{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T02:00:05Z","timestamp":1760148005755,"version":"build-2065373602"},"reference-count":99,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2023,3,20]],"date-time":"2023-03-20T00:00:00Z","timestamp":1679270400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Universidad Nacional Aut\u00f3noma de M\u00e9xico","award":["IN204319","IN200522","IN209520","IA201322","137725"],"award-info":[{"award-number":["IN204319","IN200522","IN209520","IA201322","137725"]}]},{"name":"Consejo Nacional de Ciencia y Tecnolog\u00eda","award":["IN204319","IN200522","IN209520","IA201322","137725"],"award-info":[{"award-number":["IN204319","IN200522","IN209520","IA201322","137725"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Theophylline is a drug commonly used to treat asthma due to its anti-inflammatory and bronchodilatory properties. Testosterone (TES) has been suggested to reduce the severity of asthma symptoms. This condition affects boys more than girls in childhood, and this ratio reverses at puberty. We reported that guinea pig tracheal tissue chronic exposure to TES increases the expression of \u03b22-adrenoreceptors and enhances salbutamol-induced K+ currents (IK+). Herein, we investigated whether the upregulation of K+ channels can enhance the relaxation response to methylxanthines, including theophylline. Chronic incubation of guinea pig tracheas with TES (40 nM, 48 h) enhanced the relaxation induced by caffeine, isobutylmethylxanthine, and theophylline, an effect that was abolished by tetraethylammonium. In tracheal myocytes, chronic incubation with TES increased theophylline-induced IK+; flutamide reversed this effect. The increase in IK+ was blocked by 4-aminopyridine by ~82%, whereas iberiotoxin reduced IK+ by ~17%. Immunofluorescence studies showed that chronic TES exposure increased the expression of KV1.2 and KV1.5 in airway smooth muscle (ASM). In conclusion, chronic exposure to TES in guinea pig ASM promotes upregulation of KV1.2 and KV1.5 and enhances theophylline relaxation response. Therefore, gender should be considered when prescribing methylxanthines, as teenage boys and males are likely to respond better than females.<\/jats:p>","DOI":"10.3390\/ijms24065884","type":"journal-article","created":{"date-parts":[[2023,3,20]],"date-time":"2023-03-20T07:56:37Z","timestamp":1679298997000},"page":"5884","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Theophylline-Induced Relaxation Is Enhanced after Testosterone Treatment via Increased KV1.2 and KV1.5 Protein Expression in Guinea Pig Tracheal Smooth Muscle"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6226-7363","authenticated-orcid":false,"given":"Jorge","family":"Reyes-Garc\u00eda","sequence":"first","affiliation":[{"name":"Departamento de Farmacolog\u00eda, Facultad de Medicina, Universidad Nacional Aut\u00f3noma de M\u00e9xico, Mexico City 04510, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6119-3497","authenticated-orcid":false,"given":"Ver\u00f3nica","family":"D\u00edaz-Hern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Departamento de Embriolog\u00eda y Gen\u00e9tica, Facultad de Medicina, Universidad Nacional Aut\u00f3noma de M\u00e9xico, Mexico City 04510, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1394-9971","authenticated-orcid":false,"given":"Abril","family":"Carbajal-Garc\u00eda","sequence":"additional","affiliation":[{"name":"Departamento de Farmacolog\u00eda, Facultad de Medicina, Universidad Nacional Aut\u00f3noma de M\u00e9xico, Mexico City 04510, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-8762-6798","authenticated-orcid":false,"given":"Mar\u00eda F.","family":"Casas-Hern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Departamento de Farmacolog\u00eda, Facultad de Medicina, Universidad Nacional Aut\u00f3noma de M\u00e9xico, Mexico City 04510, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1292-9418","authenticated-orcid":false,"given":"Bettina","family":"Sommer","sequence":"additional","affiliation":[{"name":"Laboratorio de Hiperreactividad Bronquial, Instituto Nacional de Enfermedades Respiratorias \u201cIsmael Cos\u00edo Villegas\u201d, Mexico City 14080, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8329-4918","authenticated-orcid":false,"given":"Luis M.","family":"Monta\u00f1o","sequence":"additional","affiliation":[{"name":"Departamento de Farmacolog\u00eda, Facultad de Medicina, Universidad Nacional Aut\u00f3noma de M\u00e9xico, Mexico City 