cinaciguat (BAY 58-2667) / Bayer - LARVOL DELTA

Vascular diameter and responsiveness to soluble guanylate cyclase modulators: A systematic review of preclinical and clinical evidence. (PubMed, Microvasc Res) - "Current evidence supports a size-dependent pattern of vascular responsiveness to sGC modulators, but inference strength is constrained by heterogeneous methodologies and inconsistent reporting. Future work should implement standardized vessel classification, rigorous biospecimen handling, and transparent methodological documentation to clarify the clinical significance of vessel diameter in sGC-based therapy."

Journal • Preclinical • Review • Cardiovascular

Neuronal regulation of myenteric interstitial cells of Cajal (ICC-MY) in the proximal colon. (PubMed, Cell Calcium) - "Tonic inhibition was mimicked by a nitric oxide donor, NONOate, and by a guanylate cyclase agonist (Bay 58-2667)...Carbachol (CCh) increased Ca2+ transients in ICC-MY, and these effects were mediated by M3 muscarinic receptors...Cessation of nitrergic stimulation resulted in a substantial increase in Ca2+ transients, known as post-stimulus excitation. In summary, ICC-MY, important for the generation of propulsive contractions in the colon, are innervated by excitatory (cholinergic) and inhibitory (nitrergic) motor neurons, and these inputs regulate the excitability of these cells."

Journal • ANO1

SMURF1 Affects Dental Implant Integration in Diabetes By Regulating PKG2 Expression. (PubMed, Appl Biochem Biotechnol) - "In T2DM, SMURF1 regulated PKG2 expression through ubiquitination, thereby interfering with osteogenic differentiation and affecting the integration of dental transplantation."

Journal • Diabetes • Inflammation • Metabolic Disorders • Targeted Protein Degradation • Transplantation • Type 2 Diabetes Mellitus • ATF4 • HSPA5 • RUNX2 • SMURF1 • UBR5

Lipocalin-2 Restores Soluble Guanylyl Cyclase-Dependent Dilation of the Afferent Arteriole After Renal Transplantation or Ex Vivo Hypoxia/Reoxygenation in Mice. (PubMed, Acta Physiol (Oxf)) - "This study identifies a novel role for holo-rLcn2 in preserving renal vascular function post-H/R and kidney transplantation, apparently by upholding iron levels in vascular cells."

Journal • Preclinical • Cardiovascular • Nephrology • Reperfusion Injury • Transplantation • LCN2

Vascular diameter determines sensitivity to soluble guanylate cyclase activation in human mesenteric and renal arteries. (PubMed, Vascul Pharmacol) - "In contrast to murine arteries, SNP- and cinaciguat-induced vasodilation is similar in human intrarenal and mesenteric arteries. In the human vasculature, small diameter arteries are more responsive to sGC activation than large diameter vessels irrespective of the degree of MLC20-S19 phosphorylation."

Journal

Stimulation of Soluble Guanylyl Cyclase (sGC) by Cinaciguat Attenuates Sepsis- Induced Cardiac Injury. (PubMed, Curr Mol Pharmacol) - "We demonstrated that cinaciguat alleviated LPS-induced cardiac dysfunction, inflammation, and apoptosis through the PRKG1/CREB/FtMt pathway, thereby protecting against LPS-induced cardiac injury. This study identified a new strategy for treating cardiac injury caused by sepsis."

IO biomarker • Journal • Cardiomyopathy • Cardiovascular • Infectious Disease • Oncology • Septic Shock • BAX • BCL2 • CASP3 • IL1B • IL6 • TNFA

Pharmacological activation of NO-sensitive guanylyl cyclase ameliorates obesity-induced arterial stiffness. (PubMed, Vascul Pharmacol) - "Collectively, our data strongly support the notion that pharmacological NO-GC activation would be beneficial in decreasing obesity-associated arterial stiffness by decreasing VSMC cytoskeletal actin hyper-polymerization. If translated to humans, NO-GC activators could become a viable approach to clinically treat arterial stiffness, which remains an unmet medical need."

