Cardiovascular and Respiratory Toxicity of Protamine Sulfate in Zebrafish and Rodent Models

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.

Reversal Activity and Toxicity of Heparin-Binding Copolymer after Subcutaneous Administration of Enoxaparin in Mice

“…We and others previously reported that polycations may induce lung congestion [ 49 ] and mononuclear cell infiltration [ 50 ]. PS impaired heart tissue, and it was previously reported to alter the cardiac function of zebrafish and the heart rate of rats [ 51 ] by directly affecting myocyte contractile functions [ 52 , 53 ]. We have also found some histological changes in the brain, the spleen, and other organs that occurred in all animals, including in the vehicle group, indicating that they were related to the experimental procedures.…”

Monitoring of Anticoagulant Activity of Dabigatran and Rivaroxaban in the Presence of Heparins

“…However, there are still issues limiting their usefulness. Protamine may interact with clotting [16][17][18], which makes it unsuitable for in vitro neutralization tests. A heparinase requires a lengthy preparation of a plasma sample [7,12].…”