{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:53:49Z","timestamp":1760147629291,"version":"build-2065373602"},"reference-count":43,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2023,2,15]],"date-time":"2023-02-15T00:00:00Z","timestamp":1676419200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"JSPS KAKENHI","doi-asserted-by":"publisher","award":["JP20K16013","JP20K07299","JP20K07091"],"award-info":[{"award-number":["JP20K16013","JP20K07299","JP20K07091"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Mechanisms for the \u03b1-adrenoceptor-mediated positive inotropy in neonatal mouse ventricular myocardium were studied with isolated myocardial preparations. The phenylephrine-induced positive inotropy was suppressed by prazosin, nifedipine, and chelerythrine, a protein kinase C inhibitor, but not by SEA0400, a selective Na+\/Ca2+ exchanger inhibitor. Phenylephrine increased the L-type Ca2+ channel current and prolonged the action potential duration, while the voltage-dependent K+ channel current was not influenced. In the presence of cromakalim, an ATP-sensitive K+ channel opener, the phenylephrine-induced prolongation of action potential duration, as well as the positive inotropy, were smaller than in the absence of cromakalim. These results suggest that the \u03b1-adrenoceptor-mediated positive inotropy is mediated by an increase in Ca2+ influx through the L-type Ca2+ channel, and the concomitant increase in action potential duration acts as an enhancing factor.<\/jats:p>","DOI":"10.3390\/ijms24043926","type":"journal-article","created":{"date-parts":[[2023,2,15]],"date-time":"2023-02-15T05:37:46Z","timestamp":1676439466000},"page":"3926","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Mechanisms for the \u03b1-Adrenoceptor-Mediated Positive Inotropy in Mouse Ventricular Myocardium: Enhancing Effect of Action Potential Prolongation"],"prefix":"10.3390","volume":"24","author":[{"given":"Shogo","family":"Hamaguchi","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Faculty of Pharmacological Science, Toho University, Chiba 274-8510, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ikue","family":"Morinou","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Pharmacological Science, Toho University, Chiba 274-8510, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuko","family":"Shiseki","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Pharmacological Science, Toho University, Chiba 274-8510, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ayako","family":"Mikami","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Pharmacological Science, Toho University, Chiba 274-8510, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maika","family":"Seki","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Pharmacological Science, Toho University, Chiba 274-8510, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Iyuki","family":"Namekata","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Pharmacological Science, Toho University, Chiba 274-8510, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hikaru","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Pharmacological Science, Toho University, Chiba 274-8510, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1093\/cvr\/cvm078","article-title":"Cardiac \u03b11-adrenergic drive in pathological remodeling","volume":"77","author":"Woodcock","year":"2008","journal-title":"Cardiovas. Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1254\/jphs.CPJ06009X","article-title":"Signal transduction and Ca2+ signaling in intact myocardium","volume":"100","author":"Endoh","year":"2006","journal-title":"J. Pharmacol. Sci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1161\/CIRCRESAHA.116.309502","article-title":"Cardiac \u03b11-adrenoceptors and inotropy. Myofilament Ca2+ sensitivity, intracellular Ca2+ mobilization, signaling pathway, and pathophysiological relevance","volume":"119","author":"Endoh","year":"2016","journal-title":"Circ. Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"H725","DOI":"10.1152\/ajpheart.00621.2020","article-title":"Cardiac \u03b11A-adrenergic receptors: Emerging protective roles in cardiovascular diseases","volume":"320","author":"Zhang","year":"2021","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1179","DOI":"10.1161\/01.RES.68.5.1179","article-title":"Myocardial \u03b11-adrenoceptors mediate positive inotropic effect and changes in phosphatidyl inositol metabolism. Species differences in receptor distribution and the intracellular coupling process in mammalian ventricular myocardium","volume":"68","author":"Endoh","year":"1991","journal-title":"Circ. Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1111\/j.1476-5381.1995.tb17191.x","article-title":"Sustained negative inotropism mediated by \u03b1-adrenoceptors in adult mouse myocardia: Developmental conversion from positive response in the neonate","volume":"114","author":"Tanaka","year":"1995","journal-title":"Br. J. Pharmacol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1285","DOI":"10.1139\/y95-181","article-title":"Effect of sympathectomy on inotropic responsiveness to \u03b1-adrenoceptor stimulation in developing mouse myocardia","volume":"73","author":"Tanaka","year":"1995","journal-title":"Can. J. Physiol. Pharmacol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"H946","DOI":"10.1152\/ajpheart.00822.2012","article-title":"Intraventricular and interventricular cellular heterogeneity inotropic responses to \u03b11-adrenergic stimulation","volume":"304","author":"Chu","year":"2013","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1097\/FJC.0000000000000604","article-title":"Human myocardium has a robust \u03b11A-subtype adrenergic receptor inotropic response","volume":"72","author":"Janssen","year":"2018","journal-title":"J. Cardiovas. Pharmacol."