NITRATE TOLERANCE--ROLE OF NO IN POSTERIOR HYPOTHALAMUS

下丘脑后部的去甲肾上腺素能传递在循环的中枢控制中起重要作用，去甲肾上腺素(NE)可增加交感神经活动和动脉压。我们以前的研究表明，作为一氧化氮(NO)供体的硝酸甘油(NTG)可以增加NE的中枢释放和合成。NTG影响孤束核中枢神经元的兴奋性和PH。与其假定的作用一致，向PH内微量注射NTG可引起升压反应，从而减弱静脉注射该药物引起的动脉压下降。局部注射胍乙定可在PH区产生去甲肾上腺素受体阻滞剂，逆转对NTO的急性耐受反应，同时交感神经活动明显减弱。我们最近的研究结果表明，全身应用NTG可增加PH中亚硝酸盐的浓度和NE的周转率。我们假设，外周NTG产生的NO增加了PH中去甲肾上腺素的激活，从而促进了交感神经活动，并有助于硝酸盐耐受。鉴于NTG/NO在PH心血管功能中的重要作用，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兴奋效应；2)PH中对NTG的耐受是否通过阻断神经元功能或去甲肾上腺素功能而被阻止；3)PH中的透析液NE、NTG和NO代谢产物是否增加并与NTG耐受的形成和恢复时间相关；4)NO和NTO诱导的NE的释放/合成是否影响PH神经元的细胞外活动和膜内特性；(5)肺组织对NTG-NO的神经和电生理反应是否由ADP核糖化和/或抑制细胞呼吸所介导。在麻醉和清醒的大鼠中，直接量化动脉压、与透析液NE、NTO和NO代谢物相关的交感神经活性将结合神经药物操作和电生理记录来验证假说。这些结果有助于我们更好地理解NTG-NO影响去甲肾上腺素释放和神经心血管调节的细胞机制。这项工作将提供关于中枢NO系统在动态平衡神经循环控制中的作用的新信息，并将为临床医学发展对硝酸盐耐受性和药效学的新见解。

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.