The impairment of the nitric oxide (NO) pathway is closely related to various cardiovascular diseases, such as heart failure, hypertension, and pulmonary hypertension. NO donor drugs or inhaled NO have significant limitations in clinical treatment. However, in recent years, with the in-depth study of the NO-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) signaling pathway-related mechanisms, the clinical application of sGC agonists in the cardiovascular system has been widely developed.

Soluble guanylate cyclase (sGC) primarily exists in platelets and vascular smooth muscle cells, serving as a central component of the NO-sGC-cyclic guanosine monophosphate (cGMP) signaling pathway. Research has shown that the NO-sGC-cGMP axis is a key signaling transduction pathway for regulating the cardiovascular system, thus sGC plays an important role in the treatment of diseases such as heart failure, hypertension, and pulmonary hypertension. sGC has a high affinity for NO. In endothelial cells, inflammatory factors stimulate the synthesis of NO by endothelial nitric oxide synthase, and then NO penetrates deeper to reach smooth muscle cells, activating sGC. Activated sGC then promotes excessive secretion of the second messenger cGMP through its C-terminal catalytic domain, triggering a series of cardiovascular responses, including vasodilation, leukocyte aggregation, and increased platelet activity. Insufficient cGMP secretion or decreased activity can lead to endothelial dysfunction, vasoconstriction, vascular stiffness and adverse remodeling, as well as reduced renal and coronary blood flow. Therefore, sGC agonists play a crucial role in anti-myocardial ischemia, improving left ventricular remodeling, treating heart failure, inhibiting inflammation and fibrosis, and improving metabolism, by activating downstream cGMP.

The protective mechanism of sGC agonists on the cardiovascular system:

Soluble guanylate cyclase agonists play a significant role in protecting against myocardial ischemia and heart failure, improving left ventricular remodeling, reducing pulmonary artery pressure, inhibiting inflammation and fibrosis, and improving myocardial metabolism, through activating downstream cyclic guanosine monophosphate (cGMP).

①I(mǎi)mprovement of ischemia-reperfusion injury: Pretreatment with sGC activator cinaciguat can reduce necrosis and apoptosis of myocardial cells, decrease the area of myocardial infarction, and improve myocardial and endothelial function after hypothermic cardiopulmonary bypass-induced cardiac arrest, providing important protection against myocardial ischemia-reperfusion injury. Additionally, studies have found that donor hearts pretreated with cinaciguat showed significant improvement in left ventricular function after heart transplantation. Drugs that stimulate the NO-GC-cGMP pathway rely on large-conductance calcium-activated potassium (BK) channels in cardiomyocytes to exert cardioprotective effects related to ischemia-reperfusion. Cardiomyocytes lacking BK channels are more susceptible to ischemia-reperfusion injury, and increasing BK activity favors the survival of ischemic-reperfused myocardium.

②Anti-heart failure and improvement of cardiac remodeling: Extensive basic research has also confirmed that sGC agonists have cardiac protective effects such as inhibiting myocardial fibrosis, improving myocardial hypertrophy, and ventricular remodeling. Cinaciguat, an sGC activator, can improve left ventricular remodeling by increasing the activity of protein kinase G (PKG), selectively inhibiting myocardial fibrosis, oxidative stress, and cardiomyocyte apoptosis. Additionally, cinaciguat can improve cardiac function by preventing structural and molecular changes in the hearts of diabetic rat models.

③Improvement of myocardial metabolic efficiency: Studies have shown that treatment with sGC activator riociguat significantly reduces coronary artery resistance and systemic vascular resistance in experimental animals, and can significantly improve cardiac metabolic efficiency in healthy piglets. 

④Reduction of pulmonary artery pressure and inhibition of pulmonary vascular remodeling: Studies have confirmed that sGC agonists can reduce pulmonary artery pressure and resistance, inhibit pulmonary vascular remodeling, and improve exercise tolerance in patients with pulmonary arterial hypertension. In 2013, riociguat was approved by the FDA for the treatment of patients with arterial pulmonary hypertension and chronic thromboembolic pulmonary hypertension with World Health Organization functional class II to III, achieving good clinical therapeutic effects. 

⑤Reduction of inflammation: In addition to reducing inflammation and oxidative stress and improving cardiomyocyte function, cinaciguat, an sGC activator, can also regulate the sGC-cGMP-PKG signaling pathway, normalizing the activities of hypertrophy-related kinases such as calmodulin-dependent protein kinase II, protein kinase C, and extracellular signal-regulated kinase 2. This suggests that cinaciguat not only improves heart failure but is also a potential treatment option for patients with myocardial hypertrophy.

