Miostat (carbachol) / Alcon - LARVOL DELTA

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

Phytochemical Diversity and Anti-Inflammatory, Antidiabetic and Bronchodilatory Activities of Sugandhmantri (Homalomena aromatica). (PubMed, Chem Biodivers) - "The HA1 and its isolates (linalool and homalomenol D) exhibited a relaxation response of isolated mouse bronchial tissue precontraction in carbachol. The study revealed the rich chemical diversity and the therapeutic potential of H. aromatica."

Journal • IL6 • TNFA

Expanding the reactive chemistry toolbox - warhead screening for covalent butyrylcholinesterase inhibitors. (PubMed, Chem Biol Interact) - "Notably, an exception to this rule of a thumb was found in a series of chalcogen carbachol analogues. The gathered insights highlight some key structure-reactivity relationships for covalent hBChE inhibitors and may assist in development of novel serine hydrolase inhibitors."

Journal

Novel Experimental Model for Investigating Metabolic Changes in Cardiovascular-Kidney-Metabolic Syndrome (KIDNEY WEEK 2025) - "Carbachol-induced vasodilation was measured in aorta preparations, plasma cystatin C levels and albuminuria were measured as readouts of renal function and injury...Interestingly, fatty acid-linked mitochondrial respiration was not affected in the renal cortex of diabetic mice with sNx, but decreased significantly in the heart compared to sham-operated db/db mice, reflecting a crosstalk between renal function decline and cardiac energy metabolism. Conclusion Our novel mouse model offers the opportunity to study pathophysiological mechanisms operating early in the development of the CKM syndrome and to test the effects of pharmacological and dietary interventions across various stages of the syndrome."

Cardiovascular • Diabetes • Diabetic Nephropathy • Hypertension • Metabolic Disorders • Nephrology • Renal Disease • CST3

DR5 Governs Compound Exocytosis in Colonic Goblet Cells via TATA-Box Binding Protein-Dependent Bestrophin-2 Transcriptional Regulation. (PubMed, Adv Sci (Weinh)) - "DR5 knockout and its ligand TRAIL knockdown inhibits carbachol-triggered goblet cell compound exocytosis, while DR5-activator Bioymifi potentiates it...Moreover, TBP knockdown abrogates Bioymifi-enhanced Best2 expression and compound exocytosis. The findings demonstrate that disruption of the DR5-TBP-Best2 axis in goblet cells perturbs goblet cell compound exocytosis and mucus layer formation, resulting in dysbiosis and heightened infection susceptibility."

Journal • Infectious Disease • MUC2 • TNFRSF10B

Target and off-target effects of vibegron on smooth muscle contraction of human detrusor and prostate tissues. (PubMed, Naunyn Schmiedebergs Arch Pharmacol) - "Similar to mirabegron, improvements of storage symptoms by vibegron involve mechanisms beyond inhibition of voiding contractions. Off-target effects occur with 10 µM, and include inhibition of neurogenic contractions and antagonism of prostatic α1A-adrenoceptors. Vibegron effects in the prostate may differ between patients with low BPH progression, and patients needing surgery for BPH."

Journal • Benign Prostatic Hyperplasia • Overactive Bladder

Aberrant hippocampal gamma oscillations in a mouse model of fragile X syndrome: insights from in vitro slice models. (PubMed, Mol Autism) - "Our findings demonstrate that hippocampal gamma oscillations are differentially affected by distinct neuromodulatory pathways in Fmr1 KO mice. Enhanced responsiveness to cholinergic and mGluR activation and reduced coherence of KA-induced rhythms suggest that multiple dysregulated mechanisms contribute to gamma oscillopathies in FXS."

Journal • Preclinical • CNS Disorders • Developmental Disorders • Fragile X Syndrome • Genetic Disorders • Immunology • Mental Retardation • CA3 • GRIK2

Effect of Dimephosphone on the Mechanical Activity of the Bladder in Rats with a Model of Autism. (PubMed, Bull Exp Biol Med) - "The valproate model of autism was used to evaluate the effect of a course of dimephosphone administration (intragastric, 50 mg/kg, 30 days) on contractions of the isolated bladder of rats induced by application of carbacholine (10-7-10-5 M), α,β-methylene-ATP (10-7-10-5 M), and stimulation with an electric field of different frequencies (1-20 Hz)...However, when evaluating the effect of dimephosphone on bladder contractions caused by α,β-methylene-ATP, no significant changes were found. Dimephosphone, when administered in a course, normalizes bladder contractility in rats with the valproate model of autism."

