Nitric oxide (NO)-stimulated cyclic guanosine monophosphate (cGMP) is a key regulator of cardiovascular health, as NO-cGMP signalling is impaired in diseases like pulmonary hypertension, heart failure and chronic kidney disease. The development of NO-independent sGC stimulators and activators provide a novel therapeutic option to restore altered NO signalling. sGC stimulators have been already approved for the treatment of pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension (CTEPH), and chronic heart failure (HFrEF), while sGC activators are currently in phase-2 clinical trials for CKD. The best characterized effect of increased cGMP via the NO-sGC-cGMP pathway is vasodilation. However, to date, none of the sGC agonists are in development for hypertension (HTN). According to WHO, the global prevalence of uncontrolled HTN continues to rise, contributing significantly to cardiovascular mortality. While there are effective antihypertensive treatments, many patients require multiple drugs, and some remain resistant to all therapies. Thus, in addition to improved diagnosis and lifestyle changes, new pharmacological strategies remain in high demand. In this review we explore the potential of sGC stimulators and activators as novel antihypertensive agents, starting with the overview of NO-sGC-cGMP signalling, followed by potential mechanisms by which the increase in cGMP may regulate vascular tone and BP. These effects may encompass not only acute vasodilation, but also mid-term and chronic effects, such as the regulation of salt and water balance, as well as mitigation of vascular ageing and remodelling. The main section summarizes the preclinical and clinical evidence supporting the BP-lowering efficacy of sGC agonists.

• MeSH
• Guanylyl Cyclase C Agonists therapeutic use   pharmacology   MeSH
• Enzyme Activators therapeutic use   pharmacology   MeSH
• Antihypertensive Agents * therapeutic use   pharmacology   MeSH
• Cyclic GMP * metabolism   MeSH
• Hypertension * drug therapy   physiopathology   MeSH
• Humans MeSH
• Nitric Oxide metabolism   MeSH
• Soluble Guanylyl Cyclase * metabolism   MeSH
• Signal Transduction drug effects   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

Heart failure (HF) has been declared as global pandemic and current therapies are still ineffective, especially in patients that develop concurrent cardio-renal syndrome. Considerable attention has been focused on the nitric oxide (NO)/soluble guanylyl cyclase (sGC)/cyclic guanosine monophosphate (cGMP) pathway. In the current study, we aimed to investigate the effectiveness of sGC stimulator (BAY41-8543) with the same mode of action as vericiguat, for the treatment of heart failure (HF) with cardio-renal syndrome. As a model, we chose heterozygous Ren-2 transgenic rats (TGR), with high-output heart failure, induced by aorto-caval fistula (ACF). The rats were subjected into three experimental protocols to evaluate short-term effects of the treatment, impact on blood pressure, and finally the long-term survival lasting 210 days. As control groups, we used hypertensive sham TGR and normotensive sham HanSD rats. We have shown that the sGC stimulator effectively increased the survival of rats with HF in comparison to untreated animals. After 60 days of sGC stimulator treatment, the survival was still 50% compared to 8% in the untreated rats. One-week treatment with sGC stimulator increased the excretion of cGMP in ACF TGR (109 ± 28 nnmol/12 h), but the ACE inhibitor decreased it (-63 ± 21 nnmol/12 h). Moreover, sGC stimulator caused a decrease in SBP, but this effect was only temporary (day 0: 117 ± 3; day 2: 108 ± 1; day 14: 124 ± 2 mmHg). These results support the concept that sGC stimulators might represent a valuable class of drugs to battle heart failure especially with cardio-renal syndrome, but further studies are necessary.

