Not the cAMP/PKA pathway but the cGMP/PKG pathway promotes branchial ammonia excretion in the green shore crab, Carcinus maenas.

Soluble guanylate cyclase stimulator vericiguat alleviates skeletal muscle injury and exercise capacity decline in ApoE-/- mice by inhibiting oxidative stress and repairing mitophagy.

Polymodal vagal afferent nerves terminating in the mucosa of the large conducting airways play essential roles in regulating cough. These cough receptors project bilaterally from the nodose ganglia, are activated by protons and by mechanical stimulation, and terminate centrally in the medial (SolM) solitary tract nuclei (nTS). While many vagal afferent nerves utilize non-NMDA type glutamate receptors exclusively for transmission centrally, cough receptor signalling requires NMDA receptor activation. We hypothesized that nTS nitric oxide synthase (NOS) activation and a cGMP transduction cascade would act as downstream messenger systems during the encoding of cough. We also hypothesized that NOS expression may be a defining characteristic of cough receptor relay neurons. NADPH-diaphorase staining identified NOS-expressing neurons throughout the brain stem (especially in the trigeminal and cuneate nuclei and in the dorsal motor nuclei of the vagus nerves). NOS expressing nTS neurons were rare but found in SolM. Bilateral SolM microinjections of NOS inhibitors or the NMDA receptor blocker SDZ 220581 markedly reduced coughing evoked by tracheal citric acid challenges. But citric acid evoked coughing was neither attenuated by inhibiting soluble guanylate cyclase in SolM nor potentiated by inhibiting the cGMP-selective phosphodiesterase-5. No changes in basal respiratory patterns were observed with NOS inhibitor or NO donor microinjections, but NMDA microinjection into SolM induced respiratory responses including cough that were at least partially NOS dependent. We conclude that NO is an essential downstream regulator of NMDA receptor mediated encoding of cough in nTS but does not act via soluble guanylate cyclase or cGMP.

Lateralization of neuronal functions plays a critical role in regulating behavioral flexibility, but the underlying molecular mechanisms are challenging to establish at a single-neuron level. We previously showed that attraction of Caenorhabditis elegans to a medium-chain alcohol switches to avoidance in a uniform background of a second attractive odorant. This context-dependent behavioral plasticity is mediated by symmetric inversion of the odor-evoked response sign in the bilateral AWC olfactory neurons. Here, we show that this symmetric response plasticity is driven by asymmetric molecular mechanisms in the AWC neuron pair. Mutations in the gcy-12 receptor guanylyl cyclase abolish odor response plasticity only in AWCOFF; the opposite odor-evoked response signs in AWCOFF and AWCON in gcy-12 mutants result in these animals being behaviorally indifferent to this chemical. We find that gcy-12 is expressed, and required, in both AWC neurons to regulate odor response plasticity only in AWCOFF. We further show that disruption of AWC fate lateralization results in loss of asymmetry in the response plasticity in gcy-12 mutants. Our results indicate that symmetric neuronal response plasticity can arise from asymmetric underlying molecular mechanisms and suggest that lateralization of signaling pathways in defined conditions may enhance neuronal and behavioral flexibility.

Vericiguat (Merck, marketed as Verquvo) is a soluble guanylate cyclase stimulator that is FDA-approved for use in heart failure patients with reduced or mildly reduced ejection fraction (HFrEF, HFmrEF) to decrease heart failure hospitalization and cardiovascular mortality. We hypothesized that earlier administration of vericiguat post-MI would reduce the workload of the viable cardiomyocytes, leading to an earlier switch towards anti-inflammatory macrophages and reduced adverse remodeling. Male and female C57BL/6J mice (n=6/sex/group) underwent permanent occlusion of the left anterior descending coronary artery followed by implantation of a subcutaneous osmotic mini-pump (vericiguat or saline) 24 hours later. Echocardiography and histological assessment were performed for cardiomyocyte size (wheat germ agglutinin), vascularity (g. simplicifolia lectin I), and collagen area fraction (picrosirius red). Macrophages were isolated from the infarct at day 3 post-MI and conditioned media was collected. While cardiomyocyte size did not significantly differ between treatment groups, female drug-treated mice trended toward smaller cardiomyocytes in the border zone compared to males. Macrophage numbers were not affected, however proteomic analysis demonstrated a pro-angiogenic phenotype with vericiguat. In vitro stimulation of endothelial cells with the macrophage conditioned media from female drug-treated mice demonstrated a more organized and robust tubule network. Drug-treated female trended towards greater collagen in the infarct at day 7 post-MI, whereas drug-treated males had decreased vessel density in the remote area compared to controls. Despite the molecular changes observed, no significant differences in cardiac function were observed at day 7 post-MI. Our data demonstrates that acute administration of vericiguat post-MI stimulates macrophages towards a pro-angiogenic phenotype that was more exaggerated in females.

