西地那非抑制心脏肥大的作用机制

    西地那非抑制心脏肥大的作用机制可能是增加心肌cGMP成分，降低心肌对异丙基肾上腺素的肥大反应，减少心肌肌酸激酶和肌钙蛋白T漏出。    

Sildenafil citrate increases myocardial cGMP content in rat heart, decreases its hypertrophic response to isoproterenol and decreases myocardial leak of creatine kinase and troponin T

Madiha AH Hassan and Amal F Ketat,BMC Pharmacol. 2005; 5: 10.

Background:Cardiac hypertrophy is a major risk factor for morbidity and mortality in a number of cardiovascular diseases. Consequently, the signaling pathways that inhibit cardiac hypertrophy are currently receiving much interest. Among them, nitric oxide (NO), signaling via cGMP and cGMP-dependent protein kinase I, has been recognized as a negative regulator of cardiac hypertrophy. The present study investigated the in-vivo effect of sildenafil as a phosphodiestrase-5A (PDE-5A) inhibitor on the hypertrophic response of rat heart to isoproterenol and the relation of this effect to the level of myocardial cGMP and integrity of the constitutive nitric oxide synthase (cNOS) activity.Results:The results showed that daily intraperitoneal administration of sildenafil per se for 10 days was without noticeable adverse effects on survival or myocardium. Conversely, daily subcutaneous administration of isoproterenol for 10 days caused significant myocardial hypertrophy, cell injury and decline in survival. When sildenafil was injected daily, one hour before isoproterenol, survival was significantly improved and the myocardium didn't show significant hypertrophy or cell injury. Interestingly, sildenafil was accompanied by significant rise in myocardial cGMP level, a parameter which was found in the present study to possess a significant negative correlation with cardiac hypertrophy and leak of cardiac troponin T into serum. At the same time, cGMP was found to possess a positive correlation with myocardial creatine kinase activity that reflects the efficiency of the energy utilization processes in the myocardium. However, in rats given Nω-nitro-L-arginine (L-NNA) as a competitive inhibitor of cNOS, sildenafil failed to show any favorable effect on survival or the myocardial injury parameters used to assess isoproterenol-induced injury.Conclusion:The present study suggests that increased cardiac cGMP level by sildenafil have a cardioprotective effect probably through acting as a post-receptor negative regulator of cardiac sympathetic responsiveness. Integrity of NOS function was an essential prerequisite for sildenafil's mediated cardioprotection encountered in the present study.

解读：

    1、心脏肥大是许多心血管疾病发病率和死亡率的主要危险因素。因此，抑制心脏肥大的信息通道对阻止心肌肥厚有重要的意义。研究证明，一氧化氮（(NO），通过cGMP 和cGMP-依赖的蛋白激酶 I信号，起到心肌肥大负性调节因子（negative regulator）的作用。实验研究发现，磷酸二酯酶-5A（PDE5A）抑制剂，西地那非抑制鼠心脏对异丙基肾上腺素的心脏肥大反应。这种作用与心肌cGMP水平和完整的结构型一氧化氮合成酶（cNOS）活性有关。本文研究表明，西地那非可能通过作用于心脏交感神经反应的受体后负性调节因子的作用，以增加心脏cGMP水平，从而保护心脏。

    2、肌钙蛋白：troponin。

    3、心肌肥大的发病机制：心肌肥大为心室重塑的特征性改变，在心肌肥大的发病机制中，血流动力学作用最早为人们所重视。心肌肥大发生的主要原因是血流动力学过载而引起心肌结构改变。由于心脏容量负荷增加，舒张期肌纤维长度增加，必然伴随着一次心肌收缩力的增强，心肌耗氧耗能增加，耗能增加作为一种代谢刺激而引起细胞内DNA活化，同时，由于心肌耗能增加，线粒体ATP分解增加，使心肌中高能磷酸物质降低，激活了心肌细胞中线粒体特异性DNA，使线粒体结构蛋白生成增多，继而产生心肌细胞中结构蛋白的生物合成增加。