Analysis of Mechanisms Underlying Vascular Nitroxidergic Innervation and its Pathogenic Implication

1996年和1997年在日本政府的资助下获得的关于血管一氧化氮能神经支配的最初发现如下：I）脑动脉。钙/钙调素依赖性蛋白激酶II抑制剂可选择性抑制刺激犬脑动脉一氧化氮能神经引起的环磷酸鸟苷（cGMP）的松弛和增加，提示该蛋白磷酸化参与神经末梢一氧化氮合酶（NO）的激活。一氧化氮介导的神经刺激猴脑动脉的松弛被乙酰胆碱和乙酰胆碱酯酶抑制剂，胆碱酯酶抑制剂，并增强阿托品，表明神经源性乙酰胆碱干扰的合成和/或释放NO的神经衰减。连接前M受体亚型为M_2。缺氧可能通过调节细胞内pH值和氟桂利嗪阻断神经末梢钙内流而损害一氧化氮能神经功能。 关于我们 als，从而减少NO的合成。在离体犬脑动脉的药理学研究的基础上，增强一氧化氮能神经功能的建议参与部分高碳酸血症引起的脑血管舒张。II）海绵体。犬海绵体条响应于透壁电刺激与松弛，取消了NO合酶抑制剂和L-精氨酸恢复。阿托品和VIP拮抗剂无效。在麻醉的狗，电刺激盆腔神经丛增加海绵体内的压力，并引起阴茎勃起，通过静脉和海绵体内注射NO合酶抑制剂的效果被取消。六烃季铵可抑制对神经刺激的反应，提示在躯体附近存在一氧化氮能神经节。结果表明，一氧化氮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和视网膜动脉以及猴的舌动脉中，通过药理学和组织化学研究提供了氮氧化物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，NO和CGRP在犬皮肤动脉中起着血管扩张介质的作用。在麻醉的猴子中，静脉注射NO合酶抑制剂N^G-硝基-L-精氨酸，会升高全身血压，而L-精氨酸则会逆转这种效应。抑制剂的升压作用减少神经节阻滞，但不通过治疗酚妥拉明，这表明NO释放血管扩张神经在静息状态下有助于降低血管阻力。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