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In particular, selective venodilation appears to explain its clinical benefit during pulmonary hypertension complicated by heart failure with preserved ejection fraction. Vasodilators increase vessel diameter in various parts of the vascular system to different degrees and thereby influence blood pressure, its distribution, and organ perfusion depending on their mechanisms of action. Levosimendan and its long-lived active metabolite OR-1896 mobilize a set of vasodilatory mechanisms, that is, the opening of the ATP-sensitive K+ channels and other K+ channels on top of a highly selective inhibition of the phosphodiesterase III enzyme. A vessel-specific combination of the above vasodilator mechanisms\u2014in concert with cardiac effects and cardiovascular reflex regulations\u2014illustrates the pharmacological profile of levosimendan in various cardiovascular disorders. While levosimendan has been known to be an inotrope, its properties as an activator of ATP-sensitive K+ channels have gone largely ignored with respect to clinical applications. Here, we provide a summary of what is known about the ATP-sensitive K+ channel properties in preclinical studies and now for the first time, its ATP-sensitive K+ channel properties in a clinical trial.<\/jats:p>","DOI":"10.1002\/ehf2.13669","type":"journal-article","created":{"date-parts":[[2021,10,30]],"date-time":"2021-10-30T05:38:40Z","timestamp":1635572320000},"page":"4454-4464","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Levosimendan-Induced Venodilation is Mediated by Opening of Potassium Channels"],"prefix":"10.1093","volume":"8","author":[{"given":"Daniel","family":"Burkhoff","sequence":"first","affiliation":[{"name":"Cardiovascular Research Foundation , New York, NY ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stuart","family":"Rich","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine , Chicago, IL ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piero","family":"Pollesello","sequence":"additional","affiliation":[{"name":"Critical Care, Orion Pharma , Espoo ,","place":["Finland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zolt\u00e1n","family":"Papp","sequence":"additional","affiliation":[{"name":"Division of Clinical Physiology, Department of Cardiology, Faculty of Medicine, University of Debrecen , 22 M\u00f3ricz Zsigmond Str., Debrecen, H-4032 ,","place":["Hungary"]},{"name":"HAS-UD Vascular Biology and Myocardial Pathophysiology Research Group, Hungarian Academy of Sciences , Budapest ,","place":["Hungary"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,10,30]]},"reference":[{"key":"2026012114191708100_ehf213669-bib-0001","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1097\/FJC.0000000000000859","article-title":"Levosimendan efficacy and safety: 20 years of SIMDAX in clinical use","volume":"76","author":"Papp","year":"2020","journal-title":"J Cardiovasc Pharmacol"},{"key":"2026012114191708100_ehf213669-bib-0002","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.ijcard.2011.07.022","article-title":"Levosimendan: molecular mechanisms and clinical implications: consensus of experts on the mechanisms of action of levosimendan","volume":"159","author":"Papp","year":"2012","journal-title":"Int J Cardiol"},{"key":"2026012114191708100_ehf213669-bib-0003","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1254\/jphs.CP0060010","article-title":"Vasodilating mechanisms of levosimendan: involvement of K channels","volume":"104","author":"Yildiz","year":"2007","journal-title":"J Pharmacol Sci"},{"key":"2026012114191708100_ehf213669-bib-0004","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1007\/978-1-4615-3362-7_5","article-title":"Potassium channel activation in vascular smooth muscle","volume":"311","author":"Siegel","year":"1992","journal-title":"Adv Exp Med Biol"},{"key":"2026012114191708100_ehf213669-bib-0005","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1016\/S0140-6736(02)09455-2","article-title":"Efficacy and safety of intravenous levosimendan compared with dobutamine in severe low-output heart failure (the LIDO study): a randomised double-blind trial","volume":"360","author":"Follath","year":"2002","journal-title":"Lancet"},{"key":"2026012114191708100_ehf213669-bib-0006","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0066195","article-title":"Levosimendan relaxes pulmonary arteries and veins in precision-cut lung slices - the role of KATP-channels, cAMP and cGMP","volume":"8","author":"Rieg","year":"2013","journal-title":"PLoS One."},{"key":"2026012114191708100_ehf213669-bib-0007","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0233176","article-title":"Levosimendan reduces segmental pulmonary vascular resistance in isolated perfused rat lungs and relaxes human pulmonary vessels","volume":"15","author":"Rieg","year":"2020","journal-title":"PLoS One."},{"key":"2026012114191708100_ehf213669-bib-0008","first-page":"360","article-title":"Levosimendan improves hemodynamics and exercise tolerance in PH-HFpEF: results of the randomized placebo-controlled HELP trial. 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