Miostat (carbachol) / Alcon - LARVOL DELTA

In Cellulo pharmacological profiling and genomic editing reveals paralog-specific targets for PA generation during PLC signaling. (PubMed, bioRxiv) - "Live-cell imaging experiments using BMS-502 with carbachol stimulation of endogenous muscarinic receptors showed that inhibition of both DGKalpha and the PLDs is needed to substantially reduce PA levels during PLC activation. Our findings both identify paralog-specific druggable targets for modulating PLC signaling events, and establish a new platform that translates typical biochemical dose response assays in cellulo."

Journal

Sodium Nitroprusside Potentiates Capsaicin-Activated TRPV1-mediated Relaxation of Goat Detrusor Smooth Muscle. (PubMed, Neurourol Urodyn) - "The present study demonstrates that goat DSM expresses functional TRPV1 channels and capsaicin elicits relaxation by activating these channels. The NO donor SNP further potentiates the capsaicin-induced relaxation through a NO-cGMP signalling pathway."

Journal

M2 muscarinic receptor-dependent contractions of airway smooth muscle are mediated by inhibition of Kv7 channels. (PubMed, Am J Physiol Cell Physiol) - "Inhibition of Kv7 channels with XE991 increased the amplitude of EFS responses at 100 s intervals, but not at 10 s. The Kv7 channel openers ICA069673 and ML213 inhibited M2R-dependent responses and similar effects were obtained using the adenylate cyclase activator forskolin and the PKA activator 6MB-cAMP. Inclusion of PIP2diC8 in the pipette prevented the inhibitory effects of carbachol on Kv7.4, but not Kv7.5, whereas 6MB-cAMP potentiated Kv7.5 currents but not Kv7.4. These data suggest that M2Rs exert their contractile effects on ASM by inhibiting Kv7 channels via pathways that deplete PIP2 and reduce PKA activity."

Journal • Asthma • Chronic Obstructive Pulmonary Disease • Immunology • Pulmonary Disease • Respiratory Diseases

Sex-specific electrophysiology and cholinergic responses underlie differential mechanisms of arrhythmia vulnerability in rabbit atria. (PubMed, bioRxiv) - "Sex differences in carbachol responses were linked to variations in muscarinic receptor and acetylcholine-activated potassium channel gene expression. These findings demonstrate sex and regional differences in atrial electrophysiology at baseline and in response to cholinergic stimulation in the healthy heart that may contribute to sex-specific mechanisms of arrhythmia."

Journal • Preclinical • Atrial Fibrillation • Cardiovascular

Proinflammatory cytokines modify Ca2+ signaling and induce an apoptotic lipidome in murine small intestinal organoids. (PubMed, Front Physiol) - "Stimulation of Cl- secretion seems to underly this swelling since it was inhibited by bumetanide, a blocker of Na+-K+-2Cl- cotransporters. Ca2+ imaging experiments revealed that the cytokine mix time-dependently enhanced the response to carbachol, a Ca2+-dependent secretagogue, which would favor Ca2+-dependent Cl- secretion...AP-SMALDI MSI showed an accumulation of ceramide-positive (apoptotic) cells within the organoid lumen. Proinflammatory cytokines induce fluid secretion and transiently upregulate Ca2+ signaling concomitant with the induction of an apoptotic lipidome in small intestinal organoids."

Journal • Preclinical • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammatory Bowel Disease • Oncology • CASP3 • IFNG • IL1B • TNFA

NONO is essential in maintaining airway smooth muscle contractility through PDE4/cAMP signaling pathways. (PubMed, Exp Cell Res) - "Furthermore, two important components of the contractile apparatus, MLCK and p-MLC, were also decreased after carbachol (CCh) stimulation. These data demonstrated that NONO was capable of regulating ASM contraction through, at least partially, PDE4/cAMP signaling pathways and provided a novel regulatory target of ASM contractility."

Journal • MYLK • NONO • PDE4A

Phytochemical characterization and multi-target protective effects of Lycopodium serratum var. longipetiolatum against dysmenorrhea. (PubMed, Phytomedicine) - "Lycopodium serratum extract confers protection against dysmenorrhea through concurrent suppression of Ca²⁺-dependent uterine contraction, inflammatory signaling, and oxidative stress. These findings identify LSE-EA as a novel bioactive fraction with therapeutic potential in redox-mediated uterine dysfunction."