04510, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1093\/chromsci\/45.5.273","article-title":"Determination of theobromine, theophylline, and caffeine in by-products of cupuacu and cacao seeds by high-performance liquid chromatography","volume":"45","author":"Lanuzza","year":"2007","journal-title":"J. Chromatogr. Sci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"725","DOI":"10.3390\/ph3030725","article-title":"Theophylline","volume":"3","author":"Barnes","year":"2010","journal-title":"Pharmaceuticals"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1164\/rccm.200210-1142PP","article-title":"Theophylline: New perspectives for an old drug","volume":"167","author":"Barnes","year":"2003","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1338","DOI":"10.1378\/chest.09-2363","article-title":"Treatment effects of low-dose theophylline combined with an inhaled corticosteroid in COPD","volume":"137","author":"Ford","year":"2010","journal-title":"Chest"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1111\/j.1440-1843.2005.00730.x","article-title":"Efficacy and safety of intravenous theophylline administration for treatment of mild acute exacerbation of bronchial asthma","volume":"10","author":"Yamauchi","year":"2005","journal-title":"Respirology"},{"key":"ref_6","first-page":"373","article-title":"A study of antispasmodic drugs on the bronchus","volume":"18","author":"Macht","year":"1921","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1007\/978-3-642-13443-2_17","article-title":"Methylxanthines in asthma","volume":"200","author":"Tilley","year":"2011","journal-title":"Handb. Exp. Pharmacol."},{"key":"ref_8","first-page":"512","article-title":"Successful treatment of persistent extreme dyspnea \u201cstatus asthmaticus\u201d. Use of theophylline ethylene diamine (aminophylline, U.S.P.) intravenously. 1938","volume":"115","author":"Herrmann","year":"1990","journal-title":"J. Lab. Clin. Med."},{"key":"ref_9","first-page":"347","article-title":"Theophylline revisited","volume":"22","author":"Somerville","year":"2001","journal-title":"Allergy Asthma Proc."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"600","DOI":"10.1056\/NEJM197309202891202","article-title":"Rational intravenous doses of theophylline","volume":"289","author":"Mitenko","year":"1973","journal-title":"N. Engl. J. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1136\/bmj.2.5036.67","article-title":"Study of theophylline plasma levels after oral administration of new theophylline compounds","volume":"2","year":"1957","journal-title":"Br. Med. J."},{"key":"ref_12","first-page":"613","article-title":"Comparison of standard- and sustained-release theophylline tablets in patients with chronic obstructive pulmonary disease","volume":"36","author":"Dasta","year":"1979","journal-title":"Am. J. Hosp. Pharm."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.ijpharm.2005.07.022","article-title":"Formulation study and drug release mechanism of a new theophylline sustained-release preparation","volume":"304","author":"Hayashi","year":"2005","journal-title":"Int. J. Pharm."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1016\/0091-6749(85)90674-8","article-title":"The bronchodilator effect and pharmacokinetics of theobromine in young patients with asthma","volume":"76","author":"Simons","year":"1985","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_15","first-page":"CD001112","article-title":"Caffeine for asthma","volume":"1","author":"Welsh","year":"2010","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/j.pharmthera.2019.02.002","article-title":"Phosphodiesterases as therapeutic targets for respiratory diseases","volume":"197","author":"Zuo","year":"2019","journal-title":"Pharmacol. Ther."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"eaax0273","DOI":"10.1126\/scisignal.aax0273","article-title":"Airway relaxation mechanisms and structural basis of osthole for improving lung function in asthma","volume":"13","author":"Wang","year":"2020","journal-title":"Sci. Signal."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1183\/09031936.95.08040637","article-title":"Theophylline and selective PDE inhibitors as bronchodilators and smooth muscle relaxants","volume":"8","author":"Rabe","year":"1995","journal-title":"Eur. Respir. J."},{"key":"ref_19","first-page":"L458","article-title":"Phosphodiesterase isozymes modulating inherent tone in human airways: Identification and characterization","volume":"264","author":"Rabe","year":"1993","journal-title":"Am. J. Physiol."