Nitric oxide from enteric nerves acts by a different mechanism from myogenic nitric oxide in canine lower esophageal sphincter

作     者：Daniel, EE Jury, J Salapatek, AM Bowes, T Lam, A Thomas, S Ramnarain, M Nguyen, V Mistry, V 

作者机构：McMaster Univ Hlth Sci Ctr Dept Med Hamilton ON L8N 3Z5 Canada 

出 版 物：《JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS》 (药理学与实验治疗学杂志)

年 卷 期：2000年第294卷第1期

页      面：270-279页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 1006[医学-中西医结合] 100706[医学-药理学] 100602[医学-中西医结合临床] 10[医学] 

主　　题：4 4'-二异硫氰基苯-2 2'-二磺酸/药理学 4-氨基吡啶/药理学 氯化物通道/生理学 食管胃接合处/生理学 肠/神经支配 一氧化氮/生理学 硝基精氨酸/药理学 钾通道/生理学 四乙基铵化合物/药理学 ω蜗牛毒素GVIA/药理学 动物 狗 

摘      要：In canine lower esophageal sphincter, myogenic constitutive nitric-oxide (NO) synthase (NOS) in plasma membrane limits tone by opening large conductance Ca2+-dependent K+ channels (BKCa channels) and hyperpolarizing the membrane. We examined whether K-V channels were involved and whether NO from enteric nerves and from NO donors used the same mechanisms. With nerves inactive, 100 nM iberiotoxin, like N-nitro-L-arginine (L-NOARG), increased tone but less. 4-Aminopyridine (4-AP) at 5 mM behaved similarly. Tetraethyl ammonium (TEA) at 20 mM equaled the effect of L-NOARG and occluded any tone increase from any combination of these agents. More than iberiotoxin or 4-AP, TEA decreased relaxations in response to sodium nitroprusside (SNP) or 3-morpholino-sydnonimine (Sin-1) by similar to 50%. In whole-cell patch-clamp recordings, TEA and 4-AP reduced outward K+ currents additively by 90% at depolarization of +90 mV. Thus, K+ channels in addition to BKCa channels are opened by myogenic NO, and exogenous NO had relaxing effects both related and unrelated to K+ channel openings. TEA (20 mM) increased tone but did not inhibit relaxations to electrical field stimulation (EFS) of enteric nerves. 4-AP relaxed tone, an effect that was abolished and reversed by L-NOARG. 4-AP apparently released NO and acetylcholine from nerves. The putative Cl- channel blocker niflumic acid (NFA;30-100 mu M) dose dependently reduced tone, but tone, restored by 10(-6) M carbachol or 20 mM TEA, was still relaxed by EFS and by SNP. 4,4 -Diisothiocyanatostilbene-2,2 -disulfonic acid (DIDS) at 500 to 1000 mu M did not inhibit relaxation to EFS or SNP. The addition of TEA (20 mM) to DIDS (1000 mu M) induced tonic and phasic activity and markedly inhibited relaxations to EFS. DIDS plus TEA reduced the relaxations to SNP like TEA alone. Reduction in extracellular [Cl-2] by isethionate substitution reduced tone but did not reduce relaxations when tone was restored. The combination of reduced extracellular