Salbach P B, Brückmann M, Turovets O, Kreuzer J, Kübler W, Walter-Sack I
University of Heidelberg, Medical School Departments of Internal Medicine III, Bergheimerstrasse 58, D-69115 Heidelberg, Germany.
Br J Clin Pharmacol. 2000 Sep;50(3):221-6. doi: 10.1111/j.1365-2125.2000.00246.x.
The aim of this investigation was to compare the effects of standard (S) with low molecular weight (LMW) heparin on circulating levels of heparin-binding growth factors (HBGF), known to have angiogenic properties in humans.
In two consecutive trials 18 healthy male volunteers were studied on three separate occasions, following a placebo-controlled crossover design. Subjects were randomised to receive either S-heparin or LMW heparin or placebo. Heparins were administered either by intravenous (i.v.) or subcutaneous (s.c.) injection and saline placebo by i.v. injection. Serum concentrations of hepatocyte growth factor (HGF), vascular endothelial cell growth factor (VEGF) and basic fibroblast growth factor (bFGF) were measured before and up to 24 h after injection.
Administration of i.v. S-or LMW-heparin (50 IU kg(-1) resulted in rapid, highly significant (47 fold for S, 30.9 fold for LMW) increases in HGF serum values, reaching maxima of 10.51+/-1.65 ng ml(-1) (S) and 8.28+/-1.04 ng ml(-1) (LMW), respectively, 10 min after drug application. S.c. injection of S-heparin or LMW heparin resulted in 4.1 and 5.4 fold increases in HGF serum values, respectively. Both agents showed no effects on circulating VEGF or bFGF levels, independent of the route of administration.
Circulating HGF levels were selectively increased in response to pharmacological doses of two, widely used heparin preparations. This may, in part, explain some of the biological effects of heparin separate from its anticoagulant properties. By this mechanism, the systemic administration of heparin may facilitate collateral vessel formation in various clinical settings of tissue ischaemia.
本研究旨在比较标准肝素（S）与低分子量肝素（LMW）对循环中肝素结合生长因子（HBGF）水平的影响，已知这些因子在人体内具有血管生成特性。
在两项连续试验中，按照安慰剂对照交叉设计，对18名健康男性志愿者在三个不同时间点进行研究。受试者被随机分配接受S-肝素、LMW肝素或安慰剂。肝素通过静脉注射（i.v.）或皮下注射（s.c.）给药，生理盐水安慰剂通过静脉注射给药。在注射前及注射后长达24小时内测量肝细胞生长因子（HGF）、血管内皮细胞生长因子（VEGF）和碱性成纤维细胞生长因子（bFGF）的血清浓度。
静脉注射S-肝素或LMW-肝素（50 IU kg⁻¹）导致HGF血清值迅速、高度显著升高（S为47倍，LMW为30.9倍），在给药后10分钟分别达到最大值10.51±1.65 ng ml⁻¹（S）和8.28±1.04 ng ml⁻¹（LMW）。皮下注射S-肝素或LMW肝素分别导致HGF血清值升高4.1倍和5.4倍。两种药物对循环中的VEGF或bFGF水平均无影响，与给药途径无关。
药理学剂量的两种广泛使用的肝素制剂可选择性地增加循环中HGF水平。这可能部分解释了肝素除抗凝特性外的一些生物学效应。通过这种机制，肝素的全身给药可能在各种组织缺血的临床情况下促进侧支血管形成。