Journal • Alzheimer's Disease • Cardiovascular • CNS Disorders • Dementia • Genetic Disorders • Obesity • Oncology • TNFA

Pharmacological Activation of NO-Sensitive Guanylyl Cyclase Ameliorates Obesity-Induced Arterial Stiffness. (PubMed, bioRxiv) - "In the current study, we tested whether activating NO-GC with an NO-GC activator (cinaciguat) modulates pVASP S239 and cytoskeletal actin polymerization in VSMCs, thereby preventing obesity-induced arterial stiffness...Collectively, our data strongly support the notion that pharmacological NO-GC activation would be beneficial in decreasing obesity-associated arterial stiffness by decreasing VSMC cytoskeletal actin hyper-polymerization. If translated to humans, NO-GC activators could become a viable approach to clinically treat arterial stiffness, which remains an unmet medical need."

Journal • Alzheimer's Disease • Cardiovascular • CNS Disorders • Dementia • Genetic Disorders • Obesity • Oncology • TNFA

Runcaciguat activates soluble guanylyl cyclase via the histidine essential for heme binding and nitric oxide activation. (PubMed, Biochem Pharmacol) - "We confirm that the first generation of sGC activators cinaciguat and BAY 60-2770 activate the α1/β1H105F and α1/β1H105A mutants. The histidine-dependency of some of the sGC activators provides a compelling rationale for a re-evaluation of previous research and drug development programs based on sGC histidine mutants. Whether the classification of sGC activators based on the activation mechanism also makes a therapeutic difference needs to be clarified in the future."

Journal • Cardiovascular • Congestive Heart Failure • Heart Failure • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases

Alanine mutation of the targeting subunit of the myosin phosphatase, MYPT1 at threonine 696 reduces cGMP responsiveness of mouse femoral arteries. (PubMed, Eur J Pharmacol) - "The effect of a direct sGC activation by cinaciguat was also attenuated in both age groups of MYPT1-T696A/+, but strongly in o-FA...Interestingly, neither eNOS-S1177 nor the phosphorylation of the PKG phosphospecific sites, MYPT1-S695 and MYPT1-S668 were altered by MYPT1-T696A-mutation or aging. These findings suggest that the alanine mutation of MYPT1-T696 reduces the ability of the NO/cGMP/PKG-system to relax FAs in aging."

Journal • Preclinical • NOS3 • RHOA

Impact of antiplatelets, anticoagulants and cyclic nucleotide stimulators on neutrophil extracellular traps (NETs) and inflammatory markers during COVID-19. (PubMed, J Thromb Thrombolysis) - "Healthy neutrophils were stimulated with phorbol-12-myristate-13-acetate (PMA) or COVID-19 sera and treated with unfractionated heparin (UFH), low molecular weight heparin (LMWH), aspirin (ASA), ticagrelor, cinaciguat, sildenafil, and milrinone. In the first week of hospitalization, NET markers rose later than inflammatory markers in severe COVID-19 cases. Cyclic nucleotide stimulators, ASA and heparin may emerge as treatment approaches as they may modulate NETosis."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases • CXCL8 • IL17A • IL6 • TNFA

Protein kinase G2 activation restores Wnt signaling and bone mass in glucocorticoid-induced osteoporosis in mice. (PubMed, JCI Insight) - "Cinaciguat reduced dexamethasone activation of osteoclasts, but this did not occur in the PKG2R242Q transgenic mice, suggesting a minor role in osteoprotection. We propose that existing PKG-targeting drugs could represent a novel therapeutic approach to prevent glucocorticoid-induced osteoporosis."

Journal • Preclinical • Musculoskeletal Diseases • Orthopedics • Osteoporosis • Rheumatology

Role of the NO-GC/cGMP signaling pathway in platelet biomechanics. (PubMed, Platelets) - "We therefore investigated the stiffness of living platelets after treatment with the NO-GC stimulator riociguat or the NO-GC activator cinaciguat using scanning ion conductance microscopy (SICM). To test for clinical applicability of NO-GC stimulators in the context of increased thrombogenicity risk, we investigated the effect of riociguat on platelets from human immunodeficiency virus (HIV)-positive patients taking abacavir sulfate (ABC)-containing regimens. Our results corroborate a functional role of the NO-GC/cGMP pathway in platelet biomechanics, indicating that biomechanical properties such as stiffness or shape could be used as novel biomarkers in clinical research."

