NITRATE TOLERANCE--ROLE OF NO IN POSTERIOR HYPOTHALAMUS

下丘脑后部（PH）的去甲肾上腺素能传递在循环中枢控制中起重要作用，PH中的去甲肾上腺素（NE）增加交感神经活动和动脉压。我们之前的研究表明，硝酸甘油（NTG），一氧化氮（NO）供体，增加中央释放和NE的合成。NTG影响孤束核中枢神经元的兴奋性和PH值。与其假设的作用一致，将NTG微量注射到PH中会引起升压反应，从而减弱静脉注射该药物引起的动脉压下降。局部注射胍乙啶在PH中产生去甲肾上腺素能阻断，逆转对NTO的急性耐受反应，并伴有交感神经活动的明显衰减。我们最近的研究结果表明，系统给药NTG增加PH中的亚硝酸盐浓度和NE的转换。我们假设外周给药NTG产生NO增加PH中的去甲肾上腺素能激活，从而促进交感神经活动并有助于硝酸盐耐受性。鉴于NTG /NO在PH中对心血管功能的重要作用，我们的主要目的是阐明：l) PH中的NO是否介导NTG和硝酸盐耐受的交感神经兴奋作用；2)如果通过阻断神经元功能或PH的去肾上腺素能功能阻止对NTG的耐受性；3)透析液NE、NTG和NO代谢产物PH值是否升高并与NTG耐受性发展和恢复时间间隔相关；4)如果PH神经元的胞外活动和内在膜性质受到NO-和nto诱导的NE的释放/合成的影响；5) PH中对NTG-NO的神经元和电生理反应是否通过adp核糖基化和/或抑制细胞呼吸介导。直接量化动脉压、交感神经活动与透析液NE、NTO和NO代谢产物在PH中的关联，结合神经药理学操作和电生理记录，在麻醉和清醒大鼠中验证假设。研究结果将增强我们对nttg -NO影响NE释放和神经心血管调节的去甲肾上腺素能和细胞机制的理解。这项工作将提供关于中枢NO系统在稳态神经循环控制中的作用的新信息，并将为临床医学提供硝酸盐耐受性和药理学的新见解。

Noradrenergic transmission in the posterior hypothalamus (PH) plays an important role in the central control of circulation, and norepinephrine (NE) in the PH increases sympathetic nerve activity and arterial pressure. Our previous studies have shown that nitroglycerin (NTG), a nitric oxide (NO) donor, increases the central release and synthesis of NE. NTG affects the excitability of central neurons in the nucleus tractus solitarius and the PH. Consistent with its postulated role, microinjection of NTG into PH causes pressor responses which attenuate the decrease in arterial pressure induced by intravenous injection of the drug. Locally injected guanethidine produces noradrenergic blockade in the PH and reverses the acute tolerance responses to NTO accompanied by a marked attenuation of the sympathetic nerve activity. Our recent results show that systemica1ly administered NTG increases the concentration of nitrite and NE turnover in the PH. We hypothesize that generation of NO from peripheral NTG administration increases noradrenergic activation in the PH which facilitates sympathetic nerve activity and contributes to nitrate tolerance. In view of the critical importance of NTG /NO on cardiovascular functions in the PH, our major aims are to elucidate: l) If NO in the PH mediates sympatho-excitatory effects of NTG and nitrate tolerance; 2) If tolerance to NTG is prevented by blockade of neuronal function or noradrenergic function in the PH; 3) Whether dialysate NE, NTG and NO metabolites in the PH are increased and correlated to NTG tolerance development and recovery intervals; 4) If extracellular activities and intrinsic membrane properties of PH neurons are affected by NO- and NTO-induced release/synthesis of NE; and 5) If neuronal and electrophysiological responses to NTG-NO in the PH are mediated by ADP-ribosylation and/or inhibiting cellular respiration. Direct quantification of arterial pressure, sympathetic nerve activity associated with dialysate NE, NTO and NO metabolites in the PH will be combined with neuropharmacological manipulations and electrophysiological recordings to test the hypotheses in anesthetized and conscious rats. The results should enhance our understanding of the noradrenergic and cellular mechanisms by which NTG-NO influence NE release and neurocardiovascular regulation in the PH. This work will provide new information about the role of central NO systems on homeostatic neurocirculatory control and will develop new insights into nitrate tolerance and pharmacodynamics for clinical medicine.