{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T12:55:30Z","timestamp":1776776130950,"version":"3.51.2"},"reference-count":39,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T00:00:00Z","timestamp":1776729600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100008431","name":"the Spanish Research Agency, FEDER Funds","doi-asserted-by":"publisher","award":["PID2022-141358OBI00"],"award-info":[{"award-number":["PID2022-141358OBI00"]}],"id":[{"id":"10.13039\/501100008431","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background: Autonomic side effects are a major determinant of tolerability for many psychotherapeutic drugs. While often attributed to receptor-mediated mechanisms, the potential contribution of direct modulation of smooth muscle excitability remains poorly characterized at a comparative pharmacological level. Methods: A systematic comparative pharmacological profiling of a broad panel of psychotherapeutic drugs (antidepressants, antipsychotics, and anxiolytics) was conducted using a standardized ex vivo model. Potassium chloride (KCl, 105 mM) was used to induce depolarization-dependent contraction in three isolated smooth muscle preparations (rat uterus, rat vas deferens, and guinea-pig ileum). Inhibitory potency (IC50), dose-dependency, and tissue consistency were integrated to define functional inhibitory profiles. Results: Psychotherapeutic drugs exhibited marked heterogeneity in their ability to inhibit K+-induced smooth muscle contraction. Integrative analysis stratified compounds into four distinct functional profiles: (i) High Inhibitory Liability (e.g., nortriptyline, paroxetine), characterized by low micromolar IC50 values and dose-dependent inhibition across multiple tissues; (ii) Non-Selective Inhibition (e.g., flunarizine, cinnarizine), showing consistent but dose-independent inhibition; (iii) Tissue-Dependent Inhibition (e.g., risperidone, reboxetine); and (iv) Minimal Inhibition (e.g., moclobemide). Agents classified within the High Inhibitory Liability profile correspond to drugs known to carry a higher clinical burden of autonomic adverse effects. Conclusions: This study reveals a previously underrecognized pharmacodynamic dimension of psychotherapeutic drugs and establishes a comparative functional taxonomy based on their direct, non-receptor-mediated inhibition of smooth muscle excitability. The identified profiles provide a mechanism-informed framework for contextualizing autonomic side-effect liability and may support improved safety evaluation in psychotherapeutic drug development.<\/jats:p>","DOI":"10.3390\/ph19040645","type":"journal-article","created":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T11:42:45Z","timestamp":1776771765000},"page":"645","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Comparative Pharmacological Profiling of Psychotherapeutic Drugs Reveals a Functional Taxonomy Based on Direct Inhibition of Smooth Muscle Excitability"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-5075-7658","authenticated-orcid":false,"given":"Mar\u00eda Jes\u00fas","family":"Castrillejo","sequence":"first","affiliation":[{"name":"Department of Cell Biology, Genetics, Histology and Pharmacology, Faculty of Medicine, University of Valladolid, 47005 Valladolid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alfonso","family":"Velasco","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Genetics, Histology and Pharmacology, Faculty of Medicine, Institute of Neurosciences of Castile and Leon (INCYL), University of Valladolid, 47005 Valladolid, Spain"},{"name":"Degeneration and Regeneration Laboratory, Institute of Neurosciences of Castile and Leon (INCYL), University of Valladolid, 47005 Valladolid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6554-4602","authenticated-orcid":false,"given":"Juan F.","family":"Mielgo-Ayuso","sequence":"additional","affiliation":[{"name":"Faculty of Health Sciences, University of Burgos (UBU), 09001 Burgos, Spain"},{"name":"Advanced Research in Integrative Physiology for Life Research Group (IAFIV), University of Burgos (UBU), 09001 Burgos, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jes\u00fas","family":"P\u00e9rez","sequence":"additional","affiliation":[{"name":"Department