Analysis of Mechanisms Underlying Vascular Nitroxidergic Innervation and its Pathogenic Implication

1996年和1997年由日本政府资助的血管氮能神经支配的初步研究结果如下：1)大脑动脉。钙/钙调素依赖的蛋白激酶II抑制剂选择性地抑制了刺激氮能神经引起的犬脑动脉环GMP的松弛和增加，提示该蛋白的磷酸化参与了神经末梢一氧化氮合成酶的激活。乙酰胆碱和胆碱酯酶抑制剂艾司林可减弱刺激神经刺激猴脑动脉的NO所介导的松弛，阿托品可增强其作用，表明神经源性乙酰胆碱干扰神经合成和/或释放NO。亚硝酸能神经功能因缺氧而受损，可能是由于细胞内pH的调节，以及氟桂利嗪阻断神经末梢…的钙内流所致更多的肌萎缩侧索硬化，从而减少NO的合成。根据对犬离体脑动脉的药理学研究，氮能神经功能的增强可能部分参与了高碳酸血症引起的脑血管扩张。犬海绵体条对跨壁的电刺激有松弛反应，这种松弛可被一氧化氮合酶抑制剂消除，并被L-精氨酸恢复。阿托品和VIP拮抗剂无效。在麻醉犬中，电刺激盆腔神经丛增加阴茎海绵体内压力并刺激阴茎勃起，这种作用可被静脉注射和阴茎海绵体内注射NO合酶抑制剂所消除。六甲溴铵取消了对神经刺激的反应，提示在体部附近存在氮氧化物能神经节。这些发现表明，氮氧能神经在阴茎勃起中起着至关重要的作用。在猴和狗的睫状动脉、视网膜动脉和猴舌动脉中，药理学和组织化学研究提供了氮能血管扩张神经和肾上腺素能血管收缩神经的证据。我们的数据表明，一氧化氮和降钙素基因相关肽在犬皮肤动脉中起着血管扩张介质的作用。在麻醉猴子中，静脉注射一氧化氮合酶抑制剂N^G-硝基-L-精氨酸可升高全身血压，而L-精氨酸则逆转这一作用。该抑制物的升压作用可被神经节阻滞剂减弱，但不能被酚妥拉明处理，这表明静息状态下血管扩张神经释放的NO有助于降低血管阻力。较少

Original findings on vascular nitroxidergic innervation obtained in 1996 and 1997 by a financial support from Japanese Government are as follows.I)Cerebral artery. Relaxations and increments in cyclic GMP induced by nitroxidergic nerve stimulation in canine cerebral arteries were selectively inhibited by inhibitors of Ca/calmodulin-dependent proteinkinase II,suggesting that the protein phosphorylation is involved in the activation of nitric oxide (NO) synthase in nerve terminals. NO-mediated relaxations by nerve stimulation of monkey cerebral arteries were attenuated by acetylcholine and eserine, a cholinesterase inhibitor, and potentiated by atropine, indicating that neurogenic acetylcholine interferes with the synthesis and/or release of NO from the nerve. Prejunctional muscarinic receptor subtype involved appears to be M_2. Nitroxidergic nerve function was impaired by hypoxia, possibly due to modulation of intracellular pH,and by flunarizine that blocks the Ca influx in nerve termin … More als, thus reducing the NO synthesis. On the basis of pharmacological study in isolated canine cerebral arteries, potentiation of nitroxidergic nerve function was suggested to be involved partially in hypercapnia-induced cerebral vasodilatation.II)Corpus cavernosum. Canine cavernous strips responded to transmural electrical stimulation with relaxations which were abolished by NO synthase inhibitors and restored by L-arginine. Atropine and VIP antagonist were ineffective. In anesthetized dogs, electrical stimulation of pelvic nerve plexus increased the intracavernous pressure and provoked penile erection, the effects being abolished by intravenous and intracavernous injections of NO synthase inhibitors. Hexamethonium abolished the response to nerve stimulation, suggesting the presence of nitroxidergic ganglion in the vicinity of corpus. The findings indicate that the nitroxidergic nerve plays a crucial role in penile erection.III)Peripheral arteries. In ciliary and retinal arteries from monkeys and dogs and lingual arteries from monkeys, evidences for nitroxidergic vasodilator nerves, together with adrenergic vasoconstrictor, were provided by pharmacological and histochemical studies. Our data indicate that NO and CGRP play a role as vasodilator mediators in canine skin arteries.IV)Blood pressure. In anesthetized monkeys, intravenous N^G-nitro-L-arginine, a NO synthase inhibitor, raised systemic blood pressure, and L-arginine reversed the effect. The pressor action of the inhibitor was reduced by ganglionic blockade but not by treatment with phentolamine, suggesting that NO liberated from vasodilator nerves under resting conditions contributes to decreased vascular resistance. Less