，这与后者推测的不依赖NO激活PKG一致。最后，BAY - 58增加了再灌注心脏中的心肌环磷酸鸟苷（cGMP）含量，而环磷酸腺苷（cAMP）未改变。
在再灌注时应用，BAY - 58是一种有效的心脏保护剂，其机制与缺血预处理相似，因此应是治疗人类急性心肌梗死的候选药物。
