Heijenbrok F J, Mathy M J, Pfaffendorf M, van Zwieten P A
Department of Pharmacotherapy, Academic Medical Center, University of Amsterdam, The Netherlands.
Naunyn Schmiedebergs Arch Pharmacol. 2000 Sep;362(3):276-83. doi: 10.1007/s002100000263.
The objective of the present study was to investigate the influence of balloon injury and subsequent neointima formation in the rat carotid artery on the beta-adrenoceptor function. Rat left common carotid artery was subjected to balloon injury with an arterial embolectomy catheter; the contralateral artery was sham-operated. Immediately, and at 2, 8 and 16 weeks post-injury, both the injured and the sham-operated carotid arteries were isolated and mounted in an isometric wire-myograph set-up. Subsequently, concentration-response curves (CRCs) were constructed for the beta-adrenoceptor agonist isoprenaline after precontraction with the thromboxane A2 (TP)-receptor agonist U46619 (30 nM) of the injured and sham-operated artery preparations. To evaluate the involvement of the beta1- and the beta2-adrenoceptor subtypes, CRCs were constructed in the presence of CGP 20712A (0.1 nM, a beta1-adrenoceptor-selective antagonist) and ICI 118,551 (10 nM, a beta2-adrenoceptor-selective antagonist). L-NAME (100 microM) and indomethacine (10 microM) were used to evaluate the influence of nitric oxide (NO) or prostanoids, respectively. Immediately post-injury, isoprenaline-induced vasorelaxation was impaired in the injured carotid artery preparations: Emax=19.6 +/- 2.2% vs. 64.0 +/- 4.6%, injured vs. sham, n=8, P<0.05. However, from 2 weeks post-injury onwards, this response appeared enhanced in the injured preparations: Emax, 2 weeks= 86.4 +/- 2.2% vs. 49.7 +/- 5.7%, injured vs. sham, n=5, P<0.05. In addition, the sensitivity for isoprenaline was increased in these preparations: pD2, 2 weeks=7.48 +/- 0.08 vs. 6.88 +/- 0.10, injured vs. sham, n=5, P<0.05. The beta-adrenoceptor population in both types of preparations consisted mainly of the beta2-adrenoceptor subtype, although at 8 and 16 weeks post-injury, the beta1-adrenoceptor subtype appeared to be present as well in the injured artery preparations. Inhibition of NO synthesis led to significant decreases of beta-adrenoceptor-mediated vasorelaxation both in injured and in sham-operated artery preparations for all time points, except at 16 weeks. Cyclo-oxygenase inhibition had no influence on isoprenaline-induced vasorelaxation in injured and sham-operated preparations. From this, it is concluded that beta-adrenoceptor-mediated vasorelaxation in rat carotid artery is partially NO-dependent and occurs mainly via activation of the beta2-adrenoceptor subtype. Balloon injury and subsequent neointima formation in the rat carotid artery lead initially to an impairment, but subsequently to an enhancement of the beta-adrenoceptor-mediated vasorelaxation. The impairment is attributable to the removal of endothelium, whereas the enhanced beta-adrenoceptor-mediated function may be related to the occurrence of an NO system in the neointimal smooth muscle cells.
本研究的目的是探讨大鼠颈动脉球囊损伤及随后的新生内膜形成对β-肾上腺素能受体功能的影响。用动脉栓子切除导管对大鼠左颈总动脉进行球囊损伤；对侧动脉进行假手术。在损伤后即刻以及损伤后2周、8周和16周，将损伤的和假手术的颈动脉分离并安装在等长线肌描记仪装置中。随后，在用血栓素A2（TP）受体激动剂U46619（30 nM）对损伤的和假手术的动脉标本进行预收缩后，构建β-肾上腺素能受体激动剂异丙肾上腺素的浓度-反应曲线（CRCs）。为了评估β1-和β2-肾上腺素能受体亚型的参与情况，在存在CGP 20712A（0.1 nM，一种β1-肾上腺素能受体选择性拮抗剂）和ICI 118,551（10 nM，一种β2-肾上腺素能受体选择性拮抗剂）的情况下构建CRCs。分别用L-NAME（100 μM）和吲哚美辛（10 μM）评估一氧化氮（NO）或前列腺素的影响。损伤后即刻，损伤的颈动脉标本中异丙肾上腺素诱导的血管舒张受损：Emax = 19.6 ± 2.2% 对比 64.0 ± 4.6%，损伤组对比假手术组，n = 8，P < 0.05。然而，从损伤后2周起，这种反应在损伤的标本中似乎增强：Emax，2周 = 86.4 ± 2.2% 对比 49.7 ± 5.7%，损伤组对比假手术组，n = 5，P < 0.05。此外，这些标本中对异丙肾上腺素的敏感性增加：pD2，2周 = 7.48 ± 0.08 对比 6.88 ± 0.10，损伤组对比假手术组，n = 5，P < 0.05。两种类型标本中的β-肾上腺素能受体群体主要由β2-肾上腺素能受体亚型组成，尽管在损伤后8周和16周，β1-肾上腺素能受体亚型在损伤的动脉标本中也似乎存在。除16周外，在所有时间点，抑制NO合成均导致损伤的和假手术的动脉标本中β-肾上腺素能受体介导的血管舒张显著降低。环氧化酶抑制对损伤的和假手术的标本中异丙肾上腺素诱导的血管舒张没有影响。由此得出结论，大鼠颈动脉中β-肾上腺素能受体介导的血管舒张部分依赖于NO，主要通过β2-肾上腺素能受体亚型的激活发生。大鼠颈动脉球囊损伤及随后的新生内膜形成最初导致损伤，但随后导致β-肾上腺素能受体介导的血管舒张增强。损伤归因于内皮的去除，而增强的β-肾上腺素能受体介导的功能可能与新生内膜平滑肌细胞中NO系统的出现有关。
