Fischer Jens W, Hawkins Suzanne, Clowes Alexander W
Molekulare Pharmakologie, Institut für Pharmakologie und Klinische Pharmakologie, Universitätsklinikum Düsseldorf, Germany.
J Vasc Surg. 2004 Jul;40(1):115-22. doi: 10.1016/j.jvs.2004.03.037.
Extensive proliferation and migration of smooth muscle cells (SMCs) contribute to development of fibromuscular intimal hyperplasia in response to balloon catheter-induced injury of the left carotid artery in Fischer 344 rats. The purpose of the present study was to test the hypothesis that endogenously generated nitric oxide (NO) and prostaglandins act synergistically to limit the extent of neointimal hyperplasia.
The left carotid artery of Fischer 344 rats was injured with a 2F balloon catheter. The following treatment was initiated 24 hours before arterial injury, and was continued for 2 weeks: N-nitro-l-arginine (L-NA; 10 mg/kg/d, in drinking water), indomethacin (1.5 mg/kg/d per gavage), and L-NA (10 mg/kg/d) plus indomethacin (1.5 mg/kg/d). After application of an overdose of pentobarbital animals were formalin-fixed. Subsequently, paraffin-embedded cross sections of the uninjured and injured carotid arteries were analyzed morphometrically. SMC proliferation was determined by incorporation of 5-bromo-2'-deoxyuridine.
Two weeks after injury, L-NA caused a 1.29-fold +/- 0.29-fold (mean +/- SD; n = 14; P <.05) increase in the intima-media ratio, compared with control animals, whereas indomethacin had no effect. Combined treatment with L-NA plus indomethacin further increased intima-media ratio (1.65-fold +/- 0.5-fold over control; n = 14; P <.05). SMC proliferation in the neointima of rats treated with L-NA and L-NA plus indomethacin was elevated. Furthermore, neointimal cell density (nuclei per square millimeter) was reduced after combined inhibition of cyclooxygenases and NO synthases.
The present results of pharmacologic NO synthase and cyclooxygenase inhibition suggest that NO and prostaglandins are part of an endogenous growth inhibitory mechanism that synergistically suppresses intimal thickening.
The role of cyclooxygenase-1 (COX1) and cyclooxygenase-2 (COX2) during vascular recurrent stenosis and atherosclerosis is not clear yet. In particular, the effects of selective COX2 inhibitors on the frequency of cardiovascular events is still controversial. It is shown here in rats that the application of a non-selective COX inhibitor does not affect arterial stenosis. However, the concurrent inhibition of endogenous nitric oxide generation and COX1 or COX2 causes overshooting neointimal hyperplasia. These results suggest that increased vascular stenosis can result from administration of drugs that pharmacologically block 2 or more inhibitory pathways that normally counterbalance the effect of promotors of neointimal hyperplasia.
在Fischer 344大鼠中，平滑肌细胞（SMC）的广泛增殖和迁移促使纤维肌性内膜增生的发展，这是对球囊导管诱导的左颈动脉损伤的反应。本研究的目的是检验内源性一氧化氮（NO）和前列腺素协同作用以限制内膜增生程度的假说。
用2F球囊导管损伤Fischer 344大鼠的左颈动脉。在动脉损伤前24小时开始以下治疗，并持续2周：N-硝基-L-精氨酸（L-NA；10 mg/kg/d，溶于饮用水）、吲哚美辛（1.5 mg/kg/d，灌胃）以及L-NA（10 mg/kg/d）加吲哚美辛（1.5 mg/kg/d）。给予过量戊巴比妥后，动物用福尔马林固定。随后，对未损伤和损伤的颈动脉石蜡包埋横断面进行形态计量分析。通过掺入5-溴-2'-脱氧尿苷来测定SMC增殖。
损伤后两周，与对照动物相比，L-NA使内膜-中膜比增加了1.29倍±0.29倍（平均值±标准差；n = 14；P <.05），而吲哚美辛无作用。L-NA加吲哚美辛联合治疗进一步增加了内膜-中膜比（比对照高1.65倍±0.5倍；n = 14；P <.05）。用L-NA和L-NA加吲哚美辛治疗的大鼠新生内膜中的SMC增殖升高。此外，联合抑制环氧化酶和NO合酶后，新生内膜细胞密度（每平方毫米细胞核数）降低。
本研究中对NO合酶和环氧化酶的药理学抑制结果表明，NO和前列腺素是内源性生长抑制机制的一部分，它们协同抑制内膜增厚。
环氧化酶-1（COX1）和环氧化酶-2（COX2）在血管再狭窄和动脉粥样硬化中的作用尚不清楚。特别是，选择性COX2抑制剂对心血管事件发生率的影响仍存在争议。本研究在大鼠中表明，应用非选择性COX抑制剂不影响动脉狭窄。然而，同时抑制内源性一氧化氮生成以及COX1或COX2会导致过度的内膜增生。这些结果表明，药理学阻断2条或更多通常可抵消内膜增生促进因子作用的抑制途径的药物给药可导致血管狭窄增加。