},{"key":"ref_10","first-page":"935","article-title":"The L-type calcium channel current is increased by alpha-1 adrenoceptor activation in neonatal rat ventricular cells","volume":"271","author":"Liu","year":"1994","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_11","first-page":"H2203","article-title":"\u03b11-Adrenergic activation of L-type Ca current in rat ventricular myocytes: Perforated patch-clamp recordings","volume":"274","author":"Liu","year":"1998","journal-title":"Am. J. Physiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1955","DOI":"10.1006\/jmcc.1998.0758","article-title":"Effects of alpha1-adrenergic Stimulation on L-type Ca2+ Current in Rat Ventricular Myocytes","volume":"30","author":"Zhang","year":"1998","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1113\/jphysiol.1990.sp018021","article-title":"\u03b1-Adrenergic modulation of the transient outward current in rabbit atrial myocytes","volume":"423","author":"Fedida","year":"1990","journal-title":"J. Physiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1007\/BF02583508","article-title":"Inhibitory effect mediated by \u03b11-adrenoceptors on transient outward current in isolated rat ventricular cells","volume":"415","author":"Tohse","year":"1990","journal-title":"Pflugers Arch."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"H132","DOI":"10.1152\/ajpheart.2001.280.1.H132","article-title":"\u03b1-Adrenoceptor stimulation-mediated negative inotropism and enhanced Na+-Ca2+ exchange in mouse ventricle","volume":"280","author":"Nishimaru","year":"2001","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1007\/s00210-005-1051-9","article-title":"Unique excitation-contraction characteristics of mouse myocardium as revealed by SEA0400, a specific inhibitor of Na+-Ca2+ exchanger","volume":"371","author":"Tanaka","year":"2005","journal-title":"Naunyn Schmiedebergs Arch. Pharmacol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1111\/j.1439-0442.2005.00772.x","article-title":"\u03b11-adrenoceptor-mediated negative inotropic effect caused by intracellular ionic activities in guinea-pig papillary muscle","volume":"52","author":"Kim","year":"2005","journal-title":"J. Vet. Med. A Physiol. Pathol. Clin. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"297","DOI":"10.2170\/physiolsci.RP007306","article-title":"Intracellular mechanism of the negative inotropic effect induced by \u03b11-adrenoceptor stimulation in mouse myocardium","volume":"56","author":"Hirano","year":"2006","journal-title":"J. Physiol. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1139\/y97-095","article-title":"Changes in electrophysiological and mechanical responses of the rat papillary muscle to \u03b1- and \u03b2-agonist in streptozotocin-induced diabetes","volume":"75","author":"Kamata","year":"1997","journal-title":"Can. J. Physiol. Pharmacol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1111\/j.1748-1716.2006.01616.x","article-title":"Enhancement of methoxamine-induced contractile responses of rat ventricular muscle in streptozotocin-induced diabetes is associated with \u03b11A adrenoceptor upregulation","volume":"188","author":"Kamata","year":"2006","journal-title":"Acta. Physiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.jphs.2017.10.005","article-title":"Pathological prolongation of action potential duration as a cause of the reduced alpha-adrenoceptor-mediated negative inotropy in streptozotocin-induced diabetic mice myocardium","volume":"135","author":"Kanae","year":"2017","journal-title":"J. Pharmacol. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1016\/S0014-2999(99)00373-8","article-title":"Developmental conversion of inotropism by endothelin I and angiotensin II from positive to negative in mice","volume":"374","author":"Sekine","year":"1999","journal-title":"Eur. J. Pharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1254\/jphs.13099FP","article-title":"Developmental changes in excitation-contraction mechanisms of the mouse ventricular myocardium as revealed by functional and confocal imaging analyses","volume":"123","author":"Hamaguchi","year":"2013","journal-title":"J. Pharmacol. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1007\/s004240050787","article-title":"Role of PKC in the effects of alpha1-adrenergic stimulation on Ca2+ transients, contraction and Ca2+ current in guinea-pig ventricular myocytes","volume":"437","author":"Woo","year":"1999","journal-title":"Pflugers. Arch."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1096","DOI":"10.1038\/sj.bjp.0704574","article-title":"Effect of SEA0400, a novel inhibitor of sodium-calcium exchanger, on myocardial ionic currents","volume":"135","author":"Tanaka","year":"2002","journal-title":"Br. J. Pharmacol."