Bottrill F E, Douglas S A, Hiley C R, White R
Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QJ.
Br J Pharmacol. 2000 Aug;130(8):1865-70. doi: 10.1038/sj.bjp.0703513.
The possible role of the endothelium in modulating responses to human urotensin-II (U-II) was investigated using isolated segments of rat thoracic aorta, small mesenteric artery, left anterior descending coronary artery and basilar artery. Human U-II was a potent vasoconstrictor of endothelium-intact isolated rat thoracic aorta (EC(50)=3.5+/-1.1 nM, R(max)=103+/-10% of control contraction induced by 60 mM KCl and 1 microM noradrenaline). However the contractile response was not significantly altered by removal of the endothelium or inhibition of nitric oxide synthesis with L-NAME (100 microM). Human U-II did not cause relaxation of noradrenaline-precontracted, endothelium-intact rat aortae. Human U-II contracted endothelium-intact rat isolated left anterior descending coronary arteries (EC(50)=1.3+/-0.8 nM, R(max)=20.1+/-4.9% of control contraction induced by 10 microM 5-HT). The contractile response was significantly enhanced by removal of the endothelium (R(max)=55.4+/-16.1%). Moreover, human U-II caused concentration-dependent relaxation of 5-HT-precontracted arteries, which was abolished by L-NAME or removal of the endothelium. No contractile effects of human U-II were found in rat small mesenteric arteries. However the peptide caused potent, concentration- and endothelium-dependent relaxations of methoxamine-precontracted vessels. The relaxant responses were potentiated by L-NAME (300 microM) but abolished in the additional presence of 25 mM KCl (which inhibits the actions of endothelium-derived hyperpolarizing factor). The present study is the first to show that human U-II is a potent endothelium-dependent vasodilator in some rat resistance vessels, and acts through release of EDHF as well as nitric oxide. Our findings have also highlighted clear anatomical differences in the responses of different vascular beds to human U-II which are likely to be important in determining the overall cardiovascular activity of this peptide.
利用大鼠胸主动脉、肠系膜小动脉、左冠状动脉前降支和基底动脉的离体节段，研究了内皮细胞在调节对人尾加压素 - II（U - II）反应中的可能作用。人U - II是内皮完整的离体大鼠胸主动脉的强效血管收缩剂（EC50 = 3.5±1.1 nM，Rmax = 由60 mM KCl和1 μM去甲肾上腺素诱导的对照收缩的103±10%）。然而，去除内皮或用L - NAME（100 μM）抑制一氧化氮合成后，收缩反应没有明显改变。人U - II不会使去甲肾上腺素预收缩的、内皮完整的大鼠主动脉舒张。人U - II使内皮完整的大鼠离体左冠状动脉前降支收缩（EC50 = 1.3±0.8 nM，Rmax = 由10 μM 5 - HT诱导的对照收缩的20.1±4.9%）。去除内皮后收缩反应显著增强（Rmax = 55.4±16.1%）。此外，人U - II使5 - HT预收缩的动脉产生浓度依赖性舒张，L - NAME或去除内皮可消除这种舒张。在大鼠肠系膜小动脉中未发现人U - II的收缩作用。然而，该肽可使甲氧明预收缩的血管产生强效的、浓度和内皮依赖性舒张。L - NAME（300 μM）可增强舒张反应，但在额外存在25 mM KCl（抑制内皮衍生超极化因子的作用）时则消除舒张反应。本研究首次表明，人U - II在一些大鼠阻力血管中是强效的内皮依赖性血管舒张剂，通过释放内皮衍生超极化因子以及一氧化氮发挥作用。我们的研究结果还突出了不同血管床对人U - II反应的明显解剖学差异，这可能对确定该肽的整体心血管活性很重要。
