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Riociguat, an orally soluble guanylate cyclase (sGC)-promoting drug, is mainly used in the clinical treatment of pulmonary hypertension (PH). In this study, a novel ultra-performance liquid chromatography-tandem mass spectrometry method was developed to quantify the concentrations of riociguat and its metabolite (M1) in plasma. The precision, stability, accuracy, matrix effect, and recovery of the methodology were satisfactory. Quercetin, a well-recognized compound, functions as a novel anticancer agent with the potential to alleviate symptoms of PH. Therefore, the potential interaction between quercetin and riociguat was investigated in this study. The levels of riociguat and M1 in rat plasma were measured using the method developed in this study to evaluate the interactions between riociguat and quercetin in rats. The results revealed that quercetin significantly inhibited riociguat and M1 metabolism with increased systemic exposure.

Cyclic guanosine monophosphate (cGMP) is a unique second messenger molecule formed in different cell types and tissues. cGMP targets a variety of downstream effector molecules and, thus, elicits a very broad variety of cellular effects. Its production is triggered by stimulation of either soluble guanylyl cyclase (sGC) or particulate guanylyl cyclase (pGC); both enzymes exist in different isoforms. cGMP-induced effects are regulated by endogenous receptor ligands such as nitric oxide (NO) and natriuretic peptides (NPs). Depending on the distribution of sGC and pGC and the formation of ligands, this pathway regulates not only the cardiovascular system but also the kidney, lung, liver, and brain function; in addition, the cGMP pathway is involved in the pathogenesis of fibrosis, inflammation, or neurodegeneration and may also play a role in infectious diseases such as malaria. Moreover, new pharmacological approaches are being developed which target sGC- and pGC-dependent pathways for the treatment of various diseases. Therefore, it is of key interest to understand this pathway from scratch, beginning with the molecular basis of cGMP generation, the structure and function of both guanylyl cyclases and cGMP downstream targets; research efforts also focus on the subsequent signaling cascades, their potential crosstalk, and also the translational and, ultimately, the clinical implications of cGMP modulation. This review tries to summarize the contributions to the “9th International cGMP Conference on cGMP Generators, Effectors and Therapeutic Implications” held in Mainz in 2019. Presented data will be discussed and extended also in light of recent landmark findings and ongoing activities in the field of preclinical and clinical cGMP research.

In this trial, 443 patients with pulmonary arterial hypertension were assigned to placebo or to the soluble guanylate cyclase stimulator riociguat. At 12 weeks, riociguat significantly improved the 6-minute walk distance and pulmonary vascular resistance. Pulmonary arterial hypertension is a life-threatening disease that is characterized by increased pulmonary vascular resistance owing to progressive vascular remodeling, which can ultimately lead to right heart failure and death. 1 , 2 Current treatments include phosphodiesterase type 5 inhibitors, prostanoids, and endothelin-receptor antagonists. 1 However, mortality remains high despite treatment, 3 and there is a considerable unmet medical need in the management of this disorder. As noted elsewhere in this issue of the Journal, 4 riociguat is a member of a novel therapeutic class known as soluble guanylate cyclase stimulators. Riociguat has a dual mode of action, acting in synergy with endogenous nitric oxide . . .

[This corrects the article DOI: 10.3389/fphar.2023.1052546.].

Contrast‐induced nephropathy (CIN) is an important cause of acute kidney injury following exposure to iodinated contrast media, and effective preventive strategies remain limited. This study investigated the renoprotective effects of riociguat, a soluble guanylate cyclase stimulator, in an experimental rat model of CIN and explored machine‐learning‐based prediction of renal injury using histopathological, biochemical, and inflammatory markers. Thirty‐six female Wistar albino rats were randomized into control, riociguat, CIN model, and CIN + riociguat groups. CIN was induced by iohexol after dehydration, and riociguat was administered orally for 5 days. Renal injury was assessed by histopathological scoring, TUNEL assay, and biochemical parameters including serum creatinine, urea, tumor necrosis factor‐alpha, nitric oxide, neutrophil gelatinase‐associated lipocalin, and advanced oxidation protein products. Riociguat significantly decreased serum creatinine, urea, apoptotic index, and histopathological injury scores, reduced inflammatory and oxidative stress markers, and increased nitric oxide levels compared with untreated CIN animals ( p < 0.05). Machine learning models (Random Forest, CatBoost, AdaBoost, and XGBoost) were applied for exploratory prediction and feature importance analysis. The apoptotic index and nitric oxide were identified as dominant predictors, indicating mechanistic relevance but limited clinical screening utility because these predictors require histological assessment. Overall, riociguat demonstrated significant renoprotective effects through anti‐apoptotic, anti‐inflammatory, and antioxidative mechanisms, and machine learning provided hypothesis‐generating insight rather than a clinically deployable predictive model.

