Miklosz Joanna, Kalaska Bartlomiej, Podlasz Piotr, Chmielewska-Krzesińska Małgorzata, Zajączkowski Miłosz, Kosiński Adam, Pawlak Dariusz, Mogielnicki Andrzej
Department of Pharmacodynamics, Medical University of Bialystok, 15-089 Białystok, Poland.
Department of Pathophysiology, Forensic Veterinary Medicine and Administration, Faculty of Veterinary Medicine, University of Warmia and Mazury in Olsztyn, 10-714 Olsztyn, Poland.
Pharmaceutics. 2021 Mar 9;13(3):359. doi: 10.3390/pharmaceutics13030359.
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, 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.
硫酸鱼精蛋白（PS）是目前唯一可用于逆转普通肝素（UFH）抗凝活性的药物，然而它可能会引发心血管和呼吸系统并发症。我们研究了PS及其与UFH复合物在斑马鱼、大鼠和小鼠中的毒性。研究了一氧化氮（NO）在上述效应中的作用。在斑马鱼幼体中观察到了浓度依赖性致死率、形态缺陷以及心率（HR）降低。PS影响大鼠的心率、血压、呼吸频率、呼出二氧化碳峰值和血氧饱和度。随着PS剂量增加，我们观察到大鼠出现低血压、心率加快、爪部血管灌注以及呼吸紊乱加剧。我们发现PS对小鼠的人hERG通道无影响，也未发现心脏损伤迹象。内皮型一氧化氮合酶抑制剂可部分减轻大鼠的低血压和斑马鱼的心动过缓。当PS与UFH联合给药时，心血管和呼吸参数的紊乱会减轻或延迟出现。PS的心肺毒性似乎与电荷有关，且涉及NO释放增加。尽管有必要仔细监测心肺参数，但以适当剂量和比例与UFH联合使用PS不应导致心脏组织的永久性损伤。
