Regulation of vascular and gastric smooth muscle contractility by pervanadate-猫眼课题宝

过钒酸盐对血管和胃平滑肌收缩力的调节

DOI：

发表时间：

1994

期刊：

British Journal of Pharmacology

影响因子：

7.3

通讯作者：

中科院分区：

医学2区

文献类型：

作者：

A. Laniyonu;M. Saifeddine;S. Ahmad;M. Hollenberg

1观察了钒酸盐（VO_4）和过钒酸盐（PV）对大鼠胃纵肌条和主动脉环的收缩作用。评价了细胞外钠和钙的作用，并考虑了神经释放激动剂的潜在作用。使用酪氨酸激酶抑制剂（染料木素、tyrphostin）并通过PV处理组织中磷酸酪氨酸蛋白的Western印迹分析，探索了这些反应是由于PV介导的酪氨酸磷酸酶抑制导致酪氨酸激酶活性增强的可能性。还研究了PV在胃制剂中模拟酪氨酸激酶受体相关激动剂表皮生长因子-尿抑胃素（EGF-Uro）作用的能力。2 PV在胃和主动脉源性组织中引起浓度依赖性收缩，效力比VO 4大1至2个数量级。3虽然胃和主动脉组织重复暴露于固定浓度的VO 4可引起两种组织的可重复收缩，但胃组织重复暴露于PV可引起收缩反应增加，3次暴露后达到平台。相反，主动脉组织单次暴露于PV（20 μm）导致组织对PV或其他激动剂后续收缩作用的脱敏时间延长。4在两种制备物中，对PV的收缩反应不受河豚毒素、阿托品、育亨宾和酚苄明的影响;在主动脉制备物中，在存在或不存在功能性内皮的情况下，对VO 4和PV的反应相同。5在不存在细胞外钠但需要细胞外钙的情况下，观察到两种组织中PV诱导的收缩，并被1 μm硝苯地平减弱。6在胃准备中，PV的收缩作用特征与EGF-Uro的收缩作用特征相似，包括（1）染料木黄酮的抑制作用，（2）消炎痛的抑制作用和（3）对细胞外钙的需求。这些反应特征不同于其他收缩激动剂，如卡巴胆碱。7在胃和主动脉制剂中，金雀异黄素能够选择性地抑制PV诱导的收缩，而不会对KCl诱导的收缩产生类似的抑制作用。Tyrphostin（AG 18）也选择性阻断PV诱导的胃收缩，但不阻断主动脉制备。8在胃和主动脉组织中，随着收缩反应的增加，PV引起组织磷酸酪氨酸蛋白含量的增加，如使用单克隆抗磷酸酪氨酸抗体的Western印迹分析所检测到的;当组织同时用PV作为酪氨酸激酶抑制剂处理时，磷酸酪氨酸蛋白含量的增加减少。在亚收缩浓度下，9 PV增强了胃和主动脉组织中血管紧张素II的收缩作用。我们得出结论，在血管和胃平滑肌组织中，生长因子模拟剂PV是比VO 4更有效的收缩激动剂。PV可导致组织磷酸酪氨酸蛋白含量增加，最有可能是通过抑制组织蛋白酪氨酸磷酸酶。PV的收缩作用需要细胞外钙，不依赖于细胞外钠，似乎不是由于Na+/K+-ATP酶抑制促进的Na+/Ca 2+交换，也不是由于Ca 2 +-ATP酶抑制，可能最好解释为PV通过酪氨酸磷酸酶抑制增强与钙进入和收缩过程相关的酪氨酸激酶途径的能力。

1 The contractile actions of vanadate (VO4) and pervanadate (PV, peroxide(s) of vanadate) were studied in rat gastric longitudinal muscle strips and in aortic rings. The roles of extracellular sodium and calcium were evaluated and the potential effects of nerve‐released agonists were considered. The possibility that these responses were due to the potentiation of tyrosine kinase activity, as a result of PV‐mediated tyrosine phosphatase inhibition was explored with the use of tyrosine kinase inhibitors (genistein, tyrphostin) and by Western blot analysis of phosphotyrosyl proteins in PV‐treated tissues. The ability of PV to mimic the action of the tyrosine kinase receptor‐associated agonist, epidermal growth factor‐urogastrone (EGF‐Uro), in the gastric preparation was also studied. 2 PV caused concentration‐dependent contractions in both gastric and aorta‐derived tissues, with a potency that was 1 to 2 orders of magnitude greater than that of VO4. 3 Although repeated exposure of gastric and aortic tissues to a fixed concentration of VO4 caused reproducible contractions in both tissues, repeated exposure of gastric tissue to PV caused an increased contractile response plateauing after 3 exposures. In contrast, a single exposure of aortic tissue to PV (20 μm) caused a prolonged desensitization of the tissue to the subsequent contractile actions of PV or other agonists. 4 The contractile responses to PV were unaffected in both preparations by tetrodotoxin, atropine, yohimbine and phenoxybenzamine; and in the aortic preparation, the responses to VO4 and PV were the same in the presence or absence of a functional endothelium. 5 PV‐induced contractions in both tissues were observed in the absence of extracellular sodium but required extracellular calcium and were attenuated by 1 μm nifedipine. 6 In the gastric preparation, the characteristics of the contractile actions of PV paralleled those of EGF‐Uro in terms of (1) inhibition by genistein, (2) inhibition by indomethacin and (3) a requirement for extracellular calcium. These response characteristics differed from those of other contractile agonists such as carbachol. 7 In both the gastric and aortic preparations genistein was able to inhibit PV‐induced contractions selectively without causing comparable inhibition of KC1‐induced contractions. Tyrphostin (AG 18) also selectively blocked PV‐induced contractions in the gastric, but not in the aortic preparation. 8 In both the gastric and aortic tissue, in step with an increased contractile response, PV caused increases in tissue phosphotyrosyl protein content, as detected by Western blot analysis using a monoclonal antiphosphotyrosine antibody; the increases in phosphotyrosyl protein content were reduced when tissues were treated with PV at the same time as a tyrosine kinase inhibitor. 9 PV, at sub‐contractile concentrations, potentiated the contractile action of angiotensin II in both the gastric and aorta tissue. 10 We conclude that the growth factor‐mimetic agent, PV, is a much more potent contractile agonist than VO4 in both vascular and gastric smooth muscle tissue. PV can cause enhanced tissue phos‐photyrosyl protein content most likely via the inhibition of tissue protein tyrosine phosphatases. The contractile actions of PV, which require extracelullar calcium and are independent of extracellular sodium, would appear not to be due either to Na+/Ca2+ exchange, promoted by Na+/K+‐ATPase inhibition or to the inhibition of Ca2+‐ATPase and might be best explained by the ability of PV, via tyrosine phosphatase inhibition, to potentiate a tyrosine kinase pathway linked to calcium entry and to the contractile process.