See Article by Nakamura et al

Acting is very start and stop.

—Estelle Parsons

Despite major therapeutic advances in the treatment of heart failure (HF), this syndrome continues to extract an oppressive clinical penalty of morbidity and mortality. Moreover, the increased prevalence of HF also imposes a major health system economic burden. Hence, this rising cascade of unmet health needs has generated intense interest in discovering novel therapeutic solutions.

In this context, NO occupies central stage given its fundamental role in activating soluble guanylate cyclase (sGC).¹ In turn, sGC generates cyclic GMP (cGMP)—a potent activator of the PKG1α (protein kinase G1α), which plays an essential and pleiotropic role in normal cardiovascular function by inhibiting vasoconstriction, inflammation, hypertrophy, and fibrosis.² Hence, reduced sGC activity is an important contributor to coronary microvascular impairment, cardiomyocyte stiffness, and interstitial fibrosis.³ It is now recognized that oxidative stress is a key feature of the HF syndrome as reflected by excess production of reactive oxygen species (ROS) which reduce NO bioavailability.⁴ In cardiovascular disease, the most important sources of ROS are the mitochondrial respiratory chain, various oxidases, uncoupled NO synthase, and MPO (myeloperoxidase) from infiltrating monocytes and neutrophils.⁵ Clinically, there are several ways to enhance NO availability. These include inhalation of NO and the addition of nitrate therapy, but both have significant limitations.⁶ Reducing degradation of cGMP offers an additional therapeutic option. A variety of cyclic nucleotide PDEs (phosphodiesterases) break down cGMP into GMP, a process sensitive to inhibitors currently in clinical use, such as milrinone and theophylline. This alternative approach also led to rediscovery of the PDE5 inhibitor sildenafil for applications in cardiovascular medicine. Retarding catabolism of cGMP through PDE5 inhibition with sildenafil appeared a potentially attractive way to mitigate the …

参见Nakamura等人的文章

演戏是很开始和停止的。

埃斯特尔·帕森斯（Estelle Parsons）

尽管在心力衰竭（HF）的治疗方面取得了重大的医学进展，但该综合征仍继续对发病率和死亡率产生压迫性的临床惩罚。而且，HF的患病率增加也给卫生系统带来了巨大的经济负担。因此，不断增长的未满足的健康需求引起了人们对发现新型治疗方案的浓厚兴趣。

在这种情况下，由于NO在激活可溶性鸟苷酸环化酶（sGC）中起基本作用，因此占据了中心位置。¹反过来，sGC产生了环状GMP（cGMP）—一种PKG1α（蛋白激酶G1α）的有效激活剂，它通过抑制血管收缩，炎症，肥大和纤维化，在正常的心血管功能中起着必不可少的作用。²因此，降低的sGC活性是导致冠状动脉微血管损伤，心肌细胞僵硬和间质纤维化的重要因素。³现在已经认识到，氧化应激是HF综合征的一个关键特征，反应活性氧（ROS）的过量产生反映了NO的生物利用度降低，这反映了HF综合征。⁴在心血管疾病中，ROS的最重要来源是线粒体呼吸链，各种氧化酶，未偶联的NO合酶和浸润的单核细胞和嗜中性粒细胞的MPO（髓过氧化物酶）。⁵临床上，有几种方法可以增强NO的可用性。这些措施包括吸入NO和添加硝酸盐疗法，但两者都有明显的局限性。⁶减少cGMP的降解提供了另一种治疗选择。多种环状核苷酸PDE（磷酸二酯酶）将cGMP分解为GMP，此过程对目前临床上使用的抑制剂（如米力农和茶碱）敏感。这种替代方法还导致重新发现了PDE5抑制剂西地那非，用于心血管医学。西地那非通过抑制PDE5来抑制cGMP分解代谢，似乎是减轻…的潜在诱人方法。