},{"key":"ref_26","first-page":"562","article-title":"Comparison of L-type calcium channel blockade by nifedipine and\/or cadmium in guinea pig ventricular myocytes","volume":"294","author":"Shen","year":"2000","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1016\/0006-291X(90)91544-3","article-title":"Chelerythrine is a potent and specific inhibitor of protein kinase C","volume":"172","author":"Herbert","year":"1990","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1006\/jmcc.2002.1530","article-title":"Cardiac Na\/Ca exchange function in rabbit, mouse and man: What\u2019s the difference?","volume":"34","author":"Bers","year":"2002","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1095","DOI":"10.1161\/01.RES.87.12.1095","article-title":"Regulation of cardiac L-type calcium channels by protein kinase A and protein kinase C","volume":"87","author":"Kamp","year":"2000","journal-title":"Circ. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1254\/jphs.92.196","article-title":"Pharmacological evidence for involvement of phospholipase D, protein kinase C, and sodium-calcium exchanger in \u03b1-adrenoceptor-mediated negative inotropy in adult mouse ventricle","volume":"92","author":"Nishimaru","year":"2003","journal-title":"J. Pharmacol. Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1161\/01.RES.71.3.673","article-title":"Mechanisms for the positive inotropic effect of \u03b11-adrenoceptor stimulation in rat cardiac myocytes","volume":"71","author":"Fedida","year":"1992","journal-title":"Circ. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1254\/jjp.80.243","article-title":"Effects of K+ channel modulators on the relationship between action potential duration and Ca2+ transients in single ventricular myocytes of the guinea pig","volume":"80","author":"Tokuno","year":"1999","journal-title":"Jpn. J. Pharmacol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"H913","DOI":"10.1152\/ajpheart.00259.2009","article-title":"Heart failure switches the RV \u03b11-adrenergic inotropic response from negative to positive","volume":"298","author":"Wang","year":"2010","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"H888","DOI":"10.1152\/ajpheart.00042.2015","article-title":"The \u03b11A-adrenergic subtype mediates increased contraction of failing right ventricular myocardium","volume":"309","author":"Cowley","year":"2015","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Odagiri, F., Inoue, H., Sugihara, M., Suzuki, T., Murayama, T., Shioya, T., Konishi, M., Nakazato, Y., Daida, H., and Sakurai, T. (2014). Effects of candesartan on electrical remodeling in the hearts of inherited dilated cardiomyopathy model mice. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0101838"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1161\/01.CIR.101.2.142","article-title":"Contrasting inotropic effects of endogenous endothelin in the normal and failing human heart: Studies with an intracoronary ET(A) receptor antagonist","volume":"101","author":"MacCarthy","year":"2000","journal-title":"Circulation"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1161\/01.RES.73.2.379","article-title":"Alterations of K+ currents in isolated human ventricular myocytes from patients with terminal heart failure","volume":"73","author":"Beuckelmann","year":"1993","journal-title":"Circ. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1161\/01.RES.78.2.262","article-title":"Ionic mechanism of action potential prolongation in ventricular myocytes from dogs with pacing-induced heart failure","volume":"78","author":"Nuss","year":"1996","journal-title":"Circ. Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1631\/jzus.B1300177","article-title":"Cellular mechanism of cardiac alternans: An unresolved chicken or egg problem","volume":"15","author":"Zang","year":"2014","journal-title":"J. Zhejiang Univ. Sci. B."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1248\/bpb.b20-00732","article-title":"Contribution of ATP-mediated positive feedback to sympathetic nerve-induced positive inotropy in guinea pig ventricular myocardium","volume":"44","author":"Hamaguchi","year":"2021","journal-title":"Biol. Pharm. Bull."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1894","DOI":"10.1248\/bpb.b21-00580","article-title":"Positive lusitropic effect of quercetin on isolated ventricular myocardia from normal and streptozotocin-induced diabetic mice","volume":"44","author":"Hamaguchi","year":"2021","journal-title":"Biol. Pharm. Bull."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1644","DOI":"10.1248\/bpb.b22-00362","article-title":"Inhibitory effect of a late sodium current blocker, NCC-3902, on the automaticity of the guinea pig pulmonary vein myocardium","volume":"45","author":"Namekata","year":"2022","journal-title":"Biol. Pharm. Bull."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1248\/bpb.b22-00644","article-title":"Negative inotropic effects of class I antiarrhythmics on guinea pig ventricular myocardium: Correlation with L-type Ca2+ channel blockade","volume":"46","author":"Hiiro","year":"2023","journal-title":"Biol. Pharm. Bull."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/4\/3926\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:36:34Z","timestamp":1760121394000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/4\/3926"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,15]]},"references-count":43,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2023,2]]}},"alternative-id":["ijms24043926"],"URL":"https:\/\/doi.org\/10.3390\/ijms24043926","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2023,2,15]]}}}