Tamai H, Gaginella T S
Searle Research and Development, Skokie, IL 60077.
Free Radic Res Commun. 1993;19(4):229-39. doi: 10.3109/10715769309056511.
Nitric Oxide (NO) is synthesized in the intestinal tract and may serve as a physiological regulator of intestinal ion transport and/or a pathophysiologic mediator of secretory diarrhea associated with inflammatory mucosal diseases. Indirect approaches, employing inhibitors of nitric oxide synthase or compounds capable of donating NO in solution, have been used to demonstrate the effects on gastrointestinal muscle and the mucosa. To determine directly whether nitric oxide itself is capable of stimulating electrolyte secretion we mounted muscle-stripped rat distal colon in Ussing chambers and monitored short-circuit current (Isc), as an indicator of effects on mucosal ion transport. Comparisons were made to sodium nitroprusside (SNP). NO and SNP stimulated concentration-dependent (0.1 microM to 100 microM) increases in Isc, with NO being more potent than SNP. The EC50 for NO was approximately 8 microM compared to a value < 20 microM for SNP. The response to NO was immediate. In contrast, SNP required a mean lag-time of 41 +/- 4 seconds, and a significantly longer time was required for SNP to reach its maximum effect. The response to both of these agonists was blocked by bumetanide, indicating that they were stimulating a chloride ion secretory response. The cyclooxygenase inhibitor piroxicam, the neurotoxin tetrodotoxin and the inhibitor of guanylate cyclase, methylene blue, all inhibited the response to both agonists. These studies demonstrate that NO itself can stimulate chloride secretion by the rat colonic mucosa through a prostaglandin-dependent, and partially neural mechanism that may involve guanylate cyclase.
一氧化氮（NO）在肠道中合成，可能作为肠道离子转运的生理调节剂和/或与炎症性黏膜疾病相关的分泌性腹泻的病理生理介质。采用一氧化氮合酶抑制剂或能够在溶液中释放NO的化合物的间接方法，已被用于证明其对胃肠道肌肉和黏膜的影响。为了直接确定一氧化氮本身是否能够刺激电解质分泌，我们将去除肌肉的大鼠远端结肠安装在Ussing室中，并监测短路电流（Isc），作为对黏膜离子转运影响的指标。与硝普钠（SNP）进行了比较。NO和SNP均刺激Isc浓度依赖性（0.1微摩尔至100微摩尔）增加，其中NO比SNP更有效。NO的半数有效浓度（EC50）约为8微摩尔，而SNP的值<20微摩尔。对NO的反应是即时的。相比之下，SNP需要平均41±4秒的延迟时间，并且SNP达到其最大效应需要明显更长的时间。布美他尼可阻断对这两种激动剂的反应，表明它们正在刺激氯离子分泌反应。环氧化酶抑制剂吡罗昔康、神经毒素河豚毒素和鸟苷酸环化酶抑制剂亚甲蓝均抑制对这两种激动剂的反应。这些研究表明，NO本身可通过依赖前列腺素且可能涉及鸟苷酸环化酶的部分神经机制刺激大鼠结肠黏膜的氯离子分泌。