},{"key":"ref_20","first-page":"L412","article-title":"Modulation of human airway smooth muscle proliferation by type 3 phosphodiesterase inhibition","volume":"276","author":"Billington","year":"1999","journal-title":"Am. J. Physiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"35980","DOI":"10.1074\/jbc.M204832200","article-title":"Cyclic AMP-dependent transcriptional up-regulation of phosphodiesterase 4D5 in human airway smooth muscle cells. Identification and characterization of a novel PDE4D5 promoter","volume":"277","author":"Shepherd","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1164\/rccm.201302-0388PP","article-title":"Theophylline","volume":"188","author":"Barnes","year":"2013","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/1465-9921-4-2","article-title":"Signaling and regulation of G protein-coupled receptors in airway smooth muscle","volume":"4","author":"Billington","year":"2003","journal-title":"Respir. Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"18023","DOI":"10.1074\/jbc.273.29.18023","article-title":"Phosphorylation of serine 1105 by protein kinase A inhibits phospholipase C\u03b23 stimulation by G\u03b1q","volume":"273","author":"Yue","year":"1998","journal-title":"J. Biol. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/S0143-4160(96)90025-1","article-title":"Effect of cAMP elevating agents on carbachol-induced phosphoinositide hydrolysis and calcium mobilization in cultured canine tracheal smooth muscle cells","volume":"19","author":"Yang","year":"1996","journal-title":"Cell Calcium"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1186\/1465-9921-7-34","article-title":"Airway smooth muscle relaxation results from a reduction in the frequency of Ca2+ oscillations induced by a cAMP-mediated inhibition of the IP3 receptor","volume":"7","author":"Bai","year":"2006","journal-title":"Respir. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"C1029","DOI":"10.1152\/ajpcell.2001.281.3.C1029","article-title":"Role of phospholamban in the modulation of arterial Ca2+ sparks and Ca2+-activated K+ channels by cAMP","volume":"281","author":"Wellman","year":"2001","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_28","first-page":"L100","article-title":"Activation of KCa channels in airway smooth muscle cells by endogenous protein kinase A","volume":"271","author":"Wang","year":"1996","journal-title":"Am. J. Physiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1172\/JCI116969","article-title":"\u03b2-adrenergic agonists regulate KCa channels in airway smooth muscle by cAMP-dependent and -independent mechanisms","volume":"93","author":"Kume","year":"1994","journal-title":"J. Clin. Investig."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1124\/mol.61.2.285","article-title":"Modulation of Kv1.5 currents by protein kinase A, tyrosine kinase, and protein tyrosine phosphatase requires an intact cytoskeleton","volume":"61","author":"Mason","year":"2002","journal-title":"Mol. Pharmacol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1016\/S0959-4388(96)80114-0","article-title":"Regulation of potassium channels by protein kinases","volume":"6","author":"Jonas","year":"1996","journal-title":"Curr. Opin. Neurobiol."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Brueggemann, L.I., Cribbs, L.L., Schwartz, J., Wang, M., Kouta, A., and Byron, K.L. (2018). Mechanisms of PKA-Dependent Potentiation of Kv7.5 Channel Activity in Human Airway Smooth Muscle Cells. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19082223"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"13239","DOI":"10.1074\/jbc.271.22.13239","article-title":"Expression and function of voltage-dependent potassium channel genes in human airway smooth muscle","volume":"271","author":"Adda","year":"1996","journal-title":"J. Biol. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1113\/jphysiol.1992.sp019005","article-title":"Delayed rectifier potassium channels in canine and porcine airway smooth muscle cells","volume":"447","author":"Boyle","year":"1992","journal-title":"J. Physiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"L476","DOI":"10.1152\/ajplung.00253.2013","article-title":"KCNQ (Kv7) potassium channel activators as bronchodilators: Combination with a \u03b22-adrenergic agonist enhances relaxation of rat airways","volume":"306","author":"Brueggemann","year":"2014","journal-title":"Am. J. Physiol. Lung Cell Mol. Physiol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1016\/j.lfs.2008.07.006","article-title":"Airway smooth muscle relaxation