Journal • Human Immunodeficiency Virus • Infectious Disease

Novel application potential of cinaciguat in the treatment of mixed hyperlipidemia through targeting PTL/NPC1L1 and alleviating intestinal microbiota dysbiosis and metabolic disorders. (PubMed, Pharmacol Res) - "In vivo evaluation showed that cinaciguat significantly reduced the plasma levels of triglycerides and cholesterol, and effectively alleviated high-fat diet-induced intestinal microbiota dysbiosis and metabolic disorders. These results collectively suggest that cinaciguat has the potential to be further developed for the therapy of mixed hyperlipidemia."

Journal • Atherosclerosis • Cardiovascular • Congestive Heart Failure • Dyslipidemia • Heart Failure • Metabolic Disorders

Targeting neurotrophin and nitric oxide signaling to promote recovery and ameliorate neurogenic bladder dysfunction following spinal cord injury - Mechanistic concepts and clinical implications. (PubMed, Continence (Amst)) - "Attenuation of the spinal cord lesion itself was discussed with respect to the potential of a trio of agents: LM11A-3, a p75 neurotrophin receptor modulator to counter activation of local apoptotic pathways; LM22B-10 to promote neuronal growth by targeting tropomyosin-related kinase (Trk) receptors; and cinaciguat, a soluble guanylate cyclase (sGC) activator as an agent promoting angiogenesis at the injury site...Finally, the importance of increased mechanosensitive signaling as a contributor to DSD was considered, as well as potential drug targets. Overall, an emphasis was placed on targets that help restore function and reduce pathological LUT consequences, rather than downregulate normal function."

Journal • Ataxia • CNS Disorders • Fibrosis • Immunology • Orthopedics • Urology

Soluble Guanylate Cyclase Activators to Treat Benign Prostatic Hyperplasia and associated LUTS. (PubMed, Continence (Amst)) - "Patient refractoriness to tadalafil may be, for example, due to sGC inactivation due to oxidative stress. The workshop discussed the superiority of cinaciguat, an sGC activator that functions even when the enzyme is oxidised, over PDE5 inhibitors, and potentially its use in combination with agents that reduce formation of reactive oxygen species."

Journal • Benign Prostatic Hyperplasia • Fibrosis • Immunology

Hydrogen sulfide regulates the redox state of soluble guanylate cyclase in CSE mice corpus cavernosum microcirculation. (PubMed, Pharmacol Res) - "Indeed, the absence of CSE-derived endogenous HS caused a significant reduction of the relaxant response to riociguat, an sGC redox-dependent stimulator. Conversely, the response to cinaciguat, an sGC redox-independent activator, was not modified...In conclusion, the endogenous CSE-derived HS plays a physiological key role in the regulation of the redox state of sGC in CC microcirculation. DATA AVAILABILITY: Data are contained within the article or supplementary material."

Journal • Preclinical • Cardiovascular • Erectile Dysfunction • NOS3

Effects of Soluble Guanylate Cyclase Stimulators and Activators on Anti-Aggregatory Signalling in Patients with Coronary Artery Spasm. (PubMed, Int J Mol Sci) - "ADP-induced platelet aggregation and its inhibition by the NO donor sodium nitroprusside (SNP), the sGC stimulator riociguat (RIO), and the sCG activator cinaciguat (CINA) alone or in addition to SNP were quantitated. However, the intrinsic anti-aggregatory effects of CINA are most marked in individuals with initially normal NO/sGC signalling, and thus their magnitude is at variance with extent of physiological impairment. These data suggest that RIO and other sGC stimulators should be evaluated for clinical utility in both prophylaxis and treatment of CAS."

