CONTROL OF COLONIC MOTILITY IN HEALTH AND DISEASE

这项拨款申请的总体目标是调查 大鼠结肠动力控制的肌源性和神经激素机制 健康和疾病。尤其令人感兴趣的是正在迁徙的巨型 收缩(GMC)和结肠运动复合体。两种运动模式都发挥作用 在结肠生理学和病理生理学中的重要作用 能动性。巨大的迁徙收缩产生了大规模的运动和 大便。GMCs的频率高于正常水平会导致腹泻和 紧迫感，而低于正常频率则与 便秘。巨型移行性宫缩的刺激及其临床意义 结肠的更近端起源是导致腹泻的主要因素， 急性呼吸窘迫综合征动物模型的紧迫感和腹部不适 炎症和溃疡性结肠炎。前述下行抑制 巨大的迁移性收缩在群体性运动中很重要，因为它 松弛接收段以容纳较大的体积 刺激伤害性感受器。结肠移行和非移行运动 复合体混合和搅动结肠内容物，并缓慢推动它们在 尾部方向。我们未来四年的具体目标是 L)神经激素的启动和繁殖机制 巨大移行性收缩，2)非肾上腺素能非胆碱能 抑制结肠时相收缩和产生的机制 在巨大的迁移性收缩之前的下行抑制。目标是 第一个目的是研究肠道和中枢神经的控制 巨大的迁移性收缩的启动和传播。这些目标 将通过近距离动脉内和脑室内实现 注射特定的神经递质、受体拮抗剂、介体 应激反应，选择性肌肉切除术和肌间神经切除术，以及 双侧盆神经切面。第二个目标将通过关闭来实现 动脉内注射一氧化氮及相关化合物，血管活性 肠多肽及其拮抗剂和抑制物 氧化合酶和其他特定的拮抗剂来检查组织 非肾上腺素能非胆碱能神经及其在生产中的作用 GMCs和气囊扩张所产生的下降抑制。这个 实验将在有手术器械的清醒狗身上进行，因为 GMCs和结肠运动复合体只在意识状态下出现。 我们的拨款提案涉及对几个重要和 结肠肌源性、神经和激素控制的重要方面 健康和疾病中的运动性，如便秘、腹泻、肠易激综合征和 IBD。对这些机制的新见解将有助于更精确地 结肠动力障碍的诊断及提出适当的建议 使结肠正常化的药剂和外科手术 疾病中的能动性。

The overall objective of this grant application is to investigate the myogenic and neurohormonal mechanisms of control of colonic motility in health and disease. Of particular interest are the giant migrating contractions (GMCs) and colonic motor complexes. Both motor patterns play a significant role in the physiology and pathophysiology of colonic motility. The giant migrating contractions produce mass movements and defecation. A higher than normal frequency of GMCs produces diarrhea and urgency while a lower than normal frequency has been associated with constipation. The stimulation of giant migrating contractions and their more proximal origin in the colon are major factors in producing diarrhea, urgency and abdominal discomfort in experimental models of acute inflammation, and ulcerative colitis. The descending inhibition preceding giant migrative contractions is important in mass movements because it relaxes the receiving segment to accommodate a large volume without stimulating nociceptors. Colonic migrating and non-migrating motor complexes mix and stir colonic contents and propel them slowly in the caudad direction. Our specific aims for the next four years are to investigate l) the neurohormonal mechanisms of initiation and propagation of giant migrating contractions, and 2) nonadrenergic non-cholinergic mechanisms of inhibition of colonic phasic contractions and production of descending inhibition that precedes giant migrating contractions. The goal in the first aim is to investigate the enteric, and central neural control of initiation and propagation of giant migrating contractions. These goals will be achieved by close-intraarterial and intracerebroventricular injections of specific neurotransmitters, receptor antagonists, mediators of stress response, selective myotomies and myenteric neurectomies, and bilateral pelvic nerve section. The second aim will be achieved by close intraarterial injections of nitric oxide and related compounds, vasoactive intestinal polypeptide (VIP) and VIP antagonists and inhibitors of nitric oxide synthase and other specific antagonists to examine the organization of non-adrenergic non-cholinergic nerves, and their role in producing descending inhibition produced by GMCs and balloon distension. The experiments will be done in surgically instrumented conscious dogs because the GMCs and colonic motor complexes occur only in the conscious state. Our grant proposal addresses investigation of several important and significant aspects of myogenic, neural and hormonal control of colonic motility in health and disease, such as constipation, diarrhea, IBS and IBD. New insights into these mechanisms will help in more precise diagnosis of colonic motility disorders and in proposing appropriate pharmaceutical agents and surgical procedures to normalize colonic motility in disease.