• MeSH
• Cyclic GMP metabolism   MeSH
• Guanylate Cyclase MeSH
• Hypertension * drug therapy   MeSH
• Cardio-Renal Syndrome * MeSH
• Rats MeSH
• Humans MeSH
• Nitric Oxide metabolism   MeSH
• Fistula * MeSH
• Rats, Transgenic MeSH
• Soluble Guanylyl Cyclase metabolism   MeSH
• Heart Failure * drug therapy   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

Významná morbidita a mortalita spojené se srdečním selháním se sníženou ejekční frakcí levé komory (HFrEF) jsou důvodem k hledání nových terapeutických modalit. Signální dráha vedoucí k aktivaci cyklického guanosinmonofosfátu (cGMP) interakcí oxidu dusnatého (NO) a solubilní guanylátcyklázy (sGC) hraje důležitou roli v regulaci kardiovaskulárních funkcí. Snížená dostupnost NO vlivem přítomnosti chronického zánětu a zvýšeného oxidativního stresu, které jsou časté u srdečního selhání, způsobuje deficit cGMP, který v konečném důsledku vede k fibróze a remodelaci myokardu, k poškození kardiomyocytů, omezení vazodilatace a ke zvýšení neurohumorální aktivace. Stimulátor sGC vericiguat zvyšuje citlivost sGC na endogenní NO. Explorativní studie fáze II SOCRATES‐REDUCED doložila u pacientů s progresí srdečního selhání, kteří užívali dávku 5–10 mg vericiguatu denně, dobrou toleranci léčby a snížení hodnot NT‐proBNP v průběhu 12 týdnů. Následovala klinická studie fáze III VICTORIA, která potvrdila klinickou bezpečnost a účinnost vericiguatu u pacientů s nedávnou dekompenzací HFrEF. Podrobnější rozbor těchto studií a náhled na perspektivu vericiguatu jako dalšího nadějného léku pro léčbu manifestního systolického srdečního selhání je předmětem tohoto souhrnného článku.

The significant morbidity and mortality associated with heart failure with reduced left ventricular ejection fraction (HFrEF) justify the search for new therapeutic agents. The signalling pathway leading to cyclic guanosine monophosphate (cGMP) activation by nitric oxide (NO) and soluble guanylate cyclase (sGC) interaction plays an important role in the regulation of cardiovascular function. Decreased NO availability due to the presence of chronic inflammation and increased oxidative stress, which is common in heart failure, causes cGMP deficiency that ultimately leads to myocardial fibrosis and remodelling, cardiomyocyte damage, decreased vasodilation and increased neurohumoral activation. The sGC stimulator vericiguat sensitises sGC to endogenous NO. A phase II exploratory study, the SOCRATES‐REDUCED trial, found good tolerance to vericiguat and a reduction in NT‐proBNP levels over 12 weeks of follow‐up in patients with progressive heart failure taking 5–10 mg of vericiguat daily. Followed by a phase III clinical study, the VICTORIA trial, the results confirmed the clinical safety and efficacy of vericiguat in patients with recently decompensated HFrEF. A more detailed analysis of these studies and an insight into the future perspective of vericiguat as another promising drug for the treatment of manifest systolic heart failure is the subject of this review article.

• Keywords
• vericiguat,
• MeSH
• Guanylyl Cyclase C Agonists * administration & dosage   therapeutic use   MeSH
• Heterocyclic Compounds, 2-Ring administration & dosage   therapeutic use   MeSH
• Clinical Trials, Phase II as Topic MeSH
• Clinical Trials, Phase III as Topic MeSH
• Humans MeSH
• Pyrimidines administration & dosage   therapeutic use   MeSH
• Heart Failure * drug therapy   MeSH
• Check Tag
• Humans MeSH

Srdeční selhání je spojeno se sníženou dosažitelností oxidu dusnatého (NO) v myokardu a ledvinách, což podporuje rozvoj fibrózy, patologické hypertrofie a zánětu. Signální dráhu NO-cGMP (cyklického guanosin monofosfátu) lze stimulovat aktivací solubilní guanylátcyklázy, která představuje endogenní receptor pro NO. Přímý stimulátor sGC vericiguat (Verquvo®) je přípravek specificky vyvinutý pro pacienty se srdečním selháním, má minimální hypotenzní efekt, nemá významné lékové interakce a lze jej použít i u pokročilé renální dysfunkce. Vericiguat byl úspěšně testován v populaci pacientů se zhoršujícím se srdečním selháním (studie VICTORIA), kde významně snížil riziko úmrtí z kardiovaskulárních příčin a hospitalizace pro srdeční selhání. Vericiguat představuje novou možnost léčby pacientů se srdečním selháním, zvláště když použití ostatní farmakoterapie je omezeno hypotenzí nebo rozvojem kardiorenálního syndromu.

