Yamato S, Saha J K, Goyal R K
Center for Swallowing and Motility Disorders, Charles A. Dana Research Institute, Boston, MA.
Life Sci. 1992;50(17):1263-72. doi: 10.1016/0024-3205(92)90326-k.
Studies were performed in the opossum to define the role of the L-arginine-nitric oxide (NO) pathway in lower esophageal sphincter (LES) relaxation to swallowing and vagal stimulation in viv and intramural nerve stimulation in vitro. In vivo, L-NAME, a water soluble NO synthase (NOS) inhibitor, caused antagonism of LES relaxation due to reflex-induced swallowing. L-NAME (20 mg/kg i.v.) reduced the amplitude of swallow induced relaxation from 88% to 28%. LES relaxation due to electrical stimulation of peripheral end of decentralized vagus nerve was also antagonized. The effects of L-NAME were reversed by L-arginine, but not by D-arginine. L-NAME treatment did not antagonize LES relaxation to intravenous administration of isoproterenol. In vitro, NO and sodium nitroprusside (SNP) caused a decrease in the sphincter tone. The relaxing effect caused by NO and SNP was not antagonized by tetrodotoxin or omega-conotoxin. Inhibitors of NO synthase, L-NMMA and L-NNA, caused slight increase in the spontaneous resting LES tone and concentration-dependent antagonism of electrical field stimulation (EFS) induced LES relaxation. L-NNA (10(-4)M) abolished EFS induced LES relaxation at low frequencies (less than 5 Hz) and antagonized the relaxation to a value 20% of the control at 20 Hz. The antagonistic action of L-NMMA and L-NNA was unaffected by D-arginine but was reversed by L-arginine. The inhibitory effect of NO, SNP, or two other putative inhibitory neurotransmitters (VIP and CGRP) on the LES was not antagonized by L-NNA. These studies show that inhibitors of NO synthase selectively antagonize LES relaxation to all three modes of intramural inhibitory nerve stimulation including physiological swallowing. These studies suggest that the L-arginine-nitric oxide pathway is involved in physiological relaxation of the LES.
本研究在负鼠身上进行，以确定L-精氨酸-一氧化氮（NO）途径在活体吞咽和迷走神经刺激以及体外壁内神经刺激引起的食管下括约肌（LES）松弛中的作用。在活体实验中，水溶性NO合酶（NOS）抑制剂L-NAME导致反射性吞咽引起的LES松弛受到拮抗。L-NAME（20mg/kg静脉注射）使吞咽诱导的松弛幅度从88%降至28%。分散迷走神经外周端电刺激引起的LES松弛也受到拮抗。L-精氨酸可逆转L-NAME的作用，而D-精氨酸则不能。L-NAME处理并未拮抗异丙肾上腺素静脉给药引起的LES松弛。在体外实验中，NO和硝普钠（SNP）导致括约肌张力降低。NO和SNP引起的松弛作用未被河豚毒素或ω-芋螺毒素拮抗。NO合酶抑制剂L-NMMA和L-NNA导致LES自发静息张力略有增加，并对电场刺激（EFS）诱导的LES松弛产生浓度依赖性拮抗作用。L-NNA（10^(-4)M）在低频（小于5Hz）时消除了EFS诱导的LES松弛，并在20Hz时将松弛作用拮抗至对照值的20%。L-NMMA和L-NNA的拮抗作用不受D-精氨酸影响，但可被L-精氨酸逆转。L-NNA并未拮抗NO、SNP或其他两种假定的抑制性神经递质（血管活性肠肽和降钙素基因相关肽）对LES的抑制作用。这些研究表明，NO合酶抑制剂选择性拮抗LES对包括生理性吞咽在内的所有三种壁内抑制性神经刺激模式的松弛作用。这些研究提示，L-精氨酸-一氧化氮途径参与LES的生理性松弛。