induced by 5-HT2A receptors: Role of Na+\/K+-ATPase pump and Ca2+-activated K+ channels","volume":"83","author":"Vargas","year":"2008","journal-title":"Life Sci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"110801","DOI":"10.1016\/j.mce.2020.110801","article-title":"Testosterone augments \u03b22 adrenergic receptor genomic transcription increasing salbutamol relaxation in airway smooth muscle","volume":"510","author":"Sommer","year":"2020","journal-title":"Mol. Cell Endocrinol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1007\/s00424-011-0997-3","article-title":"Characterization of P2Y receptors mediating ATP induced relaxation in guinea pig airway smooth muscle: Involvement of prostaglandins and K+ channels","volume":"462","author":"Figueroa","year":"2011","journal-title":"Pflugers Arch."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1164\/ajrccm\/146.1.132","article-title":"Role of potassium channels in bronchodilator responses in human airways","volume":"146","author":"Miura","year":"1992","journal-title":"Am. Rev. Respir. Dis."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1016\/j.anai.2018.01.016","article-title":"Hormones, sex, and asthma","volume":"120","author":"Yung","year":"2018","journal-title":"Ann. Allergy Asthma Immunol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1007\/978-3-030-68748-9_15","article-title":"Sex Hormones and Lung Inflammation","volume":"1304","author":"Wang","year":"2021","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_42","first-page":"8849641","article-title":"Androgen Effects on the Adrenergic System of the Vascular, Airway, and Cardiac Myocytes and Their Relevance in Pathological Processes","volume":"2020","year":"2020","journal-title":"Int. J. Endocrinol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1164\/ajrccm.162.1.9907008","article-title":"Differences in incidence of reported asthma related to age in men and women. A retrospective analysis of the data of the European Respiratory Health Survey","volume":"162","author":"Locatelli","year":"2000","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1053\/rmed.1999.0764","article-title":"Asthma from childhood to adulthood: Asthma severity, allergies, sensitization, living conditions, gender influence and social consequences","volume":"94","author":"Kjellman","year":"2000","journal-title":"Respir. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1186\/1477-7827-9-57","article-title":"Second to fourth digit ratio (2D:4D) and concentrations of circulating sex hormones in adulthood","volume":"9","author":"Muller","year":"2011","journal-title":"Reprod. Biol. Endocrinol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1210\/er.2010-0031","article-title":"Sex differences and sex steroids in lung health and disease","volume":"33","author":"Townsend","year":"2012","journal-title":"Endocr. Rev."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1405","DOI":"10.1042\/CS20170090","article-title":"Genomic and non-genomic effects of androgens in the cardiovascular system: Clinical implications","volume":"131","author":"Montezano","year":"2017","journal-title":"Clin. Sci."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1016\/j.jsbmb.2013.05.009","article-title":"Nongenomic bronchodilating action elicited by dehydroepiandrosterone (DHEA) in a guinea pig asthma model","volume":"138","author":"Espinoza","year":"2013","journal-title":"J. Steroid BioChem. Mol. Biol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1095\/biolreprod.104.036954","article-title":"Androgens induce relaxation of contractile activity in pregnant human myometrium at term: A nongenomic action on L-type calcium channels","volume":"73","author":"Navarrete","year":"2005","journal-title":"Biol. Reprod"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"108509","DOI":"10.1016\/j.steroids.2019.108509","article-title":"Androgens are effective bronchodilators with anti-inflammatory properties: A potential alternative for asthma therapy","volume":"153","author":"Sommer","year":"2020","journal-title":"Steroids"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1007\/s00424-014-1534-y","article-title":"Testosterone-induced relaxation involves L-type and store-operated Ca2+ channels blockade, and PGE2 in guinea pig airway smooth muscle","volume":"467","author":"Sommer","year":"2015","journal-title":"Pflugers Arch."