Pulmonary arterial hypertension (PAH) is a serious disorder, in which increased vascular tone is one of the critical hallmarks. Since beta arrestins (bArrs) have been shown to regulate smooth muscle tone in the airways, we investigated the function of bArr1 in the pulmonary vasculature. Here, we report that bArr1 is essential for maintaining normal pulmonary arterial tone. Specifically, pulmonary arteries from bArr1-/- mice exhibited reduced NO-dependent vasorelaxation due to impaired soluble guanylyl cyclase (sGC) activity, which was restored by the heme-independent sGC activator BAY58-2667. We identified bArr1 as a binding partner of sGC and the sGC heme reductase cytochrome b5 reductase (Cyb5r3), indicating that bArr1 is vital for sensitizing sGC to NO. Finally, mice with either ubiquitous or smooth muscle-specific bArr1 deficiency developed pulmonary hypertension (PH). These findings highlight the important role of bArr1 in regulating pulmonary vascular tone and propose it as a potential therapeutic target for the treatment of PH.

Toxins in disguise: Neuropeptide mimicry across animal venoms.

Co-administration of oral phosphodiesterase 5 inhibitors with oral soluble guanylate cyclase (sGC) stimulators is contraindicated due to the risk of systemic side effects. Frespaciguat, an inhaled sGC stimulator, has been studied in pulmonary hypertension (PH)-related conditions such as pulmonary arterial hypertension (PAH) and PH associated with chronic obstructive pulmonary disease (PH-COPD), and may allow combined use with oral PDE5i due to low systemic exposure. To evaluate a potential interaction between inhaled frespaciguat and oral sildenafil, 19 healthy participants were randomized to two treatment sequences (two periods separated by a 36-h washout). Treatment involved 3 days of dosing with open-label oral sildenafil (20mg, three times per day) and a single inhaled dose of frespaciguat 240µg or placebo on Day 3. Primary endpoints included safety assessed by adverse events (AEs) and change from baseline in systolic and diastolic blood pressure, and heart rate. Incidence of AEs was comparable across groups with no serious AEs, discontinuations due to AEs, or deaths. In conclusion, inhaled frespaciguat was well tolerated when administered on background sildenafil, without negative effects on systemic hemodynamics, versus placebo. The lack of additive systemic effects on blood pressure further documents pulmonary selectivity of inhaled frespaciguat, including when co-administered with sildenafil (EudraCT number 2019-001224-35).

Exploring the relationship between adherence and outcomes in pulmonary arterial hypertension: A retrospective cohort study in the United States.

Worsening heart failure (WHF) is a red flag in the natural history of heart failure (HF) that negatively impacts the prognosis. Urgent improvements in the management of WHF, especially among HF with reduced ejection fraction (HFrEF) patients, are needed to reduce morbidity and mortality. Vericiguat is an oral soluble guanylate cyclase (sGC) stimulator that was able to reduce the composite of HF hospitalization or cardiovascular (CV) death in the VICTORIA trial and is now recommended with a IIb indication by HF guidelines of different societies. Accordingly, several observational studies confirmed the positive findings observed in the trial. Since the population with HFrEF includes a large number of older patients with multiple comorbidities and different degrees of frailty, implementation and up-titration of guideline-directed medical treatments (GDMTs) could be challenging due to a higher odd of side effects. To this end, vericiguat possesses many advantages: once daily administration, good tolerance, limited side effects (e.g. hypotension), no need for routine laboratory testing or therapeutic drug monitoring. This makes vericiguat a good candidate for older, frail patients in order to increase patient compliance and limit drug discontinuation caused by side effects. Although commonly named as the fifth pillar of GDMTs, vericiguat should be considered as soon as possible among those patients with HFrEF and a WHF episode. However, the recently published VICTOR trial has investigated the effect of vericiguat in HFrEF patients who did not experience a recent WHF and did not demonstrate a reduction in the composite outcome of HF hospitalization or CV death, while providing beneficial effects on CV and all-cause mortality.

Pentosidine accumulation induced by Akr1a deficiency drives aggression and hyperactivity.

Heart failure with preserved ejection fraction (HFpEF): translational mechanisms, diagnostic evolution and therapeutic frontiers.

Vericiguat inhibits the progress of cardiac hypertrophy and prevents hypertrophy-induced heart failure by multiple mechanisms.

