{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T18:28:47Z","timestamp":1780079327796,"version":"3.54.0"},"reference-count":29,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Arrhythmia and Electrophysiology"],"published-print":{"date-parts":[[2011,12]]},"abstract":"<jats:sec>\n            <jats:title>Background\u2014<\/jats:title>\n            <jats:p>\n              Digitalis-induced Na\n              <jats:sup>+<\/jats:sup>\n              accumulation results in an increase in Ca\n              <jats:sup>2+<\/jats:sup>\n              <jats:sub>i<\/jats:sub>\n              via the Na\n              <jats:sup>+<\/jats:sup>\n              \/Ca\n              <jats:sup>2+<\/jats:sup>\n              exchanger, leading to enhanced sarcoplasmic reticulum (SR) Ca\n              <jats:sup>2+<\/jats:sup>\n              load, responsible for the positive inotropic and toxic arrhythmogenic effects of glycosides. A digitalis-induced increase in Ca\n              <jats:sup>2+<\/jats:sup>\n              <jats:sub>i<\/jats:sub>\n              could also activate calcium-calmodulin kinase II (CaMKII), which has been shown to have proarrhythmic effects. Here, we investigate whether CaMKII underlies digitalis-induced arrhythmias and the subcellular mechanisms involved.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods and Results\u2014<\/jats:title>\n            <jats:p>\n              In paced rat ventricular myocytes (0.5 Hz), 50 \u03bcmol\/L ouabain increased contraction amplitude by 160\u00b15%. In the absence of electric stimulation, ouabain promoted spontaneous contractile activity and Ca\n              <jats:sup>2+<\/jats:sup>\n              waves. Ouabain activated CaMKII (p-CaMKII), which phosphorylated its downstream targets, phospholamban (PLN) (Thr17) and ryanodine receptor (RyR) (Ser2814). Ouabain-induced spontaneous activity was prevented by inhibiting CaMKII with 2.5 \u03bcmol\/L KN93 but not by 2.5 \u03bcmol\/L of the inactive analog, KN92. Similar results were obtained using the CaMKII inhibitor, autocamtide-2 related inhibitory peptide (AIP) (1 to 2.5 \u03bcmol\/L), and in myocytes from transgenic mice expressing SR-targeted AIP. Consistently, CaMKII overexpression exacerbated ouabain-induced spontaneous contractile activity. Ouabain was associated with an increase in SR Ca\n              <jats:sup>2+<\/jats:sup>\n              content and Ca\n              <jats:sup>2+<\/jats:sup>\n              spark frequency, indicative of enhanced SR Ca\n              <jats:sup>2+<\/jats:sup>\n              leak. KN93 suppressed the ouabain-induced increase in Ca\n              <jats:sup>2+<\/jats:sup>\n              spark frequency without affecting SR Ca\n              <jats:sup>2+<\/jats:sup>\n              content. Similar results were obtained with digoxin. In vivo, ouabain-induced arrhythmias were prevented by KN93 and absent in SR-AIP mice.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions\u2014<\/jats:title>\n            <jats:p>\n              These results show for the first time that CaMKII mediates ouabain-induced arrhythmic\/toxic effects. We suggest that CaMKII-dependent phosphorylation of the RyR, resulting in Ca\n              <jats:sup>2+<\/jats:sup>\n              leak from the SR, is the underlying mechanism involved.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circep.111.964908","type":"journal-article","created":{"date-parts":[[2011,10,19]],"date-time":"2011-10-19T02:45:26Z","timestamp":1318992326000},"page":"947-957","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":63,"title":["Calcium-Calmodulin Kinase II Mediates Digitalis-Induced Arrhythmias"],"prefix":"10.1161","volume":"4","author":[{"given":"Luis A.","family":"Gonano","sequence":"first","affiliation":[{"name":"From the Centro de Investigaciones Cardiovasculares (L.A.G., M.S., Y.R., C.A.V., A.M., M.V.P.), Conicet La Plata, Facultad de Ciencias M\u00e9dicas, Universidad Nacional de La Plata, La Plata, Argentina; Department of Cancer and Cell Biology (M.K., J.D.), Genome Research Institute, University of Cincinnati Medical Center, Cincinnati, OH."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marisa","family":"Sep\u00falveda","sequence":"additional","affiliation":[{"name":"From the Centro de Investigaciones Cardiovasculares (L.A.G., M.S., Y.R., C.A.V., A.M., M.V.P.), Conicet La Plata, Facultad de Ciencias M\u00e9dicas, Universidad Nacional de La Plata, La Plata, Argentina; Department of Cancer and Cell Biology (M.K., J.D.), Genome Research Institute, University of Cincinnati Medical Center, Cincinnati, OH."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanina","family":"Rico","sequence":"additional","affiliation":[{"name":"From the Centro de Investigaciones Cardiovasculares (L.A.G., M.S., Y.R., C.A.V., A.M., M.V.P.), Conicet La Plata, Facultad de Ciencias M\u00e9dicas, Universidad Nacional de La Plata, La Plata, Argentina; Department of Cancer and Cell Biology (M.K., J.D.), Genome Research Institute, University of Cincinnati Medical Center, Cincinnati, OH."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcia","family":"Kaetzel","sequence":"additional","affiliation":[{"name":"From the Centro de Investigaciones Cardiovasculares (L.A.G., M.S., Y.R., C.A.V., A.M., M.V.P.), Conicet La Plata, Facultad de Ciencias M\u00e9dicas, Universidad Nacional de La Plata, La Plata, Argentina; Department of Cancer and Cell Biology (M.K., J.D.), Genome Research Institute, University of Cincinnati Medical Center, Cincinnati, OH."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos A.","family":"Valverde","sequence":"additional","affiliation":[{"name":"From the Centro de Investigaciones Cardiovasculares (L.A.G., M.S., Y.R., C.A.V., A.M., M.V.P.), Conicet La Plata, Facultad de Ciencias M\u00e9dicas, Universidad Nacional de La Plata, La Plata, Argentina; Department of Cancer and Cell Biology (M.K., J.D.), Genome Research Institute, University of Cincinnati Medical Center, Cincinnati, OH."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Dedman","sequence":"additional","affiliation":[{"name":"From the Centro de Investigaciones Cardiovasculares (L.A.G., M.S., Y.R., C.A.V., A.M., M.V.P.), Conicet La Plata, Facultad de Ciencias M\u00e9dicas, Universidad Nacional de La Plata, La Plata, Argentina; Department of Cancer and Cell Biology (M.K., J.D.), Genome Research Institute, University of Cincinnati Medical Center, Cincinnati, OH."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alicia","family":"Mattiazzi","sequence":"additional","affiliation":[{"name":"From the Centro de Investigaciones Cardiovasculares (L.A.G., M.S., Y.R., C.A.V., A.M., M.V.P.), Conicet La Plata, Facultad de Ciencias M\u00e9dicas, Universidad Nacional de La Plata, La Plata, Argentina; Department of Cancer and Cell Biology (M.K., J.D.), Genome Research Institute, University of Cincinnati Medical Center, Cincinnati, OH."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Vila Petroff","sequence":"additional","affiliation":[{"name":"From the Centro de Investigaciones Cardiovasculares (L.A.G., M.S., Y.R., C.A.V., A.M., M.V.P.), Conicet La Plata, Facultad de Ciencias M\u00e9dicas, Universidad Nacional de La Plata, La Plata, Argentina; 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