Buzun Leszek, Kleszczewski Tomasz, Kostrzewska Anna, Lisowski Piotr, Oleksza Piotr, Jackowski Ryszard, Pedzińska Anna, Hirnle Tomasz
Department of Cardiac Surgery, Medical University Hospital, Bialystok, Poland.
Eur J Cardiothorac Surg. 2004 Nov;26(5):951-5. doi: 10.1016/j.ejcts.2004.07.018.
Low molecular weight heparins (LMWHs) offer practical and potential pharmacological advantages over unfractionated heparin in multiple applications but have not been studied as vasoactive agents. The purpose of this study was to investigate the effects of two commercial preparations of LMWHs, enoxaparin sodium and nadroparin calcium, on vasoconstriction in the human internal thoracic artery (ITA) in vitro.
Samples of redundant ITA segments obtained from 36 patients who underwent coronary artery bypass surgery were cut into 3mm wide rings and suspended in 20 ml organ bath. Activity of ITA rings precontracted with 80 mM KCl, 0.1 microM endothelin-1 (ET-1) and 1 microM norepinephrine (NE) after administration of enoxaparin and nadroparin in accumulative concentration ranging from 0.1 to 13.2 UI AXa/ml were recorded under isometric conditions by means of force transducers with digital output. The contraction after 80 mmol KCl, 0.1 microM ET-1 and 1 microM NE administration was treated as a control.
Both studied LMWHs in concentration ranging from 0.12 to 13.2 UI AXa/ml did not change basal tonus and KCl precontracted ITA rings. When used in concentrations higher than 13.2 UI AXa/ml nadroparin but not enoxaparin significantly increased the tension in KCl precontracted arterial rings. In NE and ET-1 precontracted rings enoxaparin and nadroparin caused dose dependent relaxation without significant differences between both preparations. Incubation with nitric oxide blocker-Nomega-NITRO-L-ARGININE (L-NNA) in concentration 0.2 mM caused a significant attenuation of relaxant responses to both studied LMWHs in NE and ET-1 precontracted rings.
LMWHs can have vasorelaxant effects on the receptor-mediated ITA vasoconstriction. The results suggest that LMWHs-induced relaxation in the human ITA is at least partially caused by nitric oxide release. Although the vasoactive effects are not the primary advantage of these drugs used as antithrombotics, such effects might have some clinical importance in the treatment and prophylaxis of graft spasm.
在多种应用中，低分子量肝素（LMWHs）相对于普通肝素具有实际和潜在的药理学优势，但尚未作为血管活性药物进行研究。本研究的目的是在体外研究两种市售低分子量肝素制剂，即依诺肝素钠和那屈肝素钙，对人胸廓内动脉（ITA）血管收缩的影响。
从36例行冠状动脉搭桥手术的患者获取的多余ITA节段样本切成3毫米宽的环，悬挂于20毫升器官浴槽中。在等长条件下，通过数字输出的力传感器记录在累积浓度范围为0.1至13.2 UI抗Xa/ml的依诺肝素和那屈肝素给药后，用80 mM氯化钾、0.1 microM内皮素-1（ET-1）和1 microM去甲肾上腺素（NE）预收缩的ITA环的活性。将给予80 mmol氯化钾、0.1 microM ET-1和1 microM NE后的收缩作为对照。
浓度范围为0.12至13.2 UI抗Xa/ml的两种研究用低分子量肝素均未改变基础张力以及氯化钾预收缩的ITA环。当以高于13.2 UI抗Xa/ml的浓度使用时，那屈肝素而非依诺肝素显著增加了氯化钾预收缩动脉环的张力。在NE和ET-1预收缩的环中，依诺肝素和那屈肝素引起剂量依赖性舒张，两种制剂之间无显著差异。用浓度为0.2 mM的一氧化氮阻断剂-Nω-硝基-L-精氨酸（L-NNA）孵育导致NE和ET-1预收缩环中对两种研究用低分子量肝素的舒张反应显著减弱。
低分子量肝素可对受体介导的ITA血管收缩产生血管舒张作用。结果表明，低分子量肝素在人ITA中诱导的舒张至少部分由一氧化氮释放引起。尽管血管活性作用并非这些用作抗血栓药物的主要优势，但此类作用在移植物痉挛的治疗和预防中可能具有一定的临床重要性。