Journal • Atrial Fibrillation • Cardiovascular • Congestive Heart Failure • Heart Failure

Molecular and Cellular Mechanisms of Lipocalin-2 Mediated Renoprotection in Kidney Transplantation [Board No. B051] (ATC 2023) - "To assess the effect of rLcn2 on the physiology of renal microvessels, dilatation function of BAY58-2667 (sGC activator) on AngII-preconstricted murine afferent arterioles (AA) was examined following H/R (H:30min/ R:10min) and syngeneic KTx (CIT: 5.5h, R: 20h) ± rLcn2, apo-rLcn2 and deferoxamine (DFO). rLcn2 protects mouse renal allografts from CD8 + T cell mediated alloimmune response and attenuates ischemia reperfusion injury-induced loss in dilatation of renal AA both in vitro (H/R) and in vivo (KTx)."

Cardiovascular • Immune Modulation • Inflammation • Reperfusion Injury • Transplant Rejection • Transplantation • CD8 • IFNG • LCN2 • NKG2D

Soluble Guanylate Cyclase Activators and Stimulators in Patients with Heart Failure. (PubMed, Curr Cardiol Rep) - "Cinaciguat and praliciguat have shown no clear clinical benefit in patients with heart failure in clinical trials. To date, only vericiguat reduces the composite of death from cardiovascular causes or first hospitalization for heart failure in patients with heart failure with reduced ejection fraction and riociguat might improve clinical symptoms and quality of life in patients with heart failure, both heart failure with reduced and preserved ejection fraction. We need more exploration about soluble guanylate cyclase activators and stimulators in patients with heart failure."

Journal • Review • Cardiovascular • Congestive Heart Failure • Heart Failure • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases

Oxidized soluble guanylyl cyclase causes erectile dysfunction in alcoholic mice. (PubMed, Br J Pharmacol) - "Our results demonstrate that alcoholic mice show ED in vitro and in vivo due to an alteration of the redox state of sGC and suggest that sGC activators may be effective in ED associated with alcoholism."

Journal • Preclinical • Addiction (Opioid and Alcohol) • Anesthesia • Erectile Dysfunction • CYP2E1

BAY58-2667 activates different sGC species by distinct mechanisms that indicate its principal target in cells is the heme-free sGCβ-Hsp90 complex. (PubMed, Mol Pharmacol) - "This study clarifies what forms of sGC exist in living cells, which of these can be activated by the agonists, and the mechanisms and kinetics by which each form is activated. This information may help to hasten deployment of these agonists for pharmaceutical intervention and clinical therapy."

Journal • HSP90AA1 • SGCA

Methylene Blue Inhibits Cromakalim-Activated K Currents in Follicle-Enclosed Oocytes. (PubMed, Membranes (Basel)) - "The binding characteristics of the K ligand [H]glibenclamide are not altered by MB in a concentration range between 1 μM-1 mM, as suggested by radioligand binding assay. The presence of a membrane permeable cGMP analogue (8-Br-cGMP, 100 µM) and a guanylate cyclase activator (BAY 58-2667, 3 µM) did not affect the inhibitory effects of MB, suggesting that MB does not inhibit cromakalim-activated K currents through guanylate cyclase. Collectively, these results suggest that MB directly inhibits cromakalim-activated K currents in follicular cells of Xenopus oocytes."

Journal

Hyperelastic and damage properties of the hypoxic aorta treated with Cinaciguat. (PubMed, J Biomech) - "Results showed that Cinaciguat has an effect on the damage behavior at large strains, altering the damage onset under uniaxial tension. We conclude that Cinaciguat, as a vasodilator, can prevent the very early effects of vascular remodeling caused by perinatal hypoxia, and improve the aortic-tissue damage properties of hypoxic lambs."

Journal • Cardiovascular • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases

Inhibition of multidrug resistance proteins by MK571 restored the erectile function in obese mice through cGMP accumulation. (PubMed, Andrology) - "The MRPs inhibition by MK571 favored the accumulation of cGMP in the smooth muscle cells, thus improving the smooth muscle relaxation and the erectile function in obese mice."

Journal • Preclinical • Erectile Dysfunction • Obesity • ABCC4 • ABCC5