of Medicine, Faculty of Medicine, Institute of Biomedical Research (IBSAL), University of Salamanca, 37007 Salamanca, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4280-5611","authenticated-orcid":false,"given":"Manuel","family":"Garrosa","sequence":"additional","affiliation":[{"name":"Degeneration and Regeneration Laboratory, Institute of Neurosciences of Castile and Leon (INCYL), University of Valladolid, 47005 Valladolid, Spain"},{"name":"Area of Histology, Faculty of Medicine, University of Valladolid, 47005 Valladolid, Spain"},{"name":"Neurobiology Research Group, University of Valladolid, 47005 Valladolid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carlos Alberto","family":"Rodr\u00edguez-Arias","sequence":"additional","affiliation":[{"name":"Degeneration and Regeneration Laboratory, Institute of Neurosciences of Castile and Leon (INCYL), University of Valladolid, 47005 Valladolid, Spain"},{"name":"Neurobiology Research Group, University of Valladolid, 47005 Valladolid, Spain"},{"name":"Neurosurgery Department, Hospital Cl\u00ednico Universitario de Valladolid, Institute of Neurosciences of Castile and Leon (INCYL), 47003 Valladolid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6522-8896","authenticated-orcid":false,"given":"Diego","family":"Fern\u00e1ndez-L\u00e1zaro","sequence":"additional","affiliation":[{"name":"Neurobiology Research Group, University of Valladolid, 47005 Valladolid, Spain"},{"name":"Area of Histology, Faculty of Health Sciences, University of Valladolid, 42004 Soria, Spain"},{"name":"Biomedical Research Institute of Le\u00f3n (IBIOLE\u00d3N), University Hospital Complex of Le\u00f3n, 24071 Le\u00f3n, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"118","DOI":"10.18773\/austprescr.2022.031","article-title":"The Anticholinergic Burden: From Research to Practice","volume":"45","author":"Hilmer","year":"2022","journal-title":"Aust. Prescr."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1002\/wps.20567","article-title":"Management of Common Adverse Effects of Antipsychotic Medications","volume":"17","author":"Stroup","year":"2018","journal-title":"World Psychiatry"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1229","DOI":"10.1080\/13607863.2019.1594165","article-title":"The Association between Side Effects and Adherence to Antidepressants among Primary Care Community-Dwelling Older Adults","volume":"24","author":"Milan","year":"2020","journal-title":"Aging Ment. Health"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/j.psychres.2013.05.007","article-title":"Association between Antidepressant Side Effects and Functional Impairment in Patients with Major Depressive Disorders","volume":"210","author":"Kikuchi","year":"2013","journal-title":"Psychiatry Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1080\/19585969.2025.2463443","article-title":"Impact of Perceived Side-Effects of Psychotherapeutic Treatments on Quality of Life in Patients with Severe Mental Illness","volume":"27","author":"Korchia","year":"2025","journal-title":"Dialogues Clin. Neurosci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1503\/jpn.140217","article-title":"Autonomic Nervous System Dysfunction in Psychiatric Disorders and the Impact of Psychotherapeutic Medications: A Systematic Review and Meta-Analysis","volume":"41","author":"Alvares","year":"2016","journal-title":"J. Psychiatry Neurosci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1007\/s40266-020-00796-5","article-title":"Drug-Related Orthostatic Hypotension: Beyond Anti-Hypertensive Medications","volume":"37","author":"Rivasi","year":"2020","journal-title":"Drugs Aging"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1333","DOI":"10.1002\/nau.24695","article-title":"Urinary Side Effects of Psychotherapeutic Drugs: A Systematic Review and Metanalysis","volume":"40","author":"Trinchieri","year":"2021","journal-title":"Neurourol. Urodyn."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Bhanu, C., Nimmons, D., Petersen, I., Orlu, M., Davis, D., Hussain, H., Magammanage, S., and Walters, K. (2021). Drug-Induced Orthostatic Hypotension: A Systematic Review and Meta-Analysis of Randomised Controlled Trials. PLoS Med., 18.","DOI":"10.1371\/journal.pmed.1003821"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/S0074-7742(08)60138-5","article-title":"Membrane Stabilization by Drugs: Tranquilizers, Steroids, and Anesthetics","volume":"9","author":"Seeman","year":"1966","journal-title":"Int. Rev. Neurobiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1015","DOI":"10.1016\/S0022-3565(24)35384-4","article-title":"Block of Human Heart HH1 Sodium Channels by Amitriptyline","volume":"292","author":"Nau","year":"2000","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1016\/j.pain.2004.03.018","article-title":"State-Dependent Block of Voltage-Gated Na+ Channels by Amitriptyline via the Local Anesthetic Receptor and Its Implication for Neuropathic Pain","volume":"110","author":"Wang","year":"2004","journal-title":"Pain"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2052","DOI":"10.1124\/mol.106.026419","article-title":"The Mechanism of Activity-Dependent Sodium Channel Inhibition by the Antidepressants Fluoxetine and Desipramine","volume":"70","author":"Lenkey","year":"2006","journal-title":"Mol. Pharmacol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Imbrici, P., Conte Camerino, D., and Tricarico, D. (2013). Major Channels Involved in Neuropsychiatric Disorders and Therapeutic Perspectives. Front. Genet., 4.","DOI":"10.3389\/fgene.2013.00076"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1038\/nrd.2015.5","article-title":"Targeting Voltage-Gated Calcium Channels in Neurological and Psychiatric Diseases","volume":"15","author":"Zamponi","year":"2016","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1111\/j.1476-5381.1989.tb12031.x","article-title":"Block of Sodium Channels by Psychotherapeutic Drugs in Single Guinea-Pig Cardiac Myocytes","volume":"97","author":"Ogata","year":"1989","journal-title":"Br. J. Pharmacol."},{"key":"ref_17","first-page":"a004549","article-title":"Calcium Signaling in Smooth Muscle","volume":"3","author":"Werner","year":"2011","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1111\/j.1365-2982.2008.01108.x","article-title":"Regulation of Smooth Muscle Excitation and Contraction","volume":"20","author":"Sanders","year":"2008","journal-title":"Neurogastroenterol. Motil."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1016\/j.bcp.2004.05.017","article-title":"Blockade of Calcium Entry in Smooth Muscle Cells by the Antidepressant Imipramine","volume":"68","author":"Becker","year":"2004","journal-title":"Biochem. Pharmacol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1540\/jsmr1965.20.427","article-title":"Potassium-Induced Contraction in Smooth Muscle","volume":"20","author":"Karaki","year":"1984","journal-title":"Nihon Heikatsukin Gakkai Zasshi"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"S3","DOI":"10.1002\/hup.915","article-title":"Cardiac Side Effects of Psychiatric Drugs","volume":"23","author":"Mackin","year":"2008","journal-title":"Hum. Psychopharmacol. Clin. Exp."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1007\/BF02244985","article-title":"Binding of Antidepressants to Human Brain Receptors: Focus on Newer Generation Compounds","volume":"114","author":"Cusack","year":"1994","journal-title":"Psychopharmacology"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.1016\/S0025-6196(12)61375-5","article-title":"Pharmacology of Antidepressants\u2014Characteristics of the Ideal Drug","volume":"69","author":"Richelson","year":"1994","journal-title":"Mayo Clin. Proc."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"6","DOI":"10.2165\/00003495-198427010-00002","article-title":"Flunarizine. A Review of Its Pharmacodynamic and Pharmacokinetic Properties and Therapeutic Use","volume":"27","author":"Holmes","year":"1984","journal-title":"Drugs"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1055\/s-2004-815530","article-title":"The Effects of Moclobemide on Autonomic and Cognitive Functions in Healthy Volunteers","volume":"37","author":"Siepmann","year":"2004","journal-title":"Pharmacopsychiatry"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1111\/j.1600-0447.1990.tb05320.x","article-title":"Tolerability of Moclobemide, a New Reversible Inhibitor of Monoamine Oxidase-A, Compared with Other Antidepressants and Placebo","volume":"82","author":"Versiani","year":"1990","journal-title":"Acta Psychiatr. Scand."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Calvi, A. (2021). Antidepressant Drugs Effects on Blood Pressure. Front. Cardiovasc. Med., 8.","DOI":"10.3389\/fcvm.2021.704281"},{"key":"ref_28","first-page":"CD011209","article-title":"Nortriptyline for Neuropathic Pain in Adults","volume":"2015","author":"Derry","year":"2015","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1111\/j.1368-5031.2006.00865.x","article-title":"Tolerability and Safety of Fluvoxamine and Other Antidepressants","volume":"60","author":"Westenberg","year":"2006","journal-title":"Int. J. Clin. Pract."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/S0014-2999(02)02557-8","article-title":"Comparison of the Anticholinergic Effects of the Serotonergic Antidepressants, Paroxetine, Fluvoxamine and Clomipramine","volume":"454","author":"Fujishiro","year":"2002","journal-title":"Eur. J. Pharmacol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1357","DOI":"10.1016\/S0140-6736(17)32802-7","article-title":"Comparative Efficacy and Acceptability of 21 Antidepressant Drugs for the Acute Treatment of Adults with Major Depressive Disorder: A Systematic Review and Network Meta-Analysis","volume":"391","author":"Cipriani","year":"2018","journal-title":"Lancet"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e70098","DOI":"10.1111\/cts.70098","article-title":"An Overview of Drug-Induced Sodium Channel Blockade and Changes in Cardiac Conduction: Implications for Drug Safety","volume":"17","author":"Chaudhary","year":"2024","journal-title":"Clin. Transl. Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1007\/s002130000664","article-title":"The Effects of Amitriptyline, Citalopram and Reboxetine on Autonomic Nervous System: A Randomised Placebo-Controlled Study on Healthy Volunteers","volume":"154","year":"2001","journal-title":"Psychopharmacology"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"783413","DOI":"10.1093\/ecam\/nep221","article-title":"Evaluation of in Vitro Uterotonic Activities of Fruit Extracts of Ficus Asperifolia in Rats","volume":"2011","author":"Watcho","year":"2011","journal-title":"Evid.-Based Complement. Altern. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e995","DOI":"10.1002\/cpz1.995","article-title":"Mouse and Rat Anesthesia and Analgesia","volume":"4","author":"Oh","year":"2024","journal-title":"Curr. Protoc."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1177\/15353702211070535","article-title":"In Vitro Contractile Studies within Isolated Tissue Baths: Translational Research from Visible Heart\u00ae Laboratories","volume":"247","author":"Upchurch","year":"2022","journal-title":"Exp. Biol. Med."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Premrov Bajuk, B., Prem, L., Vake, T., \u017dnidar\u0161i\u010d, N., and Snoj, T. (2022). The Effect of Thymol on Acetylcholine-Induced Contractions of the Rat Ileum and Uterus under Ex Vivo Conditions. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.990654"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"C769","DOI":"10.1152\/ajpcell.00529.2004","article-title":"Regulation of Smooth Muscle Calcium Sensitivity: KCl as a Calcium-Sensitizing Stimulus","volume":"288","author":"Ratz","year":"2005","journal-title":"Am. J. Physiol. Physiol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/S0022-3565(25)03549-9","article-title":"A Simplified Method of Evaluating Dose-Effect Experiments","volume":"96","author":"Litchfield","year":"1949","journal-title":"J. Pharmacol. Exp. Ther."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/19\/4\/645\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T12:02:35Z","timestamp":1776772955000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/19\/4\/645"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,21]]},"references-count":39,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2026,4]]}},"alternative-id":["ph19040645"],"URL":"https:\/\/doi.org\/10.3390\/ph19040645","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,21]]}}}