Journal • Preclinical • Autism Spectrum Disorder • Genetic Disorders

Behavioral Changes in Caenorhabditis elegans After Exposure to Radial Extracorporeal Shock Waves. (PubMed, J Clin Med) - " Wild-type and acr-16 mutant C. elegans were exposed in liquid to varying doses of rESWs, nicotine and carbachol in different combinations...This contrasts with the clinical situation, where rESWs primarily target muscles and connective tissues. While this precludes C. elegans as a direct model for CP-related spasticity, the observation that rESWs influence nervous-system function at a systemic level points to potential therapeutic avenues for neurological diseases."

Journal • Cerebral Palsy • CNS Disorders • Movement Disorders

Bladder Dysfunction in Sickle Cell Disease Is Associated with Inflammation and Oxidative Stress. (PubMed, Int J Mol Sci) - "In vitro functional assays demonstrated detrusor hypocontractility in SCD mice, associated with a significant reduction in carbachol- and EFS-induced contractions and downregulation of muscarinic M3 receptor expression...This is the first study to characterize bladder alterations in Townes SCD mice, establishing this model as a valuable tool for investigating lower urinary tract complications in SCD. Our findings provide mechanistic insight into the genitourinary manifestations of SCD and identify redox and inflammatory pathways as potential therapeutic targets for bladder dysfunction in affected individuals."

Journal • Genetic Disorders • Hematological Disorders • Inflammation • Overactive Bladder • Sickle Cell Disease • Urology • IL1B • MPO

ANTISPASMODIC IMPACT OF AN HERBAL PREPARATION ON SMALL INTESTINE: PROMISING THERAPEUTIC BENEFITS FOR PATIENTS WITH IRRITABLE BOWEL SYNDROME (UEGW 2025) - "Previous studies have demonstrated that Amara extract targets the muscarinic receptor M2, inducing relaxation in carbachol-contracted guinea pig fundus strips, potentially improving impaired fundus accommodation in functional dyspepsia patients [1]... The findings highlight the potential of Amara-Drops in modulating visceral hypersensitivity and alleviating abdominal pain in IBS patients through the inhibition of cholinergic-induced contraction in the small intestine. Further research is necessary to identify which specific extracts contribute to the anticholinergic effect. This study lays a promising molecular foundation for the therapeutic use of Amara-Drops in IBS treatment."

Clinical • Dyspepsia • Gastrointestinal Disorder • Immunology

Establishment of a Male Rat Model Exhibiting Myogenic Underactive Bladder-Like Features Following Bladder Cryoinjury. (PubMed, Int J Urol) - "We established a practical and minimally invasive male rat model exhibiting myogenic UAB-like features 2 weeks after cryoinjury. While ex vivo cholinergic and KCl-evoked contractility was largely preserved at this time point, in vivo voiding remained impaired, suggesting contributions beyond muscle contractility. This model may facilitate mechanistic and therapeutic studies for UAB."

Journal • Preclinical • Inflammation • Urology

Effects of elexacaftor/tezacaftor/ivacaftor on CFTR function in children with CF aged 2– 11 years (NACFC 2025) - "Change in transepithelial short circuit current in response to cyclic adenosine monophosphate (cAMP)-mediated (100 μM IBMX, 1 μM forskolin, baso-lateral) and cholinergic stimulation (100 μM carbachol, basolateral) was assessed as a readout for CFTR function using perfused micro-Ussing chambers. Treatment with ETI substantially improves CFTR function in the rectal epithelium in children with CF aged 2 to 11 years with at least one F508del CFTR mutation."

Clinical • Cystic Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases • CFTR

Structural and molecular differentiation of cultured human neurons is accompanied by alterations of spontaneous and evoked calcium dynamics. (PubMed, Sci Rep) - "The carbachol-induced rise of Ca2+ in these cells showed a higher peak and biphasic decay. At all developmental stages, Ca2+ transients in response to ionomycin were indistinguishable. These findings lead us to conclude that a switch of Ca2+ dynamics accompanies structural and molecular differentiation of SH-SY5Y cell-derived human neurons, contributing to the developmental process."

