Bice Justin S, Keim Yvonne, Stasch Johannes-Peter, Baxter Gary F
School of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, UK.
Cardiovasc Res. 2014 Feb 1;101(2):220-8. doi: 10.1093/cvr/cvt257. Epub 2013 Nov 20.
Guanylyl cyclase-cyclic guanosine monophosphate signalling plays an important role in endogenous cardioprotective signalling. The aim was to assess the potential of direct pharmacological activation and stimulation of soluble guanylyl cyclase, targeting different redox states of the enzyme, to limit myocardial necrosis during early reperfusion.
Rat isolated hearts were subjected to reversible left coronary artery occlusion (ischaemia-reperfusion) and infarct size was assessed by the tetrazolium staining technique. Administration during early reperfusion of BAY 41-2272, an NO-independent, haem-dependent stimulator of soluble guanylyl cyclase targeting the reduced state, or BAY 60-2770, an NO-independent, haem-independent activator targeting the oxidized state, significantly limited infarct size. Inhibition of NO synthesis did not abrogate this protection, but exogenous perfusion of NO with BAY 41-2272 produced a synergistic effect. The haem site oxidiser, ODQ abrogated the protection afforded by BAY 41-2272 but potentiated the protection afforded by BAY 60-2770. Targeting both the reduced and oxidized forms of sGC together did not afford additive protection.
Targeting either reduced or oxidized forms of sGC during early reperfusion affords cardioprotection, providing support for the concept that direct sGC manipulation at reperfusion has therapeutic potential for the management of acute myocardial infarction.
鸟苷酸环化酶 - 环磷酸鸟苷信号传导在内源性心脏保护信号传导中起重要作用。本研究旨在评估直接药理激活和刺激可溶性鸟苷酸环化酶（针对该酶的不同氧化还原状态）在早期再灌注期间限制心肌坏死的潜力。
对大鼠离体心脏进行可逆性左冠状动脉闭塞（缺血 - 再灌注），并通过四氮唑染色技术评估梗死面积。在早期再灌注期间给予BAY 41 - 2272（一种不依赖一氧化氮、依赖血红素的可溶性鸟苷酸环化酶刺激剂，作用于还原态）或BAY 60 - 2770（一种不依赖一氧化氮、不依赖血红素的激活剂，作用于氧化态），可显著限制梗死面积。抑制一氧化氮合成并未消除这种保护作用，但外源性灌注一氧化氮与BAY 41 - 2272产生协同效应。血红素位点氧化剂ODQ消除了BAY 41 - 2272提供的保护作用，但增强了BAY 60 - 2770提供的保护作用。同时靶向可溶性鸟苷酸环化酶的还原态和氧化态并未提供额外的保护作用。
在早期再灌注期间靶向可溶性鸟苷酸环化酶的还原态或氧化态均可提供心脏保护，这为再灌注时直接操纵可溶性鸟苷酸环化酶对急性心肌梗死的治疗具有潜在价值这一概念提供了支持。
