Vascular Surgery Research Laboratories, Division of Vascular and Endovascular Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Corporate R&D Department, and Medical Affairs Department, Alfasigma S.p.A, Bologna 40133, Italy.
Biochem Pharmacol. 2019 Aug;166:347-356. doi: 10.1016/j.bcp.2019.04.021. Epub 2019 Apr 20.
Sulodexide (SDX) is a highly purified glycosaminoglycan with antithrombotic and profibrinolytic properties and reported benefits in thrombotic and atherosclerotic vascular disorders. However, the effects of SDX on vascular function are unclear. We tested whether SDX affects vascular relaxation and examined the potential underlying mechanisms. Isolated segments of male rat abdominal aorta and mesenteric artery were suspended in a tissue bath, and the changes in arterial contraction/relaxation were measured. The α-adrenergic receptor agonist phenylephrine (Phe) (10-10 M) caused concentration-dependent aortic and mesenteric artery contraction that was reduced in tissues pretreated with SDX (1 mg/ml). In aortic and mesenteric arterial segments precontracted with submaximal concentration of Phe (3 × 10-6 × 10 M), SDX (0.001-1 mg/ml) caused concentration-dependent relaxation. To test the role of endothelium, SDX-induced relaxation was compared with that of acetylcholine (ACh), a known activator of endothelium-dependent relaxation. In Phe precontracted aorta, ACh relaxation was abolished and SDX relaxation was significantly inhibited by endothelium removal or the nitric oxide synthase (NOS) inhibitor N-nitro-l-arginine methyl ester (L-NAME), suggesting a role of NO. In mesenteric artery, ACh relaxation was abolished by endothelium removal, partially blocked by L-NAME, and completely blocked by a mixture of indomethacin, a cyclooxygenase inhibitor and blocker of the PGI-cAMP pathway, and tetraethylammonium, a blocker of K channels and EDHF-dependent hyperpolarization pathway. In comparison, SDX relaxation of mesenteric artery was almost completely inhibited by endothelium removal or NOS inhibitor L-NAME. SDX enhanced vascular relaxation and increased nitrate/nitrite production in response to all ACh concentrations in the aorta, but only to low ACh concentrations (<10 M) in mesenteric artery. SDX did not affect aortic or mesenteric artery endothelium-independent relaxation to the NO donor sodium nitroprusside. Thus, SDX promotes arterial relaxation via a mechanism involving endothelium-dependent NO production; an effect that could enhance vasodilation and decrease vasoconstriction in vascular disorders.
舒洛地特（SDX）是一种高度纯化的糖胺聚糖，具有抗血栓和纤维蛋白溶解特性，并已报道可改善血栓形成和动脉粥样硬化性血管疾病。然而，SDX 对血管功能的影响尚不清楚。我们测试了 SDX 是否会影响血管舒张，并研究了潜在的机制。雄性大鼠腹主动脉和肠系膜动脉的分离节段悬浮在组织浴中，测量动脉收缩/舒张的变化。α-肾上腺素能受体激动剂苯肾上腺素（Phe）（10-10 M）引起浓度依赖性的主动脉和肠系膜动脉收缩，而用 SDX（1mg/ml）预处理的组织中这种收缩减少。在预先用 Phe（3×10-6×10 M）的亚最大浓度收缩的主动脉和肠系膜动脉节段中，SDX（0.001-1mg/ml）引起浓度依赖性舒张。为了测试内皮的作用，将 SDX 诱导的舒张与乙酰胆碱（ACh）进行比较，后者是已知的内皮依赖性舒张激活剂。在 Phe 预收缩的主动脉中，ACh 舒张被消除，而 SDX 舒张被内皮去除或一氧化氮合酶（NOS）抑制剂 N-硝基-L-精氨酸甲酯（L-NAME）显著抑制，表明 NO 的作用。在肠系膜动脉中，ACh 舒张被内皮去除消除，部分被 L-NAME 阻断，完全被吲哚美辛（一种环氧化酶抑制剂和前列环素 cAMP 途径的阻断剂）和四乙铵（一种 K 通道和 EDHF 依赖性超极化途径的阻断剂）的混合物阻断。相比之下，SDX 对肠系膜动脉的舒张几乎完全被内皮去除或 NOS 抑制剂 L-NAME 抑制。SDX 增强了对主动脉中所有 ACh 浓度的血管舒张，并增加了硝酸盐/亚硝酸盐的产生，但仅对肠系膜动脉中的低 ACh 浓度（<10 M）有反应。SDX 不影响主动脉或肠系膜动脉对一氧化氮供体硝普钠的内皮非依赖性舒张。因此，SDX 通过一种涉及内皮依赖性 NO 产生的机制促进动脉舒张；这种作用可以在血管疾病中增强血管舒张并减少血管收缩。