Journal • Neuroblastoma • Oncology • Solid Tumor • BDNF

Gd3+-doped carbon dots: modulation of mechanisms regulating gastrointestinal tract motility and the hepatobiliary system. (PubMed, Biomater Sci) - "The effects of GDNHs on carbacholine-induced contractions of the antrum SM were mainly attributed to their organic components, whereas in the caecum, they were predominantly mediated by Gd3+ ions complexed with nanohybrids...Overall, intravenous administration of GDNHs was accompanied by enhanced gastrointestinal SM motility (due to the activation of cholinergic excitation) and partial modulation of hepatic lipid and protein metabolism. However, these effects did not lead to pronounced dysfunction of the digestive system, indicating that GDNHs can be considered a promising basis for the development of MRI contrast agents."

Journal • Gastrointestinal Disorder

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

Target and off-target effects of vibegron in smooth muscle contraction of human detrusor and prostate tissues suggest class effects of β3-agonists in storage symptoms (DGU 2025) - " In detrusor tissues, 100 nM vibegron reduced carbachol- and methacholine-induced contractions (p=0.0169, p=0.0115), while inhibitory effects were lacking with 10 nM, 1 µM and 10 µM. Similar to mirabegron, improvements of storage symptoms by vibegron may be imparted by mechanisms other than inhibition of voiding contractions, as inhibition of cholinergic contractions occurs with low consistency. Off-target effects in preclinical models occur with 1-10 µM, and include inhibitions of neurogenic contractions and antagonism of prostatic α1A-adrenoceptors. Vibegron effects in the prostate may differ between patients with slow BPH progression, and patients needing surgery for BPH."

Genito-urinary Cancer • Prostate Cancer • Solid Tumor

Anticontractile and growth-promoting effects of prolonged exposure to mirabegron in human bladder smooth muscle cells suggest multiple actions on bladder function in treatment of storage symptoms (DGU 2025) - "Prolonged exposure to therapeutic concentrations of mirabegron may reduce bladder smooth muscle tone, but no carbachol-induced contractions, and enhances the growth of hBSMC. Specific and physiological concentrations are required for conclusive preclinical studies with β3-agonists, as unphysiological concentrations may induce opposing off-target effects."

Bronchorelaxant effects of 6-Nitrodopamine in human airway smooth muscle (ERS 2025) - "The effect of 6-ND was measured in isolated bronchial rings pre-contracted with carbachol (CCh) at 70% of maximal contractility and in tissue stimulated by electrical field stimulation (EFS; 3 – 25 Hz) to mimic vagal firing. Data from hASM pre-contracted by CCh were reported as a percentage of the maximal bronchorelaxant effect (Emax) induced by papaverine 100 µM...Conclusions These preliminary findings suggest that 6-ND effectively reduces hASM contractility elicited by parasympathetic activation, highlighting its potential as a bronchorelaxant agent for the treatment of chronic obstructive pulmonary disorders. Further studies with larger sample size are needed to enhance statistical accuracy."

Immunology • Pulmonary Disease • Respiratory Diseases

Impedance-based assay as an alternative strategy to measure airway smooth muscle contraction (ERS 2025) - " Histamine (EC50 = 0.82 ± 0.23 µM), Bradykinin (EC50 = 0.55 ± 0.23 nM), and Carbachol (EC50 = 2.86 ± 1.19 µM) induced dose-dependent impedance changes, evidenced by the rapid decline in normalized CI values... Thus, the impedance-based contraction assay, which requires a small number of cells, provides a sensitive and high-throughput method for studying ASM dysfunction in asthma compared to traditional approaches."

Asthma • Immunology • Respiratory Diseases • RHOA

Ensifentrine synergistically relaxes hyperreactive human bronchi from COPD donors in combination with ICS, LABA, and LAMA (ERS 2025) - "Relaxant responses were measured in epithelium intact (EP+) and denuded (EP-) bronchi pre-contracted with carbachol (EC70) and stimulated by electrical field stimulation (EFS; 3-25 Hz)...Synergy was observed at low ensifentrine concentrations (EC30) when combined with GB (+17.50±3.08%), BDP/FF (+18.65±6.26%), FF/GB (+19.28±3.77%), BDP/FF/GB (+19.39±3.06%); additive effect resulted with FF...This suggests ensifentrine is a valuable COPD adjunct, supported by Phase III ENHANCE trial data. Funding: Verona Pharma plc."

Combination therapy • Chronic Obstructive Pulmonary Disease • Immunology • Respiratory Diseases