Endogenous nitric oxide (NO)-dependent vascular relaxation plays a leading role in the homeostasis of the cardiovascular, pulmonary, and vascular systems and organs, such as the kidneys, brain, and liver. The mechanism of the intracellular action of NO in blood vessels involves the stimulation of the activity of the soluble cytosolic form of guanylyl cyclase (soluble guanylyl cyclase, sGC), increasing the level of cyclic 3′-5′—guanosine monophosphate (cGMP) in smooth muscle and subsequent vasodilation. In recent years, a new group of drugs, soluble guanylyl cyclase stimulators, has found its way into clinical practice. Based on the CHEST-1 and PATENT-1 trials, riociguat was introduced into clinical practice for treating chronic thromboembolic pulmonary hypertension (CTEPH). In January 2021, the FDA approved the use of another drug, vericiguat, for the treatment of heart failure.

Systemic sclerosis is an autoimmune connective tissue disease which is characterised by vascular perturbations, inflammation, and fibrosis. Although huge progress recently into the underlying molecular pathways that are perturbed in the disease, currently no therapy exists that targets the fibrosis element of the disease and consequently there is a huge unmet medical need. Emerging studies reveal new dimensions of complexity, and multiple aberrant pathways have been uncovered that have shed light on disturbed signalling in the disease, primarily in inflammatory pathways that can be targeted with repurposed drugs. Pre-clinical animal models using these inhibitors have yielded proof of concept for targeting these signalling systems and progressing to clinical trials. This review will examine the recent evidence of new perturbed pathways in SSc and how these can be targeted with new or repurposed drugs to target a currently intractable disease.

The pathogenesis of complex diseases such as pulmonary arterial hypertension (PAH) is entirely rooted in changes in the expression of some vasoactive factors. These play a significant role in the onset and progression of the disease. Indeed, PAH has been associated with pathophysiologic alterations in vascular function. These are often dictated by increased oxidative stress and impaired modulation of the nitric oxide (NO) pathway. NO reduces the uncontrolled proliferation of vascular smooth muscle cells that leads to occlusion of vessels and an increase in pulmonary vascular resistances, which is the mainstay of PAH development. To date, two classes of NO-pathway modulating drugs are approved for the treatment of PAH: the phosphodiesterase-5 inhibitors (PD5i), sildenafil and tadalafil, and the soluble guanylate cyclase activator (sGC), riociguat. Both drugs provide considerable improvement in exercise capacity and pulmonary hemodynamics. PD5i are the recommended drugs for first-line PAH treatment, whereas sGCs are also the only drug approved for the treatment of resistant or inoperable chronic thromboembolic pulmonary hypertension. In this review, we will focus on the current information regarding the nitric oxide pathway and its modulation in PAH.

Acute lung injury (ALI) pathogenesis is intricately linked to microvascular permeability. Soluble guanylate cyclase (sGC) is prominently expressed in the vascular system, playing a central role in vascular function. In contrast, its expression and function diminish notably during the progression of ALI, indicating sGC’s potential significance as a pivotal modulator in the pathological processes of ALI. Nonetheless, the precise localization of sGC within lung tissue and its distinct mechanism in maintaining vascular homeostasis remain unclear. Furthermore, there is a necessity for a pharmacological agent capable of consistently activating sGC for the treatment of ALI. A novel sGC stimulator, sGC003, was engineered through structural modification of Riociguat. In a mouse model of ALI, sGC003 exhibited superior sGC activation and more potent anti-inflammatory effects relative to Riociguat. It also exhibited superior efficacy in improving respiratory function and reducing pulmonary edema. Through single-cell RNA sequencing and immunofluorescence co-localization analysis, we confirmed predominant expression of soluble guanylate cyclase in pericytes. The sGC stimulators were found to modulate the LPS-induced pericyte transcriptome reprogramming via the nitric oxide (NO)-sGC-cyclic guanosine monophosphate (cGMP) pathway. Differential gene expression analysis categorized pericytes into nine distinct subgroups, which were sequentially activated during vascular development, inflammation, and myofibrosis. Pseudotime analysis revealed that sGC003 more effectively suppressed the myofibroblast differentiation of pericytes compared to Riociguat. In conclusion, sGC003 mitigates ALI-induced pulmonary inflammation by modulating pericyte differentiation, particularly in preserving microvascular integrity outstanding performance. Its exceptional efficacy suggests that it could potentially serve as a safer and more efficient option as a novel sGC stimulant in the future.