Activation of nitric oxide synthase by β2-adrenoceptors in human umbilical vein endothelium in vitro

被引:146
作者
Ferro, A
Queen, LR
Priest, RM
Xu, BA
Ritter, JM
Poston, L
Ward, JPT
机构
[1] Univ London Kings Coll, St Thomas Hosp, Dept Clin Pharmacol, London SE1 7EH, England
[2] Univ London Kings Coll, St Thomas Hosp, Dept Allergy & Resp Med, London SE1 7EH, England
[3] Univ London Kings Coll, St Thomas Hosp, Dept Obstet & Gynaecol, London SE1 7EH, England
基金
英国惠康基金;
关键词
beta-adrenergic receptors; vascular endothelium; vasodilatation; nitric oxide; nitric oxide synthase; human umbilical vein;
D O I
10.1038/sj.bjp.0702512
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
1 Some animal studies suggest that beta-adrenoceptor-mediated vasorelaxation is in part mediated through nitric oxide (NO) release. Furthermore, in humans, we have recently shown that forearm blood flow is increased by infusion of beta(2)-adrenergic agonists into the brachial artery, and the nitric oxide synthase (NOS) inhibitor N-G-monomethyl-L-arginine (L-NMMA) inhibits this response, 2 The purpose of the present study was to determine whether stimulation of human umbilical vein endothelial beta-adrenoceptors causes vasorelaxation and nitric oxide generation, and whether this might be mediated by cyclic adenosine-3',5'-monophosphate (cyclic AMP). 3 Vasorelaxant responses were determined in umbilical vein rings to the nonselective beta-adrenergic agonist isoprenaline and to the cyclic AMP analogue dibutyryl cyclic AMP, following precontraction with prostaglandin F-2 alpha. 4 NOS activity was measured in cultured human umbilical vein endothelial soils (HUVEC) by the conversion of [H-3]-L-arginine to [H-3]-L-citrulline, and adenylyl cyclase activity by the conversion of [alpha-P-32]-ATP to [P-32]-cyclic AMP. 5 Isoprenaline relaxed umbilical vein rings, and this vasorelaxation was abolished by beta(2)- (but not beta(1)-) adrenergic blockage, and by endothelium removal or 1 mM L-NMMA. In addition, vasorelaxant responses to dibutyryl cyclic AMP were inhibited by 1 mM L-NMMA, with a reduction in E-max from 90.0 +/- 9.39 to 50.5 +/- 9.9% (P < 0.05). 6 Isoprenaline 1 mu M increased NOS activity in HUVEC (34.0 +/- 5.9% above basal. P < 0.001). Furthermore, isoprenaline increased adenylyl cyclase activity in a concentration-dependent manner, this response was inhibited by beta(2) (but not beta(1)-) adrenergic blockade. Forskolin 1 mu M and dibutyryl cyclic. AMP 1 mM each increased NOS activity in HUVEC, to a degree similar to isoprenaline 1 mu M. The increase in [H-3]-L-arginine to L-citrulline conversion observed with each agent wets abolished by coincubation with NOS inhibitors. 7 These results indicate that endothelial beta(2)-adrenergic stimulation and cyclic AMP elevation activate the L-arginine/NO system, and give rise to vasorelaxation, in human umbilical vein.
引用
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页码:1872 / 1880
页数:9
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