: Spinal cord injury (SCI) frequently impairs defecation, severely affecting the quality of life. This study examines compensatory neural remodeling after SCI, focusing on basal colonic contractility, neural responses to electrical field stimulation, and alterations in excitatory cholinergic and inhibitory nitrergic pathways. : Female Sprague-Dawley rats underwent either sham surgery or T10 spinal cord transection and were categorized into 3 groups: sham, 1-week post-SCI (acute), and 4-week post-SCI (chronic). Colonic contractility was assessed in an organ bath using electrical field stimulation in the presence of a nitric oxide synthase inhibitor. Neural protein expression was analyzed by immunofluorescence and Western blotting. : SCI produced region- and time-dependent impairments in colonic contractility, with distinct alterations in the proximal circular and longitudinal muscles across acute and chronic phases. Neural excitability shifted dynamically, showing enhanced excitatory activity in the proximal longitudinal muscle at 1-week and the distal circular muscle at 4-week post-SCI. Protein analysis revealed increased neuronal nitric oxide synthase in the proximal colon, decreased soluble guanylyl cyclase in the distal colon, upregulated muscarinic M3 receptor in the proximal colon, and reduced vasoactive intestinal peptide receptor 1 in both proximal and distal regions. : SCI induces spatiotemporal remodeling of excitatory and inhibitory neural pathways, contributing to colonic dysmotility and revealing potential targets for therapeutic intervention.

Abstract Background Vericiguat, the first-in-class soluble guanylate cyclase stimulator, represents a promising therapeutic option for patients with heart failure (HF), potentially improving clinical outcomes and quality of life, particularly among those who remain at high risk despite receiving guideline-directed medical therapy (GDMT). However, vericiguat may not be uniformly effective across all patient populations, and it remains unclear which subgroups derive the greatest benefit from this treatment. Purpose We aimed to evaluate the prognostic value of echocardiographic parameters for predicting adverse outcomes following vericiguat initiation in real-world HF patients receiving GDMT. Methods A total of 72 consecutive patients with heart failure (mean age 74.9 ± 10.9 years; 54% male) who initiated vericiguat therapy were included. Baseline transthoracic echocardiography was performed within 3 months prior to vericiguat initiation. The primary endpoint was a composite of cardiovascular death or heart failure hospitalization. Results During a median follow-up of 339 days, the composite outcome occurred in 25% of patients (n=18). Baseline comorbidities, including hypertension and diabetes, did not differ significantly between the event and non-event groups. Similarly, there were no statistical differences in the use of guideline-directed medical therapy or in the maintenance dose of vericiguat. The mean left ventricular ejection fraction (LVEF) and global longitudinal strain (LVGLS) of study population were 29.9 ± 8.1% and −8.78 ± 3.4, respectively. Most baseline echocardiographic parameters were comparable between groups (Figure 1). However, patients who experienced events had a significantly lower tricuspid annular plane systolic excursion (TAPSE) to right ventricular systolic pressure (RVSP) ratio (0.30 ± 0.15 vs. 0.40 ± 0.19, P=0.045). The predictive power of TAPSE/RVSP for the composite endpoint was modest (AUC=0.695, P=0.019), and the optimal cut-off value was 0.32. Kaplan–Meier analysis further demonstrated that patients with a TAPSE/RVSP ratio ≤0.32 experienced significantly worse outcomes, with a higher cumulative incidence of cardiovascular death or heart failure hospitalization (Figure 2). Conclusion In patients with heart failure receiving vericiguat on top of guideline-directed medical therapy, a lower TAPSE/RVSP ratio was associated with an increased risk of cardiovascular death or heart failure hospitalization. TAPSE/RVSP may serve as a simple and useful echocardiographic marker to stratify residual risk in this population.Echocardiographic Comparison by Outcome Kaplan–Meier Curve by TAPSE/RVSP Cut-off

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.

Cyclosporine A (CsA)-induced nephrotoxicity is a significant cause of chronic kidney disease (CKD), primarily driven by aberrant activation of the NF-κB and TGF-β1 signaling axes. Vericiguat, a soluble guanylate cyclase (sGC) stimulator, has established cardioprotective effects, but its potential renoprotective role and underlying mechanisms in CsA-induced CKD remain unexplored. An integrative approach was employed. Network pharmacology identified common targets between vericiguat and CKD. Mendelian randomization (MR) analysis assessed the causal relationship between drug target genes and CKD risk. The therapeutic effects and mechanisms of vericiguat were subsequently validated in vivo using a CsA-induced mouse model and in vitro in human renal tubular epithelial (HK-2) cells. Integrated computational analyses pinpointed the NF-κB/TGF-β1 axis as a core target of vericiguat. In mice, vericiguat treatment dose-dependently ameliorated CsA-induced renal dysfunction, proteinuria, renal inflammation, oxidative stress, and fibrosis. In HK-2 cells, vericiguat suppressed CsA-triggered inflammatory cytokine secretion, fibrotic marker expression, and reactive oxygen species production. Mechanistically, vericiguat inhibited the phosphorylation of the IKKβ/IκBα/NF-κB p65 pathway and the activation of TGF-β1/Smad signaling, thereby disrupting the inflammation-fibrosis vicious cycle. Genetic manipulation confirmed p65 as a crucial nodal point in this regulatory network. This study demonstrates that vericiguat exerts renoprotective, anti-inflammatory, and anti-fibrotic effects in CsA-induced CKD by modulating the NF-κB/TGF-β1 axis. These findings provide a novel scientific rationale for drug repurposing of vericiguat and highlight its potential therapeutic value for CKD.