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1530\/JOE-14-0074","article-title":"Androgens are bronchoactive drugs that act by relaxing airway smooth muscle and preventing bronchospasm","volume":"222","author":"Espinoza","year":"2014","journal-title":"J. Endocrinol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1016\/j.mce.2016.10.004","article-title":"Sex steroids effects on guinea pig airway smooth muscle tone and intracellular Ca2+ basal levels","volume":"439","author":"Sommer","year":"2017","journal-title":"Mol. Cell Endocrinol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.mce.2017.12.010","article-title":"Testosterone induces hyporesponsiveness by interfering with IP3 receptors in guinea pig airway smooth muscle","volume":"473","author":"Sommer","year":"2018","journal-title":"Mol. Cell Endocrinol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1016\/j.ejphar.2008.10.039","article-title":"Modulatory role of endogenous androgens on airway smooth muscle tone in isolated guinea-pig and bovine trachea; involvement of \u03b22-adrenoceptors, the polyamine system and external calcium","volume":"601","author":"Bordallo","year":"2008","journal-title":"Eur. J. Pharmacol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1111\/j.1476-5381.1983.tb09409.x","article-title":"Effect of steroids on \u03b2-adrenoceptor-mediated relaxation of pig bronchus","volume":"78","author":"Foster","year":"1983","journal-title":"Br. J. Pharmacol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1038\/newbio238091a0","article-title":"Inhibition of the extraneuronal uptake of catecholamine in the isolated rat heart by cholesterol","volume":"238","author":"Salt","year":"1972","journal-title":"Nat. New Biol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1843","DOI":"10.4049\/jimmunol.1800293","article-title":"Testosterone Decreases House Dust Mite-Induced Type 2 and IL-17A-Mediated Airway Inflammation","volume":"201","author":"Fuseini","year":"2018","journal-title":"J. Immunol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1581","DOI":"10.1084\/jem.20161807","article-title":"Androgen signaling negatively controls group 2 innate lymphoid cells","volume":"214","author":"Laffont","year":"2017","journal-title":"J. Exp. Med."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"H1720","DOI":"10.1152\/ajpheart.2001.281.4.H1720","article-title":"Testosterone relaxes coronary arteries by opening the large-conductance, calcium-activated potassium channel","volume":"281","author":"Deenadayalu","year":"2001","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1111\/j.1743-6109.2007.00732.x","article-title":"Effect of testosterone on potassium channel opening in human corporal smooth muscle cells","volume":"5","author":"Han","year":"2008","journal-title":"J. Sex. Med."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1007\/s12576-017-0590-4","article-title":"Testosterone-mediated upregulation of delayed rectifier potassium channel in cardiomyocytes causes abbreviation of QT intervals in rats","volume":"68","author":"Masuda","year":"2018","journal-title":"J. Physiol. Sci."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1016\/S0188-4409(00)00156-9","article-title":"Sarcoplasmic reticulum Ca2+ depletion by caffeine and changes of [Ca2+]i during refilling in bovine airway smooth muscle cells","volume":"31","author":"Carbajal","year":"2000","journal-title":"Arch. Med. Res."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1111\/j.1476-5381.1991.tb12453.x","article-title":"The presence of five cyclic nucleotide phosphodiesterase isoenzyme activities in bovine tracheal smooth muscle and the functional effects of selective inhibitors","volume":"104","author":"Shahid","year":"1991","journal-title":"Br. J. Pharmacol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1111\/j.1476-5381.1987.tb11371.x","article-title":"Effects of phosphodiesterase inhibitors on normal and chemically-skinned isolated airway smooth muscle","volume":"92","author":"Bryson","year":"1987","journal-title":"Br. J. Pharmacol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"672","DOI":"10.3889\/oamjms.2015.117","article-title":"Analysis of Plasma Concentrations of Theophylline in Smoking and Nonsmoking Patients with Asthma","volume":"3","author":"Goseva","year":"2015","journal-title":"Open Access Maced J. Med. Sci."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1380","DOI":"10.1056\/NEJM199605233342107","article-title":"Theophylline in asthma","volume":"334","author":"Weinberger","year":"1996","journal-title":"N. Engl. J. Med."