Abstract
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 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–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.
Highlights
Protamine sulfate (PS) is an alkaline–strong, arginine–rich, positively–charged protein isolated from salmon sperm
PS added at concentrations of 1 and 5 μg/mL did not cause significant embryo death throughout the assay
We did not investigate the heart rate (HR) values of embryos incubated with PS at concentrations of 25, 50, or 100 μg/mL because the lethality was too high
Summary
Protamine sulfate (PS) is an alkaline–strong, arginine–rich, positively–charged protein isolated from salmon sperm. The toxicity often manifests in diabetics, those allergic to fish, and vasectomized men, which may be associated with the immunogenicity of PS [6,7,8,9]. In these patients, the UFH neutralization may lead to rapid and life–threatening anaphylactic reactions [5,7]. The above reactions are probably associated with respiratory toxicity, as manifested by pulmonary vasoconstriction leading to pulmonary hypertension and edema. This mechanism can be multifactorial and includes an increase
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