Journal • Immunology • Pain • Women's Health • IL6 • MYLK • TLR4

Vitamin E Alleviates Oxidative Damage and Attenuates Ferroptosis Caused by Prolonged Contraction of the Ciliary Muscle by Activating ACOT7. (PubMed, Invest Ophthalmol Vis Sci) - "A guinea pig model of prolonged contraction of the ciliary muscle was established through topical administration of carbachol, and primary ciliary muscle cells isolated from guinea pigs were used for in vitro experiments...Additionally, knocking down acetyl-coenzyme A thiosterase 7 attenuated the beneficial effect of VitE. These findings collectively indicated that VitE presented a viable approach to ameliorate oxidative stress and ferroptosis induced by prolonged contraction of the ciliary muscle via activating acetyl-coenzyme A thiosterase 7."

Journal • Ophthalmology • ACOT7 • CAT

Pharmacological treatment of presbyopia. (PubMed, Acta Clin Belg) - "Most eye drops contain miotic/parasympathomimetic agents (e.g. pilocarpine, carbachol, aceclidine), which create a pinhole effect...Brimochol (carbachol + brimonidine, an α-agonist that helps further reduce pupil size have been submitted for approval, Tenpoint Therapeutics) and MR-14/Nyxol (phentolamine) will be submitted in the near future...These products target specific chemical modification (destruction of disulfide bridges, deglycation). Use of deglycating enzymes (e.g. fructosyl amino oxidase, FAOD) may rejuvenate the lens by removing the advance glycation end products which have been attached to the lens crystallins over the years.As these drugs are relatively new in the treatment of presbyopia, further studies will be needed to study the long-term effects, the effects of the products which are still in the pipeline and to establish the role of drug treatment in presbyopia."

Journal • Review • Ophthalmology

Modeling Thoracic Aortic Dissection Using Patient-Specific iPSCs Reveals VSMC Dysfunction and Extracellular Matrix Dysregulation. (PubMed, Stem Cells Int) - "However, TAD-iPSC-derived VSMCs exhibited significantly reduced contraction in response to carbachol stimulation compared to their normal counterparts...This patient-specific iPSC model reveals key dysfunctions in VSMC contractility, extracellular matrix (ECM) protein expression, and dysregulated TGF-β signaling, which may contribute to TAD pathogenesis. Our findings provide new insights into the molecular mechanisms driving TAD and offer a platform for future therapeutic development."

Journal • MMP9 • TGFB1

Vanillic acid reverses castor oil-induced diarrhea in BALB/c mice through cholinergic and calcium channel blocking effects. (PubMed, Pak J Pharm Sci) - "It reduced intestinal transit stimulated by muscarinic agonist and intestinal secretion induced by PGE2. In-vitro experimental results showed vanillic acid's spasmolytic action on jejunum and ileum tissues, likely through VDCC inhibition and muscarinic receptor antagonism."

Journal • Preclinical

Relaxation of Precontracted Ciliary Artery and Ciliary Muscle In Vitro by Kinin Peptides: Relevance to Retinal Blood Flow and Intraocular Pressure Regulation. (PubMed, J Ocul Pharmacol Ther) - "Purpose: To study the ability of five kinin peptides to relax phenylephrine-contracted bovine posterior ciliary artery (PCA; major retinal blood supplier) and carbachol-contracted ciliary muscle (CM) (involved in accommodation and aqueous humor drainage) in vitro. Isolated bovine CM strips and PCA rings were mounted in small organ baths and perfused with oxygenated Krebs' solution containing 3 µM flurbiprofen...Precontracted PCA rings were significantly (generally P < 0.005-0.05) more sensitive to the relaxant activity of the kinin peptides than precontracted CM strips. The tissue relaxant agonist profile of the kinins in both precontracted CM strips and PCA rings, as judged by the 2-site-fit data, indicated the involvement of both B1- and B2-receptor subtypes."

Journal • Preclinical

Heme Modulates Bladder Contractility Through the HO-CO-sGC-cGMP Pathway: Insights into Sickle Cell Disease-Associated Bladder Dysfunction. (PubMed, Antioxidants (Basel)) - "Moreover, pre-incubation with heme (100 µM) significantly decreased the maximal contractile responses (Emax) to carbachol, KCl, and electrical field stimulation (EFS), effects that were abolished by ODQ or 1J...These findings demonstrate that heme modulates bladder contractility by activating the HO-CO-sGC-cGMP pathway, promoting detrusor relaxation. This mechanism suggests that excessive circulating heme, as occurs in hemolytic disorders such as SCD, may contribute to detrusor hypocontractility and voiding dysfunctions, identifying this pathway as a potential therapeutic target."