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1016\/j.anai.2022.02.010","article-title":"Medication adherence in Medicare-enrolled older adults with asthma before and during the coronavirus disease 2019 pandemic","volume":"128","author":"Ramey","year":"2022","journal-title":"Ann. Allergy Asthma Immunol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"105904","DOI":"10.1016\/j.rmed.2020.105904","article-title":"The effect of doxofylline in asthma and COPD","volume":"164","author":"Cazzola","year":"2020","journal-title":"Respir. Med."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1097\/FTD.0000000000000787","article-title":"Differences in Theophylline Clearance Between Patients With Chronic Hepatitis and Those With Liver Cirrhosis","volume":"42","author":"Kurata","year":"2020","journal-title":"Ther. Drug Monit."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1124\/pr.111.004580","article-title":"Pharmacology and therapeutics of bronchodilators","volume":"64","author":"Cazzola","year":"2012","journal-title":"Pharmacol. Rev."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Monteiro, J.P., Alves, M.G., Oliveira, P.F., and Silva, B.M. (2016). Structure-Bioactivity Relationships of Methylxanthines: Trying to Make Sense of All the Promises and the Drawbacks. Molecules, 21.","DOI":"10.3390\/molecules21080974"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1016\/0091-6749(84)90235-5","article-title":"Spontaneous and provoked resistance to isoproterenol in isolated human bronchi","volume":"74","author":"Guillot","year":"1984","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1165\/rcmb.2007-0171OC","article-title":"A major functional role for phosphodiesterase 4D5 in human airway smooth muscle cells","volume":"38","author":"Billington","year":"2008","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1831","DOI":"10.1096\/fj.03-0274com","article-title":"PDE4D plays a critical role in the control of airway smooth muscle contraction","volume":"17","author":"Mehats","year":"2003","journal-title":"FASEB J."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"6751","DOI":"10.1073\/pnas.97.12.6751","article-title":"Absence of muscarinic cholinergic airway responses in mice deficient in the cyclic nucleotide phosphodiesterase PDE4D","volume":"97","author":"Hansen","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/j.pupt.2012.05.007","article-title":"cAMP regulation of airway smooth muscle function","volume":"26","author":"Billington","year":"2013","journal-title":"Pulm. Pharmacol. Ther."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"23065","DOI":"10.1074\/jbc.M114.557652","article-title":"\u03b2-Agonist-mediated relaxation of airway smooth muscle is protein kinase A-dependent","volume":"289","author":"Morgan","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_79","first-page":"429","article-title":"Potassium channel modulation: A new drug principle for regulation of smooth muscle contractility. Studies on isolated airways and arteries","volume":"43","year":"1996","journal-title":"Dan. Med. Bull."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/0014-2999(93)90817-2","article-title":"Inhibition of \u03b2-adrenoceptor agonist relaxation of airway smooth muscle by Ca2+-activated K+ channel blockers","volume":"235","author":"Huang","year":"1993","journal-title":"Eur. J. Pharmacol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1111\/j.1476-5381.1991.tb12287.x","article-title":"The contribution of Rb-permeable potassium channels to the relaxant and membrane hyperpolarizing actions of cromakalim, RP49356 and diazoxide in bovine tracheal smooth muscle","volume":"102","author":"Longmore","year":"1991","journal-title":"Br. J. Pharmacol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"L898","DOI":"10.1152\/ajplung.00461.2005","article-title":"Bradykinin activates calcium-dependent potassium channels in cultured human airway smooth muscle cells","volume":"292","author":"Liu","year":"2007","journal-title":"Am. J. Physiol. Lung Cell Mol. Physiol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"15843","DOI":"10.1074\/jbc.M112.427187","article-title":"The intermediate conductance calcium-activated potassium channel KCa3.1 regulates vascular smooth muscle cell proliferation via controlling calcium-dependent signaling","volume":"288","author":"Bi","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1038\/aps.2015.139","article-title":"Peptide toxins and small-molecule blockers of BK channels","volume":"37","author":"Yu","year":"2016","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1113\/jphysiol.1981.sp013770","article-title":"The effect of tetraethylammonium chloride on potassium permeability in the smooth muscle cell membrane of canine trachea","volume":"316","author":"Imaizumi","year":"1981","journal-title":"J. Physiol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/0163-7258(93)90064-K","article-title":"Potassium channels in airway smooth muscle: A tale of two channels","volume":"58","author":"Kotlikoff","year":"1993","journal-title":"Pharmacol. Ther."