ROLE OF NEUROPEPTIDES AND BIOGENIC AMINES IN STRESS AND BRAIN ISCHEMIA

我们进一步研究了血管紧张素II AT1拮抗剂在脑缺血中的保护作用。保护依赖于动脉重塑和促进脑动脉扩张，从而增加脑血流量，减少中风时的血流量减少，减少神经元损伤。AT1拮抗剂优于其他降压药。在一项相关的研究中，我们证明了AT2基因缺陷小鼠的AT1受体上调。这解释了它们的表型、对血管紧张素II的反应增加、钠滞留和血压，并支持AT1和AT2受体之间的串扰假说。在野生型小鼠中，AT1受体在一些但不是全部表达AT1受体的器官和不表达AT2受体的细胞中的表达增加。因此，AT1和AT2受体之间的串扰机制是器官特异性的和间接的。当AT1受体被阻断时，AT2受体的相对优势至少是AT1拮抗剂治疗效果的部分原因。AT2基因缺陷的小鼠也表达了更多的血管收缩因子内皮素和血管扩张因子的受体，即分泌心钠素的钠。因此，缺乏一个受体(AT2)的表达导致相关系统中的多种反馈和适应机制的级联。我们进一步证明AT1和AT2受体在应激过程中起作用。在应激反应的急性期，脑下垂体和肾上腺中的血管紧张素受体更为重要，而大脑AT1受体的反应不仅是急性的，而且是对重复应激的适应性反应的长期和调节的反应。这些结果表明，AT1受体的药理调节可能对脑缺血和应激相关疾病的预防和治疗具有一定的治疗意义。最后，我们对AT1受体拮抗剂结合的分子条件的研究得出了结论。通过对人和沙土鼠AT1受体的定点突变，我们已经确定，所选择的氨基酸负责该受体与非肽类拮抗剂的亲和力。这些研究对于未来开发具有治疗重要性的选择性和有效的AT1拮抗剂是必不可少的。

We advanced our studies on the protective role of Angiotensin II AT1 antagonists in brain ischemia. Protection is dependent in arterial remodeling and facilitated dilation of cerebral arteries, resulting in increased cerebral blood flow, decreased reduction in blood flow during stroke and decreased neuronal injury. AT1 antagonists are superior to other anti-hypertensive drugs. In a related study, we demonstrated upregulation of AT1 receptors in AT2 gene-deficient mice. This explains their phenotype, increased response to Angiotensin II, sodium retention and blood pressure and supports the hypothesis of cross talk between AT1 and AT2 receptors. AT1 receptor expression is increased in some, but not all, organs expressing AT1 receptors, and in cells that do not express AT2 receptors in wild-type mice. Thus, mechanisms of cross talk between AT1 and AT2 receptors are organ-specific and indirect. The relative predominance of AT2 receptors when AT1 receptors are blocked is responsible for at least part of the therapeutic effects of AT1 antagonists. AT2 gene-deficient mice express also express increased numbers of receptors for the vasoconstrictor endothelin and the vasodilator, sodium excreting atrial natriuretic peptide. Thus, lack of expression of one receptor (AT2) results in a cascade of multiple feedback and adaptive mechanisms in related systems. We further demonstrate that AT1 and AT2 receptors play a role during stress. Angiotensin receptors in pituitary and adrenal glands are more important during the acute phase of the stress response, whereas the response of brain AT1 receptors is long lasting and regulatory not only of the acute but of the adaptive response to repeated stress. All these results indicate that pharmacological modulation of AT1 receptors could have therapeutic implications for the prevention and treatment of brain ischemia and stress related disorders. Finally, our studies on the molecular requirements for antagonist binding of the AT1 receptor have come to a conclusion. With the use of site-directed mutagenesis of the human and gerbil AT1 receptors, we have established that selected amino acids are responsible for the affinity of the receptor for non-peptidic antagonists. These studies are essential for the future development of selective and potent AT1 antagonists of therapeutic importance.