Cao Weibiao, Harnett Karen M, Pricolo Victor E
Department of Medicine, Brown Medical School and Rhode Island Hospital, 55 Claverick Street, Room 337, Providence, RI 02903, USA.
J Pharmacol Exp Ther. 2006 Jun;317(3):1349-55. doi: 10.1124/jpet.105.097030. Epub 2006 Mar 22.
Human colonic circular muscle produces spontaneous phasic contractions that are reduced in ulcerative colitis. How the spontaneous phasic contractions develop and why they decrease in ulcerative colitis are not known. We found that spontaneous phasic contractions of normal sigmoid circular muscle strips were significantly reduced by 90-min incubation with tetrodotoxin (10(-5) M), which blocked neurokinin A release in basal conditions and in response to electrical stimulation. In addition, spontaneous contraction of human sigmoid colon was significantly decreased by the NK2 receptor antagonists MEN10376 (Asp-Tyr-D-Trp-Val-D-Trp-D-Trp-Lys-NH2) and NK2ra (Bz-Ala-Ala-D-Trp-Phe-D-pro-Pro-Nle-NH2) but not by atropine or by the NK1 antagonist FK888 (N2-[(4R)-4-hydroxyl-1-(1-methyl-1H-indol-3-yl)carbonyl-l-prolyl]-N-methyl-N-phenylmethyl-3-(2-naphthyl)-l-alaninamide), suggesting that NK2 receptors are involved in their development. The spontaneous phasic contractions were abolished by thapsigargin and cyclopiazonic acid and significantly decreased by the protein kinase C inhibitor chelerythrine and by the calmodulin inhibitor CGS9343B (1,3-dihydro-1-[1-[(4-methyl-4H,6H-pyrrolo[1,2-a]-[4,1]-benzoxazepin-4-yl)methyl]-4-piperidinyl]-2H-benzimidazol-2-one (1:1) maleate), suggesting that spontaneous phasic contractions may be mediated by Ca2+ release from intracellular stores and by a protein kinase C- and calmodulin-dependent pathway. In strips from patients with ulcerative colitis, spontaneous contractions were significantly reduced, and this reduction was partially restored by the hydrogen peroxide scavenger catalase. Neurokinin A release, however, was not affected. We conclude that spontaneous phasic contractions of human sigmoid circular smooth muscle may be mediated by activation of NK2 receptors, calcium release from intracellular stores, and activation of calmodulin and protein kinase C. In ulcerative colitis patients, spontaneous phasic contractions are decreased, and this decrease may be in part due to overproduction of hydrogen peroxide affecting sigmoid circular muscle.
人结肠环行肌可产生自发性阶段性收缩，而在溃疡性结肠炎中这种收缩会减弱。自发性阶段性收缩是如何产生的，以及它们在溃疡性结肠炎中为何会减弱尚不清楚。我们发现，用河豚毒素（10⁻⁵ M）孵育90分钟可使正常乙状结肠环行肌条的自发性阶段性收缩显著降低90%，河豚毒素在基础状态下以及对电刺激反应时均可阻断神经激肽A的释放。此外，人乙状结肠的自发性收缩可被NK2受体拮抗剂MEN10376（天冬氨酸 - 酪氨酸 - D - 色氨酸 - 缬氨酸 - D - 色氨酸 - D - 色氨酸 - 赖氨酸 - 氨基）和NK2ra（苯甲酰基 - 丙氨酸 - 丙氨酸 - D - 色氨酸 - 苯丙氨酸 - D - 脯氨酸 - 脯氨酸 - 亮氨酸 - 氨基）显著降低，但不受阿托品或NK1拮抗剂FK888（N2 - [(4R) - 4 - 羟基 - 1 - (1 - 甲基 - 1H - 吲哚 - 3 - 基)羰基 - L - 脯氨酰基] - N - 甲基 - N - 苯基甲基 - 3 - (2 - 萘基) - L - 丙氨酰胺）的影响，这表明NK2受体参与了其产生过程。毒胡萝卜素和环匹阿尼酸可消除自发性阶段性收缩，蛋白激酶C抑制剂白屈菜红碱和钙调蛋白抑制剂CGS9343B（1,3 - 二氢 - 1 - [1 - [(4 - 甲基 - 4H,6H - 吡咯并[1,2 - a] - [4,1] - 苯并二氮杂䓬 - 4 - 基)甲基] - 4 - 哌啶基] - 2H - 苯并咪唑 - 2 - 酮（1:1）马来酸盐）可使其显著降低，这表明自发性阶段性收缩可能由细胞内钙库释放Ca²⁺以及蛋白激酶C和钙调蛋白依赖性途径介导。在溃疡性结肠炎患者的肌条中，自发性收缩显著降低，而过氧化氢清除剂过氧化氢酶可部分恢复这种降低。然而，神经激肽A的释放未受影响。我们得出结论，人乙状结肠环行平滑肌的自发性阶段性收缩可能由NK2受体激活、细胞内钙库释放钙以及钙调蛋白和蛋白激酶C的激活介导。在溃疡性结肠炎患者中，自发性阶段性收缩减弱，这种减弱可能部分归因于过氧化氢产生过多对乙状结肠环行肌的影响。