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1007\/s00210-007-0213-3","article-title":"Potassium channels are involved in testosterone-induced vasorelaxation of human umbilical artery","volume":"376","author":"Cairrao","year":"2008","journal-title":"Naunyn Schmiedebergs Arch. Pharmacol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1073\/pnas.91.2.624","article-title":"Molecular basis of cardiac potassium channel stimulation by protein kinase A","volume":"91","author":"Huang","year":"1994","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"210067","DOI":"10.1183\/16000617.0067-2021","article-title":"Sex and gender in asthma","volume":"30","author":"Chowdhury","year":"2021","journal-title":"Eur. Respir. Rev."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1016\/j.mehy.2011.01.006","article-title":"Do low testosterone levels contribute to the pathogenesis of asthma?","volume":"76","author":"Canguven","year":"2011","journal-title":"Med. Hypotheses."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1038\/nri3786","article-title":"Type 2 inflammation in asthma--present in most, absent in many","volume":"15","author":"Fahy","year":"2015","journal-title":"Nat. Rev. Immunol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"L843","DOI":"10.1152\/ajplung.00416.2018","article-title":"Regulation of IL-17A and implications for TGF-\u03b21 comodulation of airway smooth muscle remodeling in severe asthma","volume":"316","author":"Evasovic","year":"2019","journal-title":"Am. J. Physiol. Lung Cell Mol. Physiol."},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Monta\u00f1o, L.M., Sommer, B., G\u00f3mez-Verjan, J.C., Morales-Paoli, G.S., Ram\u00edrez-Salinas, G.L., Solis-Chagoy\u00e1n, H., S\u00e1nchez-Florentino, Z.A., Calixto, E., P\u00e9rez-Figueroa, G.E., and Carter, R. (2022). Theophylline: Old Drug in a New Light, Application in COVID-19 through Computational Studies. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23084167"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"123","DOI":"10.3389\/fimmu.2016.00123","article-title":"The cAMP Pathway as Therapeutic Target in Autoimmune and Inflammatory Diseases","volume":"7","author":"Raker","year":"2016","journal-title":"Front. Immunol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1016\/j.immuni.2008.12.021","article-title":"Cyclic adenosine monophosphate suppresses the transcription of proinflammatory cytokines via the phosphorylated c-Fos protein","volume":"30","author":"Koga","year":"2009","journal-title":"Immunity"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1164\/ajrccm.164.3.2010109","article-title":"Airway smooth muscle cell proliferation is increased in asthma","volume":"164","author":"Johnson","year":"2001","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1016\/S1081-1206(10)60795-8","article-title":"Profiles of proinflammatory cytokines in sputum from different groups of severe asthmatic patients","volume":"97","author":"Dente","year":"2006","journal-title":"Ann. Allergy Asthma Immunol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"3167","DOI":"10.1172\/JCI92885","article-title":"Androgen-mediated sex bias impairs efficiency of leukotriene biosynthesis inhibitors in males","volume":"127","author":"Pace","year":"2017","journal-title":"J. Clin. Investig."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"24980","DOI":"10.1074\/jbc.272.40.24980","article-title":"Efficient mammalian protein synthesis requires an intact F-actin system","volume":"272","author":"Stapulionis","year":"1997","journal-title":"J. Biol. Chem."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/6\/5884\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:59:32Z","timestamp":1760122772000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/6\/5884"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,20]]},"references-count":99,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2023,3]]}},"alternative-id":["ijms24065884"],"URL":"https:\/\/doi.org\/10.3390\/ijms24065884","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2023,3,20]]}}}