{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T18:22:21Z","timestamp":1778178141108,"version":"3.51.4"},"reference-count":58,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2021,3,9]],"date-time":"2021-03-09T00:00:00Z","timestamp":1615248000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004281","name":"Narodowe Centrum Nauki","doi-asserted-by":"publisher","award":["2016\/23\/N\/NZ7\/00442"],"award-info":[{"award-number":["2016\/23\/N\/NZ7\/00442"]}],"id":[{"id":"10.13039\/501100004281","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005297","name":"Uniwersytet Medyczny w Bialymstoku","doi-asserted-by":"publisher","award":["SUB\/2\/DN\/19\/002\/2211"],"award-info":[{"award-number":["SUB\/2\/DN\/19\/002\/2211"]}],"id":[{"id":"10.13039\/501100005297","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Protamine sulfate (PS) is the only available option to reverse the anticoagulant activity of unfractionated heparin (UFH), however it can cause cardiovascular and respiratory complications. We explored the toxicity of PS and its complexes with UFH in zebrafish, rats, and mice. The involvement of nitric oxide (NO) in the above effects was investigated. Concentration\u2013dependent lethality, morphological defects, and decrease in heart rate (HR) were observed in zebrafish larvae. PS affected HR, blood pressure, respiratory rate, peak exhaled CO2, and blood oxygen saturation in rats. We observed hypotension, increase of HR, perfusion of paw vessels, and enhanced respiratory disturbances with increases doses of PS. We found no effects of PS on human hERG channels or signs of heart damage in mice. The hypotension in rats and bradycardia in zebrafish were partially attenuated by the inhibitor of endothelial NO synthase. The disturbances in cardiovascular and respiratory parameters were reduced or delayed when PS was administered together with UFH. The cardiorespiratory toxicity of PS seems to be charge\u2013dependent and involves enhanced release of NO. PS administered at appropriate doses and ratios with UFH should not cause permanent damage of heart tissue, although careful monitoring of cardiorespiratory parameters is necessary.<\/jats:p>","DOI":"10.3390\/pharmaceutics13030359","type":"journal-article","created":{"date-parts":[[2021,3,9]],"date-time":"2021-03-09T06:22:32Z","timestamp":1615270952000},"page":"359","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Cardiovascular and Respiratory Toxicity of Protamine Sulfate in Zebrafish and Rodent Models"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0958-0454","authenticated-orcid":false,"given":"Joanna","family":"Miklosz","sequence":"first","affiliation":[{"name":"Department of Pharmacodynamics, Medical University of Bialystok, 15-089 Bia\u0142ystok, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4968-4429","authenticated-orcid":false,"given":"Bartlomiej","family":"Kalaska","sequence":"additional","affiliation":[{"name":"Department of Pharmacodynamics, Medical University of Bialystok, 15-089 Bia\u0142ystok, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9162-5449","authenticated-orcid":false,"given":"Piotr","family":"Podlasz","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology, Forensic Veterinary Medicine and Administration, Faculty of Veterinary Medicine, University of Warmia and Mazury in Olsztyn, 10-714 Olsztyn, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ma\u0142gorzata","family":"Chmielewska-Krzesi\u0144ska","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology, Forensic Veterinary Medicine and Administration, Faculty of Veterinary Medicine, University of Warmia and Mazury in Olsztyn, 10-714 Olsztyn, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5981-336X","authenticated-orcid":false,"given":"Mi\u0142osz","family":"Zaj\u0105czkowski","sequence":"additional","affiliation":[{"name":"Department of Clinical Anatomy, Medical University of Gdansk, 80-210 Gda\u0144sk, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adam","family":"Kosi\u0144ski","sequence":"additional","affiliation":[{"name":"Department of Clinical Anatomy, Medical University of Gdansk, 80-210 Gda\u0144sk, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3751-0608","authenticated-orcid":false,"given":"Dariusz","family":"Pawlak","sequence":"additional","affiliation":[{"name":"Department of Pharmacodynamics, Medical University of Bialystok, 15-089 Bia\u0142ystok, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2406-5290","authenticated-orcid":false,"given":"Andrzej","family":"Mogielnicki","sequence":"additional","affiliation":[{"name":"Department of Pharmacodynamics, Medical University of Bialystok, 15-089 Bia\u0142ystok, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,3,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1007\/s11239-008-0280-4","article-title":"Anticoagulant therapy during cardiopulmonary bypass","volume":"26","author":"Yavari","year":"2008","journal-title":"J. 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