PMID- 33803176
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20210413
IS  - 1999-4923 (Print)
IS  - 1999-4923 (Electronic)
IS  - 1999-4923 (Linking)
VI  - 13
IP  - 3
DP  - 2021 Mar 9
TI  - Cardiovascular and Respiratory Toxicity of Protamine Sulfate in Zebrafish and 
      Rodent Models.
LID - 10.3390/pharmaceutics13030359 [doi]
LID - 359
AB  - 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-dependent lethality, morphological 
      defects, and decrease in heart rate (HR) were observed in zebrafish larvae. PS 
      affected HR, blood pressure, respiratory rate, peak exhaled CO(2), 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-dependent 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.
FAU - Miklosz, Joanna
AU  - Miklosz J
AUID- ORCID: 0000-0003-0958-0454
AD  - Department of Pharmacodynamics, Medical University of Bialystok, 15-089 
      Bialystok, Poland.
FAU - Kalaska, Bartlomiej
AU  - Kalaska B
AUID- ORCID: 0000-0002-4968-4429
AD  - Department of Pharmacodynamics, Medical University of Bialystok, 15-089 
      Bialystok, Poland.
FAU - Podlasz, Piotr
AU  - Podlasz P
AUID- ORCID: 0000-0002-9162-5449
AD  - Department of Pathophysiology, Forensic Veterinary Medicine and Administration, 
      Faculty of Veterinary Medicine, University of Warmia and Mazury in Olsztyn, 
      10-714 Olsztyn, Poland.
FAU - Chmielewska-Krzesinska, Malgorzata
AU  - Chmielewska-Krzesinska M
AD  - Department of Pathophysiology, Forensic Veterinary Medicine and Administration, 
      Faculty of Veterinary Medicine, University of Warmia and Mazury in Olsztyn, 
      10-714 Olsztyn, Poland.
FAU - Zajaczkowski, Milosz
AU  - Zajaczkowski M
AUID- ORCID: 0000-0002-5981-336X
AD  - Department of Clinical Anatomy, Medical University of Gdansk, 80-210 Gdansk, 
      Poland.
FAU - Kosinski, Adam
AU  - Kosinski A
AD  - Department of Clinical Anatomy, Medical University of Gdansk, 80-210 Gdansk, 
      Poland.
FAU - Pawlak, Dariusz
AU  - Pawlak D
AUID- ORCID: 0000-0002-3751-0608
AD  - Department of Pharmacodynamics, Medical University of Bialystok, 15-089 
      Bialystok, Poland.
FAU - Mogielnicki, Andrzej
AU  - Mogielnicki A
AUID- ORCID: 0000-0003-2406-5290
AD  - Department of Pharmacodynamics, Medical University of Bialystok, 15-089 
      Bialystok, Poland.
LA  - eng
GR  - 2016/23/N/NZ7/00442/Narodowe Centrum Nauki/
GR  - SUB/2/DN/19/002/2211/Uniwersytet Medyczny w Bialymstoku/
PT  - Journal Article
DEP - 20210309
PL  - Switzerland
TA  - Pharmaceutics
JT  - Pharmaceutics
JID - 101534003
PMC - PMC8001545
OTO - NOTNLM
OT  - cardiac toxicity
OT  - hERG
OT  - heparin
OT  - ion channels
OT  - protamine
OT  - respiratory toxicity
OT  - rodents
OT  - toxicity
OT  - zebrafish
COIS- The authors declare no conflict of interest. The funders had no role in the 
      design of the study; in the collection, analyses, or interpretation of data; in 
      the writing of the manuscript; or in the decision to publish the results.
EDAT- 2021/04/04 06:00
MHDA- 2021/04/04 06:01
PMCR- 2021/03/09
CRDT- 2021/04/03 01:13
PHST- 2021/02/12 00:00 [received]
PHST- 2021/03/03 00:00 [revised]
PHST- 2021/03/05 00:00 [accepted]
PHST- 2021/04/03 01:13 [entrez]
PHST- 2021/04/04 06:00 [pubmed]
PHST- 2021/04/04 06:01 [medline]
PHST- 2021/03/09 00:00 [pmc-release]
AID - pharmaceutics13030359 [pii]
AID - pharmaceutics-13-00359 [pii]
AID - 10.3390/pharmaceutics13030359 [doi]
PST - epublish
SO  - Pharmaceutics. 2021 Mar 9;13(3):359. doi: 10.3390/pharmaceutics13030359.