DOPAMINE-3 RECEPTOR SUBTYPE AND HYPERTENSION

描述：(改编自应用程序)D3-多巴胺的中断 小鼠的受体基因与舒张期高血压和高血压相关 排泄急性氯化钠负荷的能力受损。调查员将测试 突触后或突触外D3受体参与的假说 在调节钠转运、肾脏血流动力学和肾素释放方面， 遗传性高血压中异常的变量。突触前多巴胺 D3受体可能作为自身受体调节去甲肾上腺素和 从神经末梢释放多巴胺。因此，假设一个 外周去甲肾上腺素能神经( 肾神经)是突触前多巴胺D3中断的结果 将对受体进行测试。 第一个具体目标将决定导致兴奋的机制(S) 随着D3多巴胺受体的破坏而产生的血压 老鼠身上的基因。三个假说将被检验。在D3中断后 受体基因高血压的发生可能是由于：(A)减少 作为自身受体的D3受体抑制的能力 去甲肾上腺素能神经末梢的去甲肾上腺素释放；(B)肾素增加 分泌由于后或后的抑制作用而退出 突触外D3受体对肾素分泌的影响； D1和D3受体削弱了排泄钠负荷的能力。2. 虽然小鼠体内D3受体的破坏会导致高血压，但它 目前尚不清楚D3是否存在自发产生的异常多巴胺基因 阶级或其调节导致遗传性高血压。第二个具体目标 将确定是否存在D3基因的异常或其调节 自发性高血压的大鼠。突触后或突触外 突触前D3基因的表达和功能将通过 手术/化学切断单侧肾神经。如果在以下方面存在差异 D3基因表达和/或功能，那么D3受体基因就会 测序，并与Wistar-京都大鼠进行比较。任何一种 高血压患者D3受体功能和基因表达的变化 在SHR和WKY的F2代中确定。第三个具体目标是 检验D3多巴胺受体参与 拮抗D1的刺激作用对肾素释放的调节 感受器。研究将在分离的肾小球旁细胞中进行 WKY和SHR以及缺乏D或D3多巴胺受体的小鼠。这些研究 将决定D3受体在血液调节中的重要性 遗传性高血压患者的血压和肾功能。

DESCRIPTION: (Adapted from the application) Disruption of the D3-dopamine receptor gene in mice is associated with diastolic hypertension and an impaired ability to excrete an acute NaCl load. The investigator will test the hypothesis that postsynaptic or extrasynaptic D3 receptors are involved in the regulation sodium transport, renal hemodynamics and renin release, variables that are abnormal in genetic hypertension. Presynaptic dopamine D3 receptors may function as autoreceptors regulating norepinephrine and dopamine release from nerve terminals. Thus, the hypothesis that an increased norepinephrine release in peripheral noradrenergic nerves (the renal nerves) occurs as a result of disruption of presynaptic dopamine D3 receptors will be tested. The first Specific Aim will determine the mechanism(s) causing the high blood pressure that occurs with the disruption of the D3 dopamine receptor gene in mice. Three hypotheses will be tested. After disruption of the D3 receptor gene high blood pressure could occurs due to: (a) decreased ability of the D3 receptor, functioning as an autoreceptor, to inhibit norepinephrine release in noradrenergic nerve terminals; (b) increased renin secretion because of a withdrawal of the inhibitory action of post- or extrasynaptic D3 receptors on renin secretion; decreased synergism between D1, and D3 receptors impairing the ability to excrete a sodium load. 2. While disruption of the D3 receptor in mice produces high blood pressure, it is not known if a spontaneously occurring abnormal dopamine gene of the D3 class or its regulation causes genetic hypertension. The 2nd specific aim will determine if an abnormality of the D3 gene or its regulation exists in rats that develop hypertension spontaneously. Post- or extra-synaptic from pre-synaptic D3 gene expression and function will be distinguished by surgical/chemical unilateral renal denervation. If there are differences in D3 gene expression and/or function, then the D3 receptor gene will be sequenced and compared with the Wistar-Kyoto rat. The relevance of any changes in the D3 receptor function and gene expression in hypertension will be determined in F2 generation of SHR and WKY. The 3rd specific aim will test the hypothesis that the D3 dopamine receptor participates in the regulation of renin release by antagonizing the stimulatory effect of D1 receptors. Studies will be performed in isolated juxtaglomerular cells from WKY and SHR and mice lacking the D, or D3 dopamine receptor. These studies will determine the importance of the D3 receptor in the regulation of blood pressure and renal function in genetic hypertension.