Korkmaz Sevil, Radovits Tamás, Barnucz Eniko, Hirschberg Kristóf, Neugebauer Philipp, Loganathan Sivakkanan, Veres Gábor, Páli Szabolcs, Seidel Beatrice, Zöllner Stefan, Karck Matthias, Szabó Gábor
Department of Cardiac Surgery, University of Heidelberg, Germany.
Circulation. 2009 Aug 25;120(8):677-86. doi: 10.1161/CIRCULATIONAHA.109.870774. Epub 2009 Aug 10.
The role of the nitric oxide/cGMP/cGMP-dependent protein kinase G pathway in myocardial protection and preconditioning has been the object of intensive investigations. The novel soluble guanylate cyclase activator cinaciguat has been reported to elevate intracellular [cGMP] and activate the nitric oxide/cGMP/cGMP-dependent protein kinase G pathway in vivo. We investigated the effects of cinaciguat on myocardial infarction induced by isoproterenol in rats.
Rats were treated orally twice a day for 4 days with vehicle or cinaciguat (10 mg/kg). Isoproterenol (85 mg/kg) was injected subcutaneously 2 days after the first treatment at an interval of 24 hours for 2 days to produce myocardial infarction. After 17 hours, histopathological observations and left ventricular pressure-volume analysis to assess cardiac function with a Millar microtip pressure-volume conductance catheter were performed, and levels of biochemicals of the heart tissues were measured. Gene expression analysis was performed by quantitative real-time polymerase chain reaction. Isolated canine coronary arterial rings exposed to peroxynitrite were investigated for vasomotor function, and immunohistochemistry was performed for cGMP and nitrotyrosine. The present results show that cinaciguat treatment improves histopathological lesions, improves cardiac performance, improves impaired cardiac relaxation, reduces oxidative stress, ameliorates intracellular enzyme release, and decreases cyclooxygenase 2, transforming growth factor-beta, and beta-actin mRNA expression in experimentally induced myocardial infarction in rats. In vitro exposure of coronary arteries to peroxynitrite resulted in an impairment of endothelium-dependent vasorelaxation, increased nitro-oxidative stress, and reduced intracellular cGMP levels, which were all improved by cinaciguat. A cardioprotective effect of postischemic cinaciguat treatment was shown in a canine model of global ischemia/reperfusion.
Pharmacological soluble guanylate cyclase activation could be a novel approach for the prevention and treatment of ischemic heart disease.
一氧化氮/cGMP/依赖cGMP的蛋白激酶G通路在心肌保护和预处理中的作用一直是深入研究的对象。据报道，新型可溶性鸟苷酸环化酶激活剂西那吉特可提高细胞内[cGMP]水平，并在体内激活一氧化氮/cGMP/依赖cGMP的蛋白激酶G通路。我们研究了西那吉特对异丙肾上腺素诱导的大鼠心肌梗死的影响。
大鼠每天口服两次，连续4天给予赋形剂或西那吉特（10mg/kg）。首次治疗2天后，每隔24小时皮下注射异丙肾上腺素（85mg/kg），共注射2天，以诱导心肌梗死。17小时后，进行组织病理学观察，并用Millar微尖端压力-容积电导导管进行左心室压力-容积分析以评估心脏功能，并测量心脏组织的生化指标水平。通过定量实时聚合酶链反应进行基因表达分析。研究暴露于过氧亚硝酸盐的离体犬冠状动脉环的血管舒缩功能，并对cGMP和硝基酪氨酸进行免疫组织化学检测。目前的结果表明，西那吉特治疗可改善组织病理学损伤，改善心脏功能，改善受损的心脏舒张功能，减轻氧化应激，改善细胞内酶释放，并降低实验性诱导的大鼠心肌梗死中环氧化酶2、转化生长因子-β和β-肌动蛋白mRNA的表达。冠状动脉在体外暴露于过氧亚硝酸盐会导致内皮依赖性血管舒张功能受损、硝基氧化应激增加和细胞内cGMP水平降低，而西那吉特均可改善这些情况。在犬全脑缺血/再灌注模型中显示了缺血后西那吉特治疗的心脏保护作用。
药理学可溶性鸟苷酸环化酶激活可能是预防和治疗缺血性心脏病的一种新方法。
