{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,29]],"date-time":"2025-12-29T11:31:35Z","timestamp":1767007895202},"reference-count":50,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2015,3,17]],"date-time":"2015-03-17T00:00:00Z","timestamp":1426550400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan","award":["25670130"],"award-info":[{"award-number":["25670130"]}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2015,5]]},"abstract":"Background and Purpose<\/jats:title>The Ca2+<\/jats:sup><\/jats:roman><\/jats:styled-content> sensitizer pimobendan is a unique inotropic agent that improves cardiac contractility with less of an increase in oxygen consumption and potentially fewer adverse effects on myocardial remodelling and arrhythmia, compared with traditional inotropes. However, clinical trials report contradictory effects of pimobendan in patients with heart failure (HF<\/jats:styled-content>). We provide mechanistic experimental evidence of the efficacy of pimobendan using a novel mouse model of progressive HF<\/jats:styled-content>.<\/jats:p><\/jats:sec>Experimental Approach<\/jats:title>A knock\u2010in mouse model of human genetic dilated cardiomyopathy, which shows a clear transition from compensatory to end\u2010stage HF<\/jats:styled-content> at a fixed time during growth, was used to evaluate the efficacy of pimobendan and explore the underlying molecular and cellular mechanisms.<\/jats:p><\/jats:sec>Key Results<\/jats:title>Pimobendan prevented myocardial remodelling in compensated HF<\/jats:styled-content> and significantly extended life span in both compensated and end\u2010stage HF<\/jats:styled-content>, but dose\u2010dependently increased sudden death in end\u2010stage HF<\/jats:styled-content>. In cardiomyocytes isolated from end\u2010stage HF<\/jats:styled-content> mice, pimobendan induced triggered activity probably because of early or delayed afterdepolarizations. The L<\/jats:styled-content>\u2010type Ca2+<\/jats:sup><\/jats:roman><\/jats:styled-content> channel blocker verapamil decreased the incidence of triggered activity, suggesting that this was from over\u2010elevated cytoplasmic Ca2+<\/jats:sup><\/jats:roman><\/jats:styled-content> through increased Ca2+<\/jats:sup><\/jats:roman><\/jats:styled-content> entry by PDE<\/jats:styled-content>3 inhibition under diminished sarcoplasmic reticulum Ca2+<\/jats:sup><\/jats:roman><\/jats:styled-content> reuptake and increased Ca2+<\/jats:sup><\/jats:roman><\/jats:styled-content> leakage from sarcoplasmic reticulum in end\u2010stage HF<\/jats:styled-content>.<\/jats:p><\/jats:sec>Conclusions and Implications<\/jats:title>Pimobendan was beneficial regardless of HF<\/jats:styled-content> stage, but increased sudden cardiac death in end\u2010stage HF<\/jats:styled-content> with extensive remodelling of Ca2+<\/jats:sup><\/jats:roman><\/jats:styled-content> handling. Reduction of cytoplasmic Ca2+<\/jats:sup><\/jats:roman><\/jats:styled-content> elevated by PDE<\/jats:styled-content>3 inhibition might decrease this risk of sudden cardiac death.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.13062","type":"journal-article","created":{"date-parts":[[2015,1,5]],"date-time":"2015-01-05T09:15:02Z","timestamp":1420449302000},"page":"2369-2382","update-policy":"http:\/\/dx.doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Stage\u2010dependent benefits and risks of pimobendan in mice with genetic dilated cardiomyopathy and progressive heart failure"],"prefix":"10.1111","volume":"172","author":[{"given":"Miki","family":"Nonaka","sequence":"first","affiliation":[{"name":"Department of Clinical Pharmacology Graduate School of Medical Sciences Kyushu University Fukuoka 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