Sustained elevation of serum cortisol level causes sensitization of coronary vasoconstricting responses in pigs in vivo - A possible link between stress and coronary vasospasm
Sustained elevation of serum cortisol level causes sensitization of coronary vasoconstricting responses in pigs in vivo - A possible link between stress and coronary vasospasm
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DOI：
10.1161/01.res.0000244093.69985.2f
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发表时间：
2006-09-29
影响因子：
20.1
通讯作者：
Shimokawa, Hiroaki
中科院分区：
文献类型：
--
作者：
Hizume, Takatoshi;Morikawa, Keiko;Shimokawa, Hiroaki
血管痉挛性心绞痛是由应激引起的，激活的下丘脑/垂体/肾上腺轴分泌的皮质醇可能发挥重要作用。然而，这一观点仍然缺乏直接证据。在这项研究中，我们检查了血清皮质醇水平的持续升高是否使猪体内的冠状血管收缩反应敏感，如果是这样，我们发现Rho激酶（我们发现它是冠状血管痉挛的关键分子）是否参与其中。口服皮质醇（每天 20 毫克/千克）可使其血清水平升高至猪的束缚应激水平。因此，我们检查了以下 4 组的冠状血管舒缩反应：（1）对照组（不含皮质醇）； (2)皮质醇(每天20mg/kg，PO)9天； (3)皮质醇加RU38486(一种糖皮质激素受体拮抗剂，每天10mg/kg，PO)9天； (4) 皮质醇治疗 9 天，然后停药 6 周。冠状动脉造影显示，冠状动脉内血清素仅在皮质醇组中引起冠状动脉过度收缩和冠状动脉血流量减少，并与缺血性心电图变化（冠状血管痉挛）相关。所有这些反应均在体内被 Hydroxyfasudil（一种特定的 Rho 激酶抑制剂）消除。器官室实验表明，仅在皮质醇组中，血清素浓度依赖性地引起与 Rho 激酶激活相关的冠状血管平滑肌过度收缩（如 Rho 激酶底物肌球蛋白结合亚基的磷酸化增强所证明）。所有这些反应在体外再次被羟基法舒地尔抑制。这些结果表明，血清皮质醇水平的持续升高通过 Rho 激酶激活使冠状血管收缩反应敏感，这表明应激与冠状血管痉挛之间存在联系。
Vasospastic angina is induced by stress, for which cortisol secreted by activated hypothalamic/pituitary/adrenal axis may play an important role. However, direct evidence for this notion is still lacking. In this study, we examined whether sustained elevation of serum cortisol level sensitizes coronary vasoconstricting responses in pigs in vivo and, if so, whether Rho-kinase, which we found is a key molecule of coronary vasospasm, is involved. Oral administration of cortisol (20 mg/kg per day) increased its serum level to that seen in restraint stress in pigs. Thus, we examined coronary vasomotor responses in the following 4 groups: ( 1) control ( without cortisol); ( 2) cortisol ( 20 mg/kg per day, PO) for 9 days; ( 3) cortisol plus RU38486 ( a glucocorticoids receptor antagonist, 10 mg/kg per day, PO) for 9 days; and ( 4) cortisol for 9 days followed by 6-week withdrawal. Coronary angiography showed that intracoronary serotonin caused coronary hyperconstriction and reduction in coronary blood flow associated with ischemic ECG changes ( coronary vasospasm) in only the cortisol group. All of these responses were abolished by hydroxyfasudil, a specific Rho-kinase inhibitor, in vivo. Organ chamber experiments demonstrated that serotonin concentration-dependently caused hypercontractions of coronary vascular smooth muscle associated with Rho-kinase activation ( as evidenced by the enhanced phosphorylation of myosin binding subunit, a substrate of Rho-kinase) in only the cortisol group. All of these responses were again inhibited by hydroxyfasudil in vitro. These results indicate that sustained elevation of serum cortisol level sensitizes coronary vasoconstricting responses through Rho-kinase activation, suggesting the link between stress and coronary vasospasm.