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Modulation of central sodium / osmo-homeostatic mechanisms by novel peptides-Integrative studies

新型肽对中枢钠/渗透压稳态机制的调节-综合研究

基本信息

批准号：
17390061
负责人：
KANNAN Hiroshi
金额：
$ 9.56万
依托单位：
University of Miyazaki
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2007
项目状态：
已结题

项目摘要

・Modification of adaptive responses to hypertonic saline (HS) loading by the endogenous vasopressin system: The paraventricular nucleus (PVN) of the hypothalamus consists of the magnocellular and parvicellular divisions. The PVN division that is activated following HS loading and is affected by pretreatment with vasopressin (AVP) V1 receptor antagonist (OPC-21268) was examined using the expression of Fos-like immunoreactivity (FLI). Although both PVN divisions were activated, the parvocellular division, but not the magnocellular division, was enhanced by the pretreatment, indicating the inhibitory action of the AVP system on the sympathetic promotor neurons in the PVN. In addition, the responses of the cardiovascular system and FLI expression to HS loading in conscious vasopressin-overexpressing transgenic (Tg) rats were examined. Central HS loading enhanced arterial blood pressure (ABP) and FLI expression in the PVN, the supraoptic nucleus (SON), the median preoptic nucleus (MnPO), th … More e area postrema (AP), and the organum vasculosum laminae terminalis (OVLT) in Tg rats compared to the control rats. The pretreatment with OPC-21268 blocked the increase in ABP and significantly decreased the FLI expression in the magnocellular division of the PVN induced by HS loading in the Tg rats.・Roles of novel peptides in the regulation of body water balance and the cardiovascular system: The effects of corticotrophin-releasing factor (CRF)and neuromedin U (NMU) on rat PVN neurons were studied using whole-cell patch-clamp recordings. Under current clamp, CRF and NMU increased the neuronal basal firing rate and depolarized neurons in a dose-dependent manner. Under voltage clamp, both peptides significantly increased the hyperpolarization-activated cation current (IH) in a dose-dependent manner. The results showed that CRF and NMU modulate the subpopulation of PVN parovocellular neuronal function by CRF receptor 1 and NMU receptor 2, respectively, via the potentiation of HCN ion channel activity. In addition, intracerebroventricular (i.c.v.)administration of another novel peptide, neuropeptide W (NPW), increased ABP, heart rate, and plasma norepinephrine and epinephrine concentrations in conscious rats. Furthermore, i.c.v. administration of NPW excited 22 and inhibited 7 but did not affect 6 out of 35 PVN neurons tested in conscious, freely moving rats.・Functional analysis of vasopressin V1b receptor knockout (V1b-/-)mice: Daily drinking behavior and renal secretory function were measured in V1b-/- and control (V1b+/+) mice. In addition, body temperature and locomotor activity were measured with a biotelemetry system. The baseline daily water intake and urine volume were larger in V1b-/- mice than in V1b+/+ mice. V1b-/- mice had significantly higher locomotor activity than did wild-type mice, whereas the body temperature and oxygen consumption were lower in V1b-/- than in V1b+/+ mice. Next, the mice were subjected to water deprivation for 48 hr. Under this condition, their body temperature decreased with the time course, and the decrease was significantly greater for V1b-/- than for V1b+/+ mice. The V1b receptor may be, at least in part, involved in body water balance and body temperature regulation. Less

·内源性加压素系统对高渗盐水（HS）负荷的适应性反应的改变：下丘脑室旁核（PVN）由大细胞和小细胞分裂组成。用Fos样免疫反应性（FLI）的表达检测了HS负荷后激活的PVN分裂，以及加压素（AVP）V1受体拮抗剂（OPC-21268）预处理对PVN分裂的影响。虽然这两个PVN分裂被激活，小细胞分裂，而不是大细胞分裂，增强了预处理，表明AVP系统的抑制作用的交感神经元的PVN。此外，心血管系统的反应和FLI表达HS负荷在清醒的加压素过表达转基因（Tg）大鼠进行了检查。中枢HS负荷增加了PVN、视上核（SON）、正中视前核（MnPO）、视上核（SON）和视上核（SON）中的动脉血压（ABP）和FLI表达。 ...更多信息 e最后区（AP）和终板血管器（OVLT）的Tg大鼠相比，对照组大鼠。OPC-21268预处理阻断了Tg大鼠ABP的增加，并显著降低了HS负荷诱导的PVN大细胞分裂中FLI的表达。新型肽在调节体内水平衡和心血管系统中的作用：使用全细胞膜片钳记录研究了促肾上腺皮质激素释放因子（CRF）和神经介肽U（NMU）对大鼠PVN神经元的作用。在电流钳下，CRF和NMU以剂量依赖的方式增加神经元的基础放电频率和去极化神经元。在电压钳下，两种肽以剂量依赖性方式显著增加超极化激活的阳离子电流（IH）。结果表明，CRF和NMU分别通过CRF受体1和NMU受体2，通过增强HCN离子通道活性，调节PVN旁细胞神经元功能亚群。此外，脑室内（i. c. v.）给予另一种新的肽，神经肽W（NPW），在清醒大鼠中增加ABP、心率和血浆去甲肾上腺素和肾上腺素浓度。此外，在清醒、自由活动的大鼠中，35个PVN神经元中，NPW的i. c. v.给药兴奋了22个，抑制了7个，但对6个没有影响。血管加压素V1 b受体敲除（V1 b-/-）小鼠的功能分析：在V1 b-/-和对照（V1 b +/+）小鼠中测量每日饮水行为和肾分泌功能。此外，用生物遥测系统测量体温和自发活动。V1 b-/-小鼠的基线每日饮水量和尿量大于V1 b +/+小鼠。V1 b-/-小鼠的自发活动显著高于野生型小鼠，而V1 b-/-小鼠的体温和耗氧量低于V1 b +/+小鼠。接着，将小鼠禁水48小时，在此条件下，它们的体温随着时间的推移而降低，V1 b-/-小鼠的降低幅度显著大于V1 b +/+小鼠。V1 b受体可能至少部分参与体内水分平衡和体温调节。少