内皮素（B）受体参与内皮素-1诱导大鼠乳腺肿瘤血流变化的证据。

Evidence for the involvement of ET(B) receptors in ET-1-induced changes in blood flow to the rat breast tumor.

作者信息

Rai Aarati, Gulati Anil

机构信息

Department of Biopharmaceutical Sciences, The University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612, USA.

出版信息

Cancer Chemother Pharmacol. 2003 Jan;51(1):21-8. doi: 10.1007/s00280-002-0534-3. Epub 2002 Nov 8.

DOI:10.1007/s00280-002-0534-3

PMID:12497202

Abstract

PURPOSE

Structure, growth, and function of the blood vessels in breast tumors are markedly different from those in normal breast tissue due to changes in the production of growth factors such as vascular endothelial growth factor (VEGF), vasoactive substances such as endothelin-1 (ET-1) and cytokines. The role of ET-1 in breast tumor angiogenesis is not adequately understood. Studies have shown that the expression of proET-1, proET-3, and ET(B) receptors is increased in breast tumor. However, it is unclear whether there are any changes in ET-1-induced vascular responses in breast tumor. Hence, in the present study we investigated systemic hemodynamics and regional circulatory effects of ET-1 in rats with breast tumors.

METHODS

Female Sprague-Dawley rats weighing 180-200 g were divided into the following groups: (1) normal rats treated with saline ( n=6), (2) tumor-bearing rats treated with methylnitrosourea (MNU) ( n=6), (3) normal rats treated with saline plus the specific ET(B) receptor antagonist BQ 788 ( n=5), and (4) tumor-bearing rats treated with MNU plus BQ 788 ( n=5). Tumor development was monitored by regular palpation and measurement of tumor size. Once tumors had reached approximately 2-4 cm in diameter, the rats were anesthetized with urethane (1.5 g/kg i.p.) and their cardiovascular parameters were measured using a radioactive microsphere technique. Simultaneously, blood perfusion to the breast tissue was also measured using a laser Doppler technique.

RESULTS

ET-1 produced a significant increase in mean arterial pressure in normal and tumor-bearing rats. Blood flow to the tumor tissue increased significantly in response to ET-1 as compared to breast tissue in normal rats. This response was accompanied by a concomitant decrease in vascular resistance in the tumor tissue. These results were confirmed by laser Doppler flowmetry, which showed a significant increase in blood perfusion to breast tumor compared to normal breast tissue. This increase in blood perfusion was attenuated by pretreatment with BQ 788, suggesting an ET(B) receptor-mediated vasodilator action of ET-1 in rat breast tumor.

CONCLUSIONS

The results indicate that ET-1 induced an increase in blood flow to breast tumor tissue mediated through ET(B) receptors.

摘要

目的

由于血管内皮生长因子（VEGF）等生长因子、内皮素-1（ET-1）等血管活性物质以及细胞因子产生的变化，乳腺肿瘤中血管的结构、生长和功能与正常乳腺组织明显不同。ET-1在乳腺肿瘤血管生成中的作用尚未得到充分了解。研究表明，乳腺肿瘤中前ET-1、前ET-3和ET（B）受体的表达增加。然而，尚不清楚ET-1诱导的乳腺肿瘤血管反应是否存在任何变化。因此，在本研究中，我们研究了ET-1对乳腺肿瘤大鼠的全身血流动力学和局部循环的影响。

方法

将体重180 - 200 g的雌性Sprague-Dawley大鼠分为以下几组：（1）用生理盐水处理的正常大鼠（n = 6），（2）用甲基亚硝基脲（MNU）处理的荷瘤大鼠（n = 6），（3）用生理盐水加特异性ET（B）受体拮抗剂BQ 788处理的正常大鼠（n = 5），以及（4）用MNU加BQ 788处理的荷瘤大鼠（n = 5）。通过定期触诊和测量肿瘤大小来监测肿瘤的发展。一旦肿瘤直径达到约2 - 4 cm，用乌拉坦（1.5 g/kg腹腔注射）麻醉大鼠，并使用放射性微球技术测量其心血管参数。同时，也使用激光多普勒技术测量乳腺组织的血流灌注。

结果

ET-1使正常大鼠和荷瘤大鼠的平均动脉压显著升高。与正常大鼠的乳腺组织相比，ET-1使肿瘤组织的血流显著增加。这种反应伴随着肿瘤组织血管阻力的相应降低。激光多普勒血流仪证实了这些结果，其显示与正常乳腺组织相比，乳腺肿瘤的血流灌注显著增加。用BQ 788预处理可减弱这种血流灌注的增加，表明ET-1在大鼠乳腺肿瘤中具有ET（B）受体介导的血管舒张作用。