The mechanism of action of sGC agonists in heart failure with preserved ejection fraction (HFpEF)

The NO-sGC-cGMP signaling pathway plays a pivotal role in the cardiovascular system, particularly in the context of pulmonary arterial hypertension, hypertension, and heart failure. HFpEF is a type of heart failure characterized by impaired active relaxation during left ventricular diastole and reduced myocardial compliance, leading to impaired left ventricular filling during diastole, reduced stroke volume, and increased diastolic end pressure. The mechanism of action of sGC agonists in HFpEF is not fully elucidated, but the currently known pathophysiological mechanisms primarily include the following:

①Changes in diastolic function: sGC reduces myofilament calcium sensitivity and has beneficial effects on cross-bridge detachment, consistent with the role of NO in increasing cGMP production and accelerating left ventricular diastole. Activation of cGMP-dependent protein kinases is conducive to improving ventricular hypertrophy, diastole, and stiffness.

②Changes in contractile function: In the myocardium, sGC can regulate contractility and attenuate adrenergic stimulation. In addition to myocardial effects, reversal of cardiac endothelial dysfunction can also improve diastolic function.

③Cardiac structural changes: sGC agonists, which target the cGMP signaling pathway, have antihypertensive effects and can favorably improve cardiac remodeling and reduce myocardial fibrosis at doses that do not affect blood pressure.

④Phosphorylation of cGMP-dependent protein kinases: Myosin is a protein anchored to the Z-line of the sarcomere and is a major determinant of myocardial passive tension and stiffness. It can be regulated by phosphorylation, which promotes the reduction of passive tension in titin and thus holds promise as a therapeutic target for reducing myocardial stiffness.

⑤Changes in vascular function and stiffness: In HFpEF patients, systemic vasodilation during exercise is significantly impaired, limiting cardiac output under stress conditions and manifesting as limited flow-mediated vasodilation. NO-dependent regulation is an important regulator of vascular tone, and reduced NO bioavailability in heart failure patients leads to vasoconstriction and vascular stiffness, increasing afterload. At the same time, reduced NO bioavailability may also upregulate sympathetic drive, promote catecholamine release, and enhance endothelin-1-induced vasoconstriction.

⑥Pulmonary hypertension: In elderly patients with normal left ventricular ejection fraction, HFpEF is the most common cause of elevated pulmonary artery pressure, and elevated pulmonary artery pressure also predicts increased mortality in HFpEF. There is significant overlap between diastolic dysfunction and pulmonary hypertension, and studies have confirmed that sGC agonists effective in pulmonary arterial hypertension are also beneficial in HFpEF.

sGC agonists demonstrate promising results in the treatment of cardiovascular diseases such as heart failure and pulmonary arterial hypertension, and they also represent a potential clinical option for future treatments of diseases like cardiac ischemia-reperfusion injury, myocardial hypertrophy, and myocardial metabolic abnormalities. With a deeper understanding of the NO-sGC-cGMP axis and the mechanistic studies of sGC, sGC agonists are providing more pharmaceutical options for the treatment of cardiovascular diseases. On the current basis, the clinical safety and efficacy of sGC agonists have been confirmed to a certain degree. It is evident that the production of cGMP triggered by sGC agonists holds broader market prospects for the treatment of cardiovascular diseases.

Reference Sources

[1] Wang Ximei, Wu Yongjian. Progress in Research on Cardiovascular Protective Effects of Soluble Guanylate Cyclase Agonists [J]. Advances in Cardiovascular Diseases, 2021, 42(05): 404-407.

[2] Lu Jun, Jin Jieni, Wang Hui, Hu Jingjing, Yu Qing, Cai Zhaobin. Clinical Application Progress of Soluble Guanylate Cyclase Agonists in the Treatment of Chronic Heart Failure [J]. Zhejiang Medical Journal, 2021, 43(22): 2492-2496.

[3] Jia Xiaoyan, An Jinyang, Peng Keling, Liu Yongming. Research Progress on the Treatment of Heart Failure with Preserved Ejection Fraction with Soluble Guanylate Cyclase Agonists [J]. Advances in Cardiovascular Diseases, 2022, 43(02): 141-145.

About the Author

Xiaomichong, a pharmaceutical quality researcher, has been committed to pharmaceutical quality research and drug analysis method validation for a long time. Currently employed by a large domestic pharmaceutical research and development company, she is engaged in drug inspection and analysis as well as method validation.