Chronic heart failure is associated with reduced bioavailability of nitric oxide (NO) in the myocardial tissue and in the kidney, leading to fibrosis, inflammation and pathologic hypertrophy. It is possible to stimulate directly NO-cGMP signaling pathway by stimulating soluble guanylate cyclase (sGC) that represents an endogenous receptor for NO. Direct sGC stimulator vericiguat (Verquvo®) is a drug developed specifically for patients with chronic heart failure and that has minimal hypotensive effects, has no significant drug interactions and can be used also in advanced renal dysfunction. Vericiguat was effectively tested in population of patients with worsening heart failure (VICTORIA global trial) in which it reduced risk of cardiovascular death or hospitalization for heart failure. Vericiguat represents a new therapeutic option for heart failure, especially in subjects where other therapies are limited by hypotension or development of cardiorenal syndrome.

• Keywords
• vericiguat,
• MeSH
• Heterocyclic Compounds, 2-Ring pharmacology   therapeutic use   MeSH
• Cardio-Renal Syndrome MeSH
• Clinical Studies as Topic MeSH
• Humans MeSH
• Nitric Oxide MeSH
• Pyrimidines pharmacology   therapeutic use   MeSH
• Heart Failure * drug therapy   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Review MeSH

Heart failure (HF) is a leading cause of morbidity and mortality, often driven by prolonged exposure to pathological stimuli such as pressure and volume overload. These factors contribute to excessive oxidative stress, adverse cardiac remodeling, and dysregulation of the nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate (NO-sGC-cGMP) signaling pathway. Given the urgent need for effective treatments, this study investigated the potential of sGC stimulators to mitigate HF progression. We utilized male hypertensive Ren-2 transgenic (TGR) rats and a volume-overload HF model induced by an aortocaval fistula (ACF). Rats received the sGC stimulator BAY 41-8543 (3 mg/kg/day) for 30 weeks, while normotensive Hannover Sprague-Dawley rats served as controls. At the study endpoint (40 weeks of age), left ventricular tissue was analyzed using mass spectrometry, Western blotting, and histological assessment. TGR rats treated with sGC stimulators exhibited a significant increase in key antioxidant proteins (SOD1, CH10, ACSF2, NDUS1, DHE3, GSTM2, and PCCA), suggesting enhanced resistance to oxidative stress. However, sGC stimulator treatment also upregulated extracellular matrix remodeling markers (MMP-2, TGF-β, and SMAD2/3), which are typically associated with fibrosis. Despite this, Masson's trichrome staining revealed reduced collagen deposition in both TGR and TGR-ACF rats receiving sGC stimulators. Notably, all untreated TGR-ACF rats succumbed before the study endpoint, preventing direct assessment of sGC stimulator effects in advanced HF. These findings highlight the therapeutic potential of sGC stimulators in HF, particularly through their antioxidant effects. However, their concurrent influence on fibrosis warrants further investigation to optimize treatment strategies.

• MeSH
• Chronic Disease MeSH
• Fibrosis MeSH
• Cyclic GMP metabolism   MeSH
• Rats MeSH
• Disease Models, Animal MeSH
• Morpholines MeSH
• Oxidative Stress * drug effects   MeSH
• Rats, Sprague-Dawley * MeSH
• Rats, Transgenic MeSH
• Pyridines pharmacology   therapeutic use   MeSH
• Pyrimidines MeSH
• Ventricular Remodeling drug effects   MeSH
• Soluble Guanylyl Cyclase * metabolism   MeSH
• Signal Transduction drug effects   MeSH
• Heart Failure * drug therapy   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH