{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T16:13:08Z","timestamp":1753891988279,"version":"3.41.2"},"reference-count":46,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,8,16]],"date-time":"2023-08-16T00:00:00Z","timestamp":1692144000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p><jats:bold>Background:<\/jats:bold> Mucociliary clearance is a pivotal physiological mechanism that protects the lung by ridding the lower airways of pollution and colonization by pathogens, thereby preventing infections. The fixed 20:1 combination of cafedrine and theodrenaline has been used to treat perioperative hypotension or hypotensive states due to emergency situations since the 1960s. Because mucociliary clearance is impaired during mechanical ventilation and critical illness, the present study aimed to evaluate the influence of cafedrine\/theodrenaline on mucociliary clearance.<\/jats:p><jats:p><jats:bold>Material and Methods:<\/jats:bold> The particle transport velocity (PTV) of murine trachea preparations was measured as a surrogate for mucociliary clearance under the influence of cafedrine\/theodrenaline, cafedrine alone, and theodrenaline alone. Inhibitory substances were applied to elucidate relevant signal transduction cascades.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> All three applications of the combination of cafedrine\/theodrenaline, cafedrine alone, or theodrenaline alone induced a sharp increase in PTV in a concentration-dependent manner with median effective concentrations of 0.46\u00a0\u00b5M (consisting of 9.6\u00a0\u00b5M cafedrine and 0.46\u00a0\u00b5M theodrenaline), 408 and 4\u00a0\u03bcM, respectively. The signal transduction cascades were similar for the effects of both cafedrine and theodrenaline at the murine respiratory epithelium. While PTV remained at its baseline value after non-selective inhibition of \u03b2-adrenergic receptors and selective inhibition of \u03b2<jats:sub>1<\/jats:sub> receptors, cafedrine\/theodrenaline, cafedrine alone, or theodrenaline alone increased PTV despite the inhibition of the protein kinase A. However, IP<jats:sub>3<\/jats:sub> receptor activation was found to be the pivotal mechanism leading to the increase in murine PTV, which was abolished when IP<jats:sub>3<\/jats:sub> receptors were inhibited. Depleting intracellular calcium stores with caffeine confirmed calcium as another crucial messenger altering the PTV after the application of cafedrine\/theodrenaline.<\/jats:p><jats:p><jats:bold>Discussion:<\/jats:bold> Cafedrine\/theodrenaline, cafedrine alone, and theodrenaline alone exert their effects via IP<jats:sub>3<\/jats:sub> receptor-associated calcium release that is ultimately triggered by \u03b2<jats:sub>1<\/jats:sub>-adrenergic receptor stimulation. Synergistic effects at the \u03b2<jats:sub>1<\/jats:sub>-adrenergic receptor are highly relevant to alter the PTV of the respiratory epithelium at clinically relevant concentrations. Further investigations are needed to assess the value of cafedrine\/theodrenaline-mediated alterations in mucociliary function in clinical practice.<\/jats:p>","DOI":"10.3389\/fphar.2023.1155930","type":"journal-article","created":{"date-parts":[[2023,8,17]],"date-time":"2023-08-17T10:31:38Z","timestamp":1692268298000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["A 20:1 synergetic mixture of cafedrine\/theodrenaline accelerates particle transport velocity in murine tracheal epithelium via IP3 receptor-associated calcium release"],"prefix":"10.3389","volume":"14","author":[{"given":"G\u00f6tz","family":"Schmidt","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gerrit","family":"Rienas","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sabrina","family":"M\u00fcller","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fabian","family":"Edinger","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Sander","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christian","family":"Koch","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Henrich","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2023,8,16]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"850","DOI":"10.1124\/mol.118.111948","article-title":"Small-molecule positive allosteric modulators of the \u03b22-adrenoceptor isolated from DNA-encoded libraries","volume":"94","author":"Ahn","year":"2018","journal-title":"Mol. Pharmacol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"1114","DOI":"10.1152\/ajpcell.00343.2003","article-title":"Plasma and intracellular membrane inositol 1,4,5-trisphosphate receptors mediate the Ca2+ increase associated with the ATP-induced increase in ciliary beat frequency","volume":"287","author":"Barrera","year":"2004","journal-title":"Am. J. Physiology - Cell. Physiology"},{"key":"B3","doi-asserted-by":"publisher","first-page":"518","DOI":"10.1097\/01.CCM.0000299741.32078.E9","article-title":"Following tracheal intubation, mucus flow is reversed in the semirecumbent position: possible role in the pathogenesis of ventilator-associated pneumonia","volume":"36","author":"Bassi","year":"2008","journal-title":"Crit. Care Med."},{"key":"B4","doi-asserted-by":"publisher","first-page":"68","DOI":"10.3389\/fphar.2017.00068","article-title":"Cafedrine\/theodrenaline (20:1) is an established alternative for the management of arterial hypotension in Germany-a review based on a systematic literature search","volume":"8","author":"Bein","year":"2017","journal-title":"Front. Pharmacol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"C790","DOI":"10.1152\/ajpcell.1998.275.3.c790","article-title":"PKA induces Ca2+ release and enhances ciliary beat frequency in a Ca2+-dependent and -independent manner","volume":"275","author":"Braiman","year":"1998","journal-title":"Am. J. Physiology - Cell. Physiology"},{"key":"B6","doi-asserted-by":"publisher","first-page":"410","DOI":"10.1378\/chest.89.3.410","article-title":"Oxidant-mediated ciliary dysfunction. Possible role in airway disease","volume":"89","author":"Burman","year":"1986","journal-title":"Chest"},{"key":"B7","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1165\/rcmb.2005-0417OC","article-title":"Ciliary beat frequency is maintained at a maximal rate in the small airways of mouse lung slices","volume":"35","author":"Delmotte","year":"2006","journal-title":"Am. J. Respir. Cell. Mol. Biol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"953","DOI":"10.1080\/03007995.2018.1438379","article-title":"A non-interventional comparative study of the 20:1 combination of cafedrine\/theodrenaline versus ephedrine for the treatment of intra-operative arterial hypotension: the \u201cHYPOTENS\u201d study design and rationale","volume":"34","author":"Eberhart","year":"2018","journal-title":"Curr. Med. Res. Opin."},{"key":"B9","doi-asserted-by":"publisher","first-page":"810","DOI":"10.1016\/j.str.2020.04.012","article-title":"Activation of phospholipase C \u03b2 by g\u03b2\u03b3 and g\u03b1q involves C-terminal rearrangement to release autoinhibition","volume":"28","author":"Fisher","year":"2020","journal-title":"Structure"},{"key":"B10","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1097\/00000542-197901000-00006","article-title":"Mucociliary clearance in the canine lung during and after general anesthesia","volume":"50","author":"Forbes","year":"1979","journal-title":"Anesthesiology"},{"key":"B11","doi-asserted-by":"publisher","first-page":"9967","DOI":"10.1074\/jbc.M117.787119","article-title":"\u03b22-Adrenergic receptor activation mobilizes intracellular calcium via a non-canonical cAMP-independent signaling pathway","volume":"292","author":"Galaz-Montoya","year":"2017","journal-title":"J. Biol. Chem."},{"key":"B12","doi-asserted-by":"publisher","first-page":"190","DOI":"10.1007\/s00101-015-0005-y","article-title":"Cafedrine\/theodrenaline in anaesthesia: influencing factors in restoring arterial blood pressure","volume":"64","author":"Heller","year":"2015","journal-title":"Anaesthesist"},{"key":"B13","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1007\/s00210-003-0860-y","article-title":"Comparative pharmacology of human \u03b2-adrenergic receptor subtypes - characterization of stably transfected receptors in CHO cells","volume":"369","author":"Hoffmann","year":"2004","journal-title":"Naunyn-Schmiedeberg\u2019s Archives Pharmacol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1016\/j.jpeds.2020.11.040","article-title":"Understanding primary ciliary dyskinesia and other ciliopathies","volume":"230","author":"Horani","year":"2021","journal-title":"J. Pediatr."},{"key":"B15","first-page":"107","article-title":"Volatile anesthetics and mucociliary clearance","volume":"74","author":"Kesimci","year":"2008","journal-title":"Minerva Anestesiol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"1491","DOI":"10.1007\/s00134-004-2235-3","article-title":"Mucociliary function deteriorates in the clinical range of inspired air temperature and humidity","volume":"30","author":"Kilgour","year":"2004","journal-title":"Intensive Care Med."},{"key":"B17","doi-asserted-by":"publisher","first-page":"272","DOI":"10.3389\/fphar.2017.00272","article-title":"AkrinorTM, a cafedrine\/theodrenaline mixture (20:1), increases force of contraction of human atrial myocardium but does not constrict internal mammary artery in vitro","volume":"8","author":"Kloth","year":"2017","journal-title":"Front. Pharmacol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1007\/s001010050038","article-title":"The effect of theophylline on the mucociliary clearance function in ventilated intensive care patients","volume":"43","author":"Konrad","year":"1994","journal-title":"Anaesthesist"},{"key":"B19","doi-asserted-by":"publisher","first-page":"1067","DOI":"10.1097\/EJA.0000000000001474","article-title":"Treatment of spinal anaesthesia-induced hypotension with cafedrine\/theodrenaline versus ephedrine during caesarean section: results from HYPOTENS, a national, multicentre, prospective, noninterventional study","volume":"38","author":"Kranke","year":"2021","journal-title":"Eur. J. Anaesthesiol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1016\/j.bbrc.2018.11.010","article-title":"Spontaneous oscillation of the ciliary beat frequency regulated by release of Ca2+ from intracellular stores in mouse nasal epithelia","volume":"507","author":"Kuremoto","year":"2018","journal-title":"Biochem. Biophysical Res. Commun."},{"key":"B21","first-page":"1349","article-title":"Potentiation of beta-adrenoceptor agonist mediated-lipolysis by cholesterol-derived oxysterols","volume":"35","author":"Lau","year":"1995","journal-title":"Biochem. Mol. Biol. Int."},{"key":"B22","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.semcdb.2020.11.007","article-title":"Motile cilia and airway disease","volume":"110","author":"Legendre","year":"2021","journal-title":"Seminars Cell. Dev. Biol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"1181","DOI":"10.1124\/mol.65.5.1181","article-title":"Synergistic contributions of the functional groups of epinephrine to its affinity and efficacy at the beta2 adrenergic receptor","volume":"65","author":"Liapakis","year":"2004","journal-title":"Mol. Pharmacol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"6387","DOI":"10.1074\/jbc.RA118.002354","article-title":"G protein subunits directly interact with and activate phospholipase C","volume":"293","author":"Madukwe","year":"2018","journal-title":"J. Biol. Chem."},{"key":"B25","first-page":"98","article-title":"Effect of theophylline on mucociliary clearance in man","volume":"61","author":"Matthys","year":"1980","journal-title":"Eur. J. Respir. Dis."},{"key":"B26","doi-asserted-by":"publisher","first-page":"e0066921","DOI":"10.1128\/AAC.00669-21","article-title":"Echinocandins accelerate particle transport velocity in the murine tracheal epithelium: dependency on intracellular Ca2+ stores","volume":"65","author":"M\u00fcller","year":"2021","journal-title":"Antimicrob. agents Chemother."},{"key":"B27","doi-asserted-by":"publisher","first-page":"2772","DOI":"10.1378\/chest.128.4.2772","article-title":"Mucociliary clearance is impaired in acutely ill patients","volume":"128","author":"Nakagawa","year":"2005","journal-title":"Chest"},{"key":"B28","doi-asserted-by":"publisher","first-page":"981","DOI":"10.1002\/cphy.c170031","article-title":"Store-operated calcium entry mediated by ORAI and STIM","volume":"8","author":"Nguyen","year":"2018","journal-title":"Compr. Physiol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"4289","DOI":"10.26355\/eurrev_202206_29067","article-title":"Effects of sugammadex and neostigmine on mucociliary clearance in general anesthesia","volume":"26","author":"Ozciftci","year":"2022","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"B30","doi-asserted-by":"publisher","first-page":"683","DOI":"10.1016\/j.immuni.2020.03.005","article-title":"Chemosensory cell-derived acetylcholine drives tracheal mucociliary clearance in response to virulence-associated formyl peptides","volume":"52","author":"Perniss","year":"2020","journal-title":"Immunity"},{"key":"B31","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1146\/annurev.physiol.69.040705.141253","article-title":"Regulation of mammalian ciliary beating","volume":"69","author":"Salathe","year":"2007","journal-title":"Annu. Rev. Physiology"},{"key":"B32","doi-asserted-by":"publisher","first-page":"7302","DOI":"10.1073\/pnas.83.19.7302","article-title":"Mechanosensitivity of cultured ciliated cells from the mammalian respiratory tract: implications for the regulation of mucociliary