McCann S M, Karanth S, Kimura M, Yu W H, Rettori V
Pennington Biomedical Research Center (LSU), Baton Rouge, Louisiana 70808-4124, USA.
Rev Bras Biol. 1996 Dec;56 Su 1 Pt 1:105-12.
Neurons containing neural nitric oxide synthase (nNOS) are found in various locations in the hypothalamus and, in particular, in the paraventricular and supraoptic nuclei with axons which project to the median eminence and extend into the neural lobe where the highest concentrations of NOS are found in the rat. Furthermore, nNOS is also located in folliculostellate cells and LH gonadotropes in the anterior pituitary gland. To define the role of NO in the release of hypothalamic peptides and pituitary hormones, we injected an inhibitor of NOS, Ng-monomethyl-L-arginine (NMMA) or a releasor of NO, nitroprusside (NP) into the third ventricle (3V) of conscious castrate rats and determined the effect on the release of various pituitary hormones. In vitro, we incubated medial basal hypothalamic (MBH) fragments and studied inhibitors of NO synthase and also releasors of NO. The results indicate that NOergic neurons play an important role in stimulating the release of corticotrophin-releasing hormone (CRH), luteinizing hormone releasing-hormone (LHRH), prolactin-RH's, particularly oxytocin, growth hormone-RH (GHRH) and somatostatin, but not FSH-releasing factor from the hypothalamus. NO stimulates the release of LHRH, which induces sexual behavior, and causes release of LH from the pituitary gland. The intrahypothalamic pathway by which NO controls LHRH release is as follows: glutamergic neurons synapse with noradrenergic terminals in the MBH which release nonepinephrine (NE) that acts on alpha 1 receptors on the NOergic neuron to increase intracellular free Ca++ which combines with calmodulin to activate NOS. The NOS diffuses to the LHRH terminal and activates guanylate cyclase (GC), cyclooxygenase and lipoxygenase causing release of LHRH via release of cyclic GMP, PGE2 and leukotrienes, respectively. Alcohol and cytokines can block LHRH release by blocking the activation of cyclooxygenase and lipoxygenase without interfering with the activation of GC. GABA also blocks the response of the LHRH neurons to NO and recent experiments indicate that granulocyte macrophage colony-stimulating factor (GMCSF) blocks the response of the LHRH neuron to NP by activation of GABA neurons since the blockade can be reversed by the competitive inhibitor of GABAa receptors, bicuculine.
含有神经型一氧化氮合酶（nNOS）的神经元存在于下丘脑的各个部位，特别是室旁核和视上核，其轴突投射到正中隆起并延伸至神经叶，在大鼠的神经叶中一氧化氮合酶的浓度最高。此外，nNOS也位于垂体前叶的滤泡星状细胞和促黄体生成素促性腺激素细胞中。为了确定一氧化氮在释放下丘脑肽和垂体激素中的作用，我们将一氧化氮合酶抑制剂Nω-单甲基-L-精氨酸（NMMA）或一氧化氮释放剂硝普钠（NP）注入清醒去势大鼠的第三脑室（3V），并测定其对各种垂体激素释放的影响。在体外，我们孵育内侧基底下丘脑（MBH）片段，研究一氧化氮合酶抑制剂和一氧化氮释放剂。结果表明，一氧化氮能神经元在刺激促肾上腺皮质激素释放激素（CRH）、促黄体生成素释放激素（LHRH）、催乳素释放激素，尤其是催产素、生长激素释放激素（GHRH）和生长抑素的释放中起重要作用，但对下丘脑促卵泡生成素释放因子的释放无影响。一氧化氮刺激诱导性行为的LHRH的释放，并导致垂体释放促黄体生成素。一氧化氮控制LHRH释放的下丘脑内途径如下：谷氨酸能神经元与MBH中的去甲肾上腺素能终末形成突触，后者释放去甲肾上腺素（NE），NE作用于一氧化氮能神经元上的α1受体，增加细胞内游离Ca++，Ca++与钙调蛋白结合以激活一氧化氮合酶。一氧化氮合酶扩散至LHRH终末并激活鸟苷酸环化酶（GC）、环氧化酶和脂氧合酶，分别通过释放环磷酸鸟苷、前列腺素E2和白三烯导致LHRH释放。酒精和细胞因子可通过阻断环氧化酶和脂氧合酶的激活来阻断LHRH释放，而不干扰GC的激活。γ-氨基丁酸（GABA）也阻断LHRH神经元对一氧化氮的反应，最近的实验表明，粒细胞巨噬细胞集落刺激因子（GMCSF）通过激活GABA神经元来阻断LHRH神经元对NP的反应，因为这种阻断可被GABAA受体竞争性抑制剂荷包牡丹碱逆转。