Septic shock remains one of the most lethal emergency and critical care conditions, with underlying pathophysiology closely linked to uncontrolled vasodilation mediated by nitric oxide activation of the soluble guanylate cyclase pathway (NO-sGC-cGMP pathway). Methylene blue (MB), through its inhibition of this pathway, has demonstrated hemodynamic benefits and may serve as a targeted adjunctive therapy particularly in patients with septic shock requiring high-dose vasopressors, a severely vasoplegic subpopulation characterized by markedly elevated mortality. However, large-scale randomized controlled trials (RCTs) evaluating MB treatment for mortality benefit in high-dose vasopressor-dependent septic shock patients are currently lacking. This is an investigator-initiated, multicenter, open-label, blinded endpointRCT that will recruit adult septic shock patients requiring norepinephrine equivalent doses > 0.3μg/kg/min within 24h of vasopressor initiation across multiple centers in China. A total of 566 patients will be randomized 1:1 to receive MB treatment (2mg/kg loading dose followed by 0.25mg/kg/h maintenance infusion for up to 48h or 4h after vasopressor discontinuation) or equal volume 5% dextrose control. Randomization will be stratified by baseline SOFA-1 score and study center. The primary endpoint is 28-day all-cause mortality. Secondary outcomes include ICU-free days, vasopressor-free days, ventilator-free days, in-hospital mortality, and SOFA score improvement. This multicenter RCT will generate evidence on whether early MB administration reduces mortality in patients with high-dose vasopressor-dependent septic shock, potentially informing clinical practice regarding MB's role as an adjunctive therapy in severe septic shock management. ChiCTR2500112352.

Thermosensation is evolutionarily conserved for survival, yet the roles of glia in temperature coding and circuit dynamics remain poorly understood. Here, we identify C. elegans AMsh glia as dual-mode thermosensory hubs that autonomously detect temperature fluctuations by co-expressing the heat receptor GCY-28 (guanylate cyclase) and cold receptor GLR-3 (ionotropic glutamate receptor). Thermal changes induce spatiotemporal calcium dynamics in glia, driving GABA release to bidirectionally modulate neural circuits: enhancing AFD-mediated warmth detection through the excitatory receptor EXP-1 and suppressing ASH-dependent cold avoidance via the inhibitory receptor LGC-38. This GABAergic hub-and-spoke architecture regulates a broad range of thermal behaviors, including thermal avoidance, thermal resistance, and thermal preference. These findings establish glia as critical interpreters of environmental cues, highlighting their dual roles as sensors and modulators in sensory processing and providing a paradigm for understanding conserved glial mechanisms in neural circuit dynamics and behavioral plasticity.

Caldesmon is an actomyosin-tropomyosin-binding protein with pleiotropic functions that generally acts as an inhibitor of actomyosin ATPase activity. This study aims to explore the role of caldesmon in regulation of preglomerular vascular tone. Expression of caldesmon, myosin light chain, and α-smooth muscle actin was assessed by western blot of interlobar arteries (IAs) from young and old mice or human renal arteries from patients who underwent nephrectomy or tumor enucleation. IAs were obtained from wild-type or heterozygous mice, carrying a mutant allele that ablates both caldesmon isoforms (caldesmon+/-). In IAs, the vasoreactivity to α1-agonist phenylephrine, the soluble guanylate cyclase activator cinaciguat, and inhibitors of RhoA-associated protein kinase Y27632 or p21-activated protein kinase 1 IPA-3 were tested by wire myography. Caldesmon was expressed in all preglomerular vessels of mice and humans. In caldesmon+/- IAs of young mice, caldesmon protein was 50% less than in IAs of wild-type mice. In IAs of old mice, caldesmon was less than in IAs of young mice and not significantly different between caldesmon+/- and wild-type. Caldesmon mutation did not affect phenylephrine-induced contraction or cinaciguat sensitivity but induced a rightward shift of Y27632-induced relaxation in IAs of young and old mice and a reduction in IPA-3-induced relaxation by 50% only in IAs of young mice. In human renal arteries, caldesmon expression negatively correlated with age and the presence of renal inflammation. In the inflammation group, a reduction in estimated glomerular filtration rate was detected. This study provides cumulative evidence that caldesmon is a marker of age and inflammation-related changes in preglomerular vascular function. Our work supports the view that in the renal vasculature, caldesmon expression is age dependent and determines its sensitivity to the RhoA-associated protein kinase/p21-activated protein kinase 1 regulatory pathway.