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
• Names of Substances
• Guanylyl Cyclase C Agonists MeSH
• Enzyme Activators MeSH
• Antihypertensive Agents * MeSH
• Cyclic GMP * MeSH
• Nitric Oxide MeSH
• Soluble Guanylyl Cyclase * MeSH

Pig oocytes matured in vitro were parthenogenetically activated (78%) after treatment with 2 mM nitric oxide-donor (+/-)-S-nitroso-N-acetylpenicillamine (SNAP) for 24 h. Inhibition of soluble guanylyl cyclase with the specific inhibitors 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) or 6-anilino-5,8-quinolinequinone (LY83583) suppressed the SNAP-induced activation in a dose-dependent manner (23% of activated oocytes after treatment with 400 microM ODQ; 12% of activated oocytes after treatment with 40 microM LY83583). 8-Bromo-cyclic guanosine monophosphate (8-Br-cGMP), a phosphodiesterase-resistant analogue of cGMP, enhances the effect of suboptimal doses (0.1 or 0.5 mM) of the NO donor SNAP. DT3, a specific inhibitor of cGMP-dependent protein kinase (PKG, PKG), is also able to inhibit the activation of pig oocytes after NO donor treatment. Involvement of the cGMP-dependent signalling pathway is specific for NO-induced oocyte activation, because both the guanylyl cyclase inhibitor ODQ and the PKG inhibitor DT3 are unable to inhibit activation in oocytes treated with the calcium ionophore A23187. These data indicate that the activation of pig oocytes with an NO donor is cGMP-dependent and that PKG plays an important role in this mode of oocyte activation.

• MeSH
• Enzyme Activation drug effects   MeSH
• Aminoquinolines metabolism   pharmacology   MeSH
• Quinoxalines metabolism   pharmacology   MeSH
• Digitoxin metabolism   pharmacology   MeSH
• Phosphoric Diester Hydrolases metabolism   MeSH
• Cyclic GMP analogs & derivatives   metabolism   pharmacology   MeSH
• Guanylate Cyclase MeSH
• Protein Kinase Inhibitors metabolism   pharmacology   MeSH
• Oocytes cytology   drug effects   enzymology   MeSH
• Oxadiazoles metabolism   pharmacology   MeSH
• Nitric Oxide metabolism   MeSH
• Penicillamine analogs & derivatives   metabolism   pharmacology   MeSH
• Cell Membrane Permeability drug effects   MeSH
• Swine metabolism   MeSH
• Cyclic GMP-Dependent Protein Kinases antagonists & inhibitors   metabolism   MeSH
• Receptors, Cytoplasmic and Nuclear metabolism   MeSH
• Soluble Guanylyl Cyclase MeSH
• Signal Transduction * drug effects   MeSH
• Nitric Oxide Synthase metabolism   MeSH
• Dose-Response Relationship, Drug MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one MeSH Browser
• 6-anilino-5,8-quinolinedione MeSH Browser
• 8-bromocyclic GMP MeSH Browser
• Aminoquinolines MeSH
• Quinoxalines MeSH
• Digitoxin MeSH
• Phosphoric Diester Hydrolases MeSH
• Cyclic GMP MeSH
• Guanylate Cyclase MeSH
• Protein Kinase Inhibitors MeSH
• Oxadiazoles MeSH
• Nitric Oxide MeSH
• Penicillamine MeSH
• Cyclic GMP-Dependent Protein Kinases MeSH
• Receptors, Cytoplasmic and Nuclear MeSH
• Soluble Guanylyl Cyclase MeSH
• S-nitro-N-acetylpenicillamine MeSH Browser
• Nitric Oxide Synthase 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.

• Keywords
• ACF, BAY41-8543, Heart failure, Vericiguat, cGMP, sGC stimulator,
• 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
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Cyclic GMP MeSH
• Guanylate Cyclase MeSH
• Nitric Oxide MeSH
• Soluble Guanylyl Cyclase MeSH

All anthracyclines, including doxorubicin (DOXO), the most common and still indispensable drug, exhibit cardiotoxicity with inherent risk of irreversible cardiomyopathy leading to heart failure with reduced ejection fraction (HFrEF). Current pharmacological strategies are clearly less effective for this type of HFrEF, hence an urgent need for new therapeutic approaches. The prerequisite for success is thorough understanding of pathophysiology of this HFrEF form, which requires an appropriate animal model of the disease. The aim of this study was to comprehensively characterise a novel model of HF with cardiorenal syndrome, i.e. DOXO-induced HFrEF with nephrotic syndrome, in which DOXO was administered to Ren-2 transgenic rats (TGR) via five intravenous injections in a cumulative dose of 10 mg/kg of body weight (BW). Our analysis included survival, echocardiography, as well as histological examination of the heart and kidneys, blood pressure, but also a broad spectrum of biomarkers to evaluate cardiac remodelling, fibrosis, apoptosis, oxidative stress and more. We have shown that the new model adequately mimics the cardiac remodelling described as "eccentric chamber atrophy" and myocardial damage typical for DOXO-related cardiotoxicity, without major damage of the peritoneum, lungs and liver. This pattern corresponds well to a clinical situation of cancer patients receiving anthracyclines, where HF develops with some delay after the anticancer therapy. Therefore, this study may serve as a comprehensive reference for all types of research on DOXO-related cardiotoxicity, proving especially useful in the search for new therapeutic strategies.

• Keywords
• Chemotherapy induced heart failure, Doxorubicin, Experimental model of heart failure, NO/sGC/cGMP pathway, Ren-2 transgenic hypertensive rat,
• MeSH
• Doxorubicin * adverse effects   MeSH
• Rats MeSH
• Kidney drug effects   physiopathology   MeSH
• Disease Models, Animal * MeSH
• Nephrotic Syndrome * chemically induced   drug therapy   physiopathology   MeSH
• Oxidative Stress drug effects   MeSH
• Rats, Transgenic * MeSH
• Antibiotics, Antineoplastic adverse effects   MeSH
• Heart Failure * chemically induced   physiopathology   MeSH
• Stroke Volume * drug effects   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Doxorubicin * MeSH
• Antibiotics, Antineoplastic 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.

• Keywords
• heart failure with reduced ejection fraction, reactive oxygen/nitrogen species, renin‐angiotensin system, soluble guanylate cyclase stimulator,
• MeSH
• Guanylyl Cyclase C Agonists * pharmacology   therapeutic use   MeSH
• Rats MeSH
• Disease Models, Animal MeSH
• Morpholines MeSH
• Oxidative Stress drug effects   MeSH
• Rats, Sprague-Dawley MeSH
• Rats, Transgenic MeSH
• Pyrazoles * pharmacology   therapeutic use   MeSH
• Pyrimidines * pharmacology   therapeutic use   MeSH
• Ventricular Remodeling drug effects   MeSH
• Soluble Guanylyl Cyclase * metabolism   MeSH
• Heart Failure * drug therapy   etiology   physiopathology   metabolism   pathology   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Guanylyl Cyclase C Agonists * MeSH
• BAY 41-8543 MeSH Browser
• Morpholines MeSH
• Pyrazoles * MeSH
• Pyrimidines * MeSH
• Soluble Guanylyl Cyclase * MeSH