Journal • Genetic Disorders • Hematological Disorders • Sickle Cell Disease • Urology

Ionic dependency, sensitivity to transport inhibitors and signal transduction of propionate-induced anion secretion in rat caecum. (PubMed, Eur J Pharmacol) - "Propionate stimulates anion secretion, probably in order to buffer the caecal luminal content, by a mechanism exhibiting a unique anion dependency different from that of other secretagogues."

Journal • Preclinical • Cystic Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases • WNK1

Biomarkers. (PubMed, Alzheimers Dement) - P1 | "Results from the non-clinical studies suggest SUVN-I6107 may have memory enhancing property in various forms of dementias. SUVN-I6107 is currently being studied in a Phase-1 study (NCT06705088) to evaluate its safety, tolerability, pharmacokinetics, and pharmacodynamic effects after single and repeated administrations in healthy human subjects."

Biomarker • Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • APP

Epithelial Ion Transport in Spring-Lengthened Jejunum in a Porcine Model. (PubMed, J Pediatr Surg) - "Spring-lengthening of small bowel does not disrupt mucosal barrier function, based on histological and functional assessments. While spring-lengthened jejunum showed reduced transepithelial secretory function, its absorptive function appears intact. This change may be related to early tissue remodeling during distraction enterogenesis and further investigation into the cellular changes induced by distraction enterogenesis are ongoing."

Journal • Preclinical • Gastrointestinal Disorder • Short Bowel Syndrome

ER calcium stores contribute to glucose-induced Ca2+ waves and intercellular connectivity in mouse pancreatic islets. (PubMed, Cell Calcium) - "Unexpectedly, the activation of IP3 receptors with the muscarinic acetylcholine receptor agonist carbachol had minimal impact on the initial peak elicited by 11 mM glucose, but Ca2+ waves at 11 and 25 mM glucose were more poorly coordinated. To determine whether ER calcium mobilization was sufficient to initiate Ca2+ waves we next blocked sarco(endo)plasmic Ca2+ ATPase (SERCA) pumps with thapsigargin, whilst preventing plasma membrane depolarization with the KATP-channel opener, diazoxide...After genetic deletion of SERCA2 in beta cells, Ca2+wave frequency, but not connectivity, were lowered. Our results show that ER Ca2+ mobilization plays a relatively minor role in the initiation and propagation of Ca2+ waves in response to glucose but is needed for sustained Ca2+waves."

Journal • Preclinical • Diabetes • Metabolic Disorders

Differential Sensitivity of TRPC- and ORAI-Mediated Calcium Entries to 1‑[2-(4-Methoxyphenyl)-2-[3-(4-methoxyphenyl)propoxy]ethyl]imidazole Chloride (SKF-96365). (PubMed, ACS Pharmacol Transl Sci) - "SKF-96365 suppressed thapsigargin (Tg)-induced SOCE similarly in wild-type and TRPC hepta-KO MEFs, with IC50 values around 4-5 μM. Comparable inhibition was observed for carbachol (CCh)-activated ROCE in TRPC-deficient cells...GSK-7975A further confirmed the ORAI selectivity by blocking SOCE without affecting TRPC channels. These results clarify the pharmacological profile of SKF-96365, confirming its primary action on ORAI channels and highlight the need for concentration-aware interpretation in calcium signaling studies, particularly in the context of CRAC channel-related disorders."

Journal • STIM1 • TRPC3 • TRPC6 • TRPC7

Muscarinic Receptor-Mediated Electroacupuncture Modulation of Reactive Enteric Glial Cells Ameliorates Postoperative Ileus. (PubMed, J Inflamm Res) - "Fluorocitrate (a glial cell inhibitor) and carbachol (a cholinergic agonist) replicated the effects of EA ST 36, which was abolished by either pretreatment with J104129 (a specific m3AChR antagonist) or surgical vagotomy. The results suggest that EA ST 36 exerts its effects through vagally-mediated modulation of m3AChR signaling, which involves the reduction of the reactivity of EGCs and the improvement of GI dysfunction induced by IM."

