Ketamine and midazolam differentially inhibit nonadrenergic noncholinergic lower esophageal sphincter relaxation in rabbits - Role of superoxide anion and nitric oxide synthase
Ketamine and midazolam differentially inhibit nonadrenergic noncholinergic lower esophageal sphincter relaxation in rabbits - Role of superoxide anion and nitric oxide synthase
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DOI：
10.1097/00000542-200302000-00026
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发表时间：
2003-02-01
期刊：
影响因子：
8.8
通讯作者：
Shimada, M
中科院分区：
文献类型：
--
作者：
Kohjitani, A;Miyawaki, T;Shimada, M
背景：作者先前报道氯胺酮和咪达唑仑通过一氧化氮-3',5'-环鸟苷单磷酸通路调节抑制一氧化氮介导的非肾上腺素能非胆碱能（NANC）下食管约约肌（LES）松弛。研究了氯胺酮和咪达唑仑抑制NANC弛豫的机制。方法：对日本大白兔环形食管远端肌条进行等长张力测定。在阿托品（3 × 10(-6) M）和胍乙啶（3 × 10(-6) M）存在下，KCl （30 mm）诱导NANC松弛。采用L-[H-3]精氨酸转化为L-[H-3]瓜氨酸的生化方法，分析了氯胺酮和咪达唑仑不存在和不存在时一氧化氮合酶的活性。超氧化物歧化酶（200、400 U/ml）可部分逆转氯胺酮对NANC松弛的抑制作用，过氧化氢酶（100 U/ml）则不能。氯胺酮浓度依赖性地抑制n-乙基乙胺、1,1-二乙基-2-羟基-2-亚硝基肼（二乙胺NONOate）和s -亚硝基谷胱甘肽诱导的松弛。NANC弛豫本身不受超氧化物歧化酶的影响。超氧化物歧化酶和过氧化氢酶都不能逆转咪达唑仑对NANC松弛的抑制作用，咪达唑仑不影响一氧化氮供体诱导的松弛。咪达唑仑对一氧化氮合酶活性有浓度依赖性抑制作用，而氯胺酮对一氧化氮合酶活性无明显抑制作用。邻苯三酚，一种超氧化物发生器，抑制NANC和二乙胺nonoate诱导的松弛。超氧化物歧化酶可逆转邻苯三酚诱导的NANC松弛抑制。结论：氯胺酮通过胞外产生超氧阴离子抑制NANC LES松弛，咪达唑仑通过抑制一氧化氮合酶活性抑制NANC LES松弛。
Background: The authors previously reported that ketamine and midazolam inhibited nitric oxide-mediated nonadrenergic noncholinergic (NANC) lower esophageal sphincter (LES) relaxation via nitric oxide-3',5'-cyclic guanosine monophosphate pathway modulation. The mechanisms inhibiting the NANC relaxation by ketamine and midazolam were investigated.Methods: The isometric tension of circular distal esophageal muscle strips from Japanese White rabbits was examined. NANC relaxation was induced by KCl (30 mm) in the presence of atropine (3 x 10(-6) M) and guanethidine (3 x 10(-6) M). Nitric oxide synthase activity in the absence and presence of ketamine and midazolam was analyzed using the biochemical conversion of L-[H-3]arginine to L-[H-3]citrulline.Results. The ketamine-induced inhibition of the NANC relaxation was partly reversed by superoxide dismutase (200, 400 U/ml) but not by catalase (100 U/ml). Ketamine concentration-dependently inhibited the relaxation induced by N-ethylethanamine:1,1-diethyl-2-hydroxy-2-nitrosohydrazine (diethylamine NONOate) and S-nitrosoglutathione. The NANC relaxation itself was not affected by superoxide dismutase. The midazolam-induced inhibition of the NANC relaxation was reversed neither by superoxide dismutase nor by catalase, and midazolam did not affect the relaxations induced by nitric oxide donors. The nitric oxide synthase activity was concentration-dependently suppressed by midazolam, but there was no marked effect of ketamine. Pyrogallol, a superoxide generator, inhibited the NANC and the diethylamine NONOate-induced relaxations. The pyrogallol-induced inhibition of the NANC relaxation was reversed by superoxide dismutase.Conclusion: These findings suggest that ketamine inhibits NANC LES relaxation by the extracellular production of superoxide anion, and that midazolam inhibits it by the inhibition of nitric oxide synthase activity.