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.
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.
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DOI：
10.1186/1471-2210-5-10
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发表时间：
2005-04-06
期刊：
影响因子：
--
通讯作者：
Ketat AF
中科院分区：
文献类型：
--
作者：
Hassan MA;Ketat AF
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，抑制心脏肥大的信号通路目前受到了极大的关注。其中，一氧化氮（NO），通过cGMP和cGMP依赖的蛋白激酶I信号传导，已被认为是心肌肥厚的负调节剂。本研究探讨了磷酸二酯酶-5A（PDE-5A）抑制剂西地那非对异丙肾上腺素引起的大鼠心肌肥厚反应的体内作用，以及这种作用与心肌cGMP水平和组成型一氧化氮合酶（cNOS）活性完整性的关系。结果表明，每天腹腔注射西地那非本身10天，对存活率或心肌没有明显的不良影响。相反，每天皮下注射异丙肾上腺素10天可引起显著的心肌肥大、细胞损伤和存活率下降。当每天注射西地那非，在异丙肾上腺素之前一小时，存活率显著提高，心肌没有显示出显著的肥大或细胞损伤。有趣的是，西地那非伴随着心肌cGMP水平的显著升高，在本研究中发现该参数与心脏肥大和心肌肌钙蛋白T渗漏到血清中具有显著的负相关性。与此同时，cGMP被发现具有正相关性与心肌肌酸激酶活性，反映了在心肌中的能量利用过程的效率。然而，在给予Nω-硝基-L-精氨酸（L-NNA）作为cNOS竞争性抑制剂的大鼠中，西地那非未能显示出对用于评估异丙肾上腺素诱导的损伤的存活率或心肌损伤参数的任何有利影响。本研究提示西地那非升高心脏cGMP水平可能通过对心脏交感神经反应性的受体后负调节而发挥心脏保护作用。NOS功能的完整性是本研究中遇到的西地那非介导的心脏保护作用的必要前提。
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. 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. 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.
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影响因子：
20.1
作者：
Vila-Petroff, MG;Younes, A;Sollott, SJ
通讯作者：
Sollott, SJ
影响因子：
2.2
作者：
PORSTMANN, T;KIESSIG, ST
通讯作者：
KIESSIG, ST
影响因子：
37.8
作者：
Hare, JM;Givertz, MM;Colucci, WS
通讯作者：
Colucci, WS
影响因子：
37.8
作者：
Mohan, P;Brutsaert, DL;Sys, SU
通讯作者：
Sys, SU
影响因子：
3
作者：
Straznicka, M;Gong, G;Weiss, HR
通讯作者：
Weiss, HR