Journal • Gastrointestinal Disorder • Inflammation • Inflammatory Bowel Disease • FAP • FOS • GFAP

Cholinergic modulation of hippocampal CA1 pyramidal cell excitability in ArxGCG+7 mice. (PubMed, Exp Neurol) - "Despite reduced ChAT, carbachol- and pilocarpine-induced firing responses were preserved, while nicotinic receptor-mediated excitation was abolished. Molecular analysis revealed increased muscarinic receptor 1 expression and decreased β4 nicotinic receptor expression in CA1.Together, these findings demonstrate histological, electrophysiological, and molecular alterations in the septo-hippocampal network of ArxGCG+7 mice. Together, they suggest impaired cholinergic signaling contributes to ISS pathogenesis and highlight the cholinergic system as a potential therapeutic target."

Journal • Preclinical • CNS Disorders • Developmental Disorders • Epilepsy • Psychiatry • CHAT • GCG

Negative Allosteric Modulation of Agonist-Induced M2 Muscarinic Receptor/β-Arrestin Interaction by Serum Autoantibodies from Patients with Chronic Chagas Disease. (PubMed, Cells) - "When cells were preincubated with DCD IgG and then treated with carbachol, arrestin-2 translocation decreased in a concentration-dependent manner, while arrestin-3 recruitment remained unaffected...We conclude that anti-M2R autoantibodies selectively inhibit agonist-induced arrestin-2 recruitment, acting as negative allosteric modulators of agonist efficacy. The direction of autoantibody-induced allosteric modulation depends on the timing of IgG application relative to the agonist and the duration of receptor exposure to autoantibodies."

Journal • Cardiovascular • Heart Failure • ARRB1

Structural and functional bladder changes associated with disrupted voiding cycle in a murine model of cutaneous vesicostomy. (PubMed, J Pediatr Urol) - "Our findings suggest that CV-induced bladder cycling disruption leads to significant structural and functional bladder changes mediated by upregulation of Mrgprb2 and increased response to its agonist, Substance P, suggesting this receptor plays a key role in mediating bladder changes following UD."

Journal • Preclinical • Chronic Kidney Disease • Fibrosis • Immunology • Inflammation • Nephrology • Renal Disease • CHRM3

Store-operated Ca2+ entry mediated by STIM1 and STIM2 regulates salivary secretion and KCa channels in salivary gland. (PubMed, Biochem Biophys Res Commun) - "Epithelium-specific conditional knockout mice for Stim1 and Stim2 (Stim1/2 cKO) were generated, and pilocarpine-stimulated salivary secretions in Stim1/2 cKO mice and control mice (Stim1/2fl/fl) were measured...In these cells, the initial release of Ca2+ from ER stores was comparable between genotypes following carbachol stimulation...The gene expression levels of KCa1.1 and KCa3.1 remained unchanged; however, KCa channel activity was significantly diminished in Stim1/2 cKO cells, similar to the effects of KCa channel inhibitors. These findings indicate that the loss of SOCE decreases the [Ca2+]i and intracellular Ca2+ signals required for salivary secretion, possibly through the ORAI1 channel, in turn reducing KCa channel activation."

Journal • STIM1

Metformin Attenuates Spontaneous and Stimulated Myometrium Contractions in Rat Uterine Strips. (PubMed, Eurasian J Med) - "The spontaneous contractions and dose- response curves for oxytocin (10-11-10-4M) and carbachol (CCh, 10-8-10-4M) were recorded. Metformin may be beneficial in conditions favorable to fertilization, implantation, and prevention of preterm labor by reducing myometrial contractility during pregnancy and in non-pregnant indications. However, use of metformin should be approached with caution when strong myometrium contractions are required near term or postpartum."

Journal • Preclinical

Long-acting β2 agonist (LABA) with a long-acting muscarinic receptor antagonist (LAMA) promotes human airway smooth muscle (HASM) relaxation and circumvents β2 adrenergic receptor tachyphylaxis. (PubMed, Respir Res) - "In primary HASM and human precision-cut lung slices (hPCLS) obtained from non-diseased donors, we show that the combination of umeclidinium (LAMA) and vilanterol (LABA) robustly attenuated carbachol-induced E-C coupling markers, compared to that induced by either compound individually. Furthermore, the umeclidinium-vilanterol combination showed little change in the ability to dilate pre-constricted hPCLS in the presence of albuterol-induced β2AR desensitization compared to relaxation to vilanterol alone, which was significantly attenuated by albuterol-induced desensitization. Our data suggest that targeting Gαq and Gαi signaling through muscarinic receptor antagonism serves as an effective therapy for obstructive lung diseases, even in the face of β2AR tachyphylaxis."

Journal • Asthma • Chronic Obstructive Pulmonary Disease • Immunology • Pulmonary Disease • Respiratory Diseases