transport","volume":"83","author":"Sanderson","year":"1986","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B33","doi-asserted-by":"publisher","first-page":"1020","DOI":"10.1038\/ncb1101-1020","article-title":"A new phospholipase-C-calcium signalling pathway mediated by cyclic AMP and a Rap GTPase","volume":"3","author":"Schmidt","year":"2001","journal-title":"Nat. Cell. Biol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"C402","DOI":"10.1152\/ajpcell.00355.2015","article-title":"Orai channel-mediated Ca2+ signals in vascular and airway smooth muscle","volume":"310","author":"Spinelli","year":"2016","journal-title":"Am. J. Physiology - Cell. Physiology"},{"key":"B35","first-page":"401","article-title":"Die Beeinflussung der Herz-Kreislauf-Dynamik durch die Theophyllin-Verbindung Cafedrin und Theodrenalin sowie durch ihre Kombination","volume":"8","author":"Sternitzke","year":"1984","journal-title":"Herz Kreislauf"},{"key":"B36","doi-asserted-by":"publisher","first-page":"519","DOI":"10.1113\/jphysiol.2004.068171","article-title":"Regulation of human airway ciliary beat frequency by intracellular pH","volume":"560","author":"Sutto","year":"2004","journal-title":"J. Physiology"},{"key":"B37","doi-asserted-by":"publisher","first-page":"450","DOI":"10.1097\/01.fjc.0000211710.87863.89","article-title":"Akrinor-induced relaxation of pig coronary artery in vitro is transformed into alpha1-adrenoreceptor-mediated contraction by pretreatment with propranolol","volume":"47","author":"Usichenko","year":"2006","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"568","DOI":"10.1124\/molpharm.121.000359","article-title":"\u03b2-arrestin\u2013biased allosteric modulator potentiates carvedilol-stimulated \u03b2 adrenergic receptor cardioprotection","volume":"100","author":"Wang","year":"2021","journal-title":"Mol. Pharmacol."},{"key":"B39","doi-asserted-by":"publisher","first-page":"e0143163","DOI":"10.1371\/journal.pone.0143163","article-title":"Galactomannan and zymosan block the epinephrine-induced particle transport in tracheal epithelium","volume":"10","author":"Weiterer","year":"2015","journal-title":"PLoS ONE"},{"key":"B40","doi-asserted-by":"publisher","first-page":"e91705","DOI":"10.1371\/journal.pone.0091705","article-title":"Tumor necrosis factor alpha induces a serotonin dependent early increase in ciliary beat frequency and epithelial transport velocity in murine tracheae","volume":"9","author":"Weiterer","year":"2014","journal-title":"PLoS ONE"},{"key":"B41","doi-asserted-by":"publisher","first-page":"766","DOI":"10.1007\/s00101-018-0472-z","article-title":"Hemodynamic effects of cafedrine\/theodrenaline on anesthesia-induced hypotension","volume":"67","author":"Weitzel","year":"2018","journal-title":"Anaesthesist"},{"key":"B42","first-page":"S143","article-title":"Airway epithelial differentiation and mucociliary clearance","volume-title":"Annals of the American thoracic society","author":"Whitsett","year":"2018"},{"key":"B43","doi-asserted-by":"publisher","first-page":"827","DOI":"10.1152\/ajplung.1998.275.4.l827","article-title":"Regulation of ciliary beat frequency by both PKA and PKG in bovine airway epithelial cells","volume":"275","author":"Wyatt","year":"1998","journal-title":"Am. J. Physiology - Lung Cell. Mol. Physiology"},{"key":"B44","first-page":"315","volume-title":"\u2018Cyclic GMP and cilia motility\u2019,","author":"Wyatt","year":"2015"},{"key":"B45","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1085\/jgp.20028519","article-title":"The mechanism of ciliary stimulation by acetylcholine: roles of calcium, PKA, and PKG","volume":"119","author":"Zagoory","year":"2002","journal-title":"J. General Physiology"},{"key":"B46","doi-asserted-by":"publisher","first-page":"38S-43S","DOI":"10.1378\/chest.92.1_supplement.38s","article-title":"Theophylline and mucociliary clearance","volume":"92","author":"Ziment","year":"1987","journal-title":"Chest"}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2023.1155930\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,17]],"date-time":"2023-08-17T10:31:46Z","timestamp":1692268306000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2023.1155930\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,16]]},"references-count":46,"alternative-id":["10.3389\/fphar.2023.1155930"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2023.1155930","relation":{},"ISSN":["1663-9812"],"issn-type":[{"type":"electronic","value":"1663-9812"}],"subject":[],"published":{"date-parts":[[2023,8,16]]},"article-number":"1155930"}}