Hurst R D, Ballantyne G H, Modlin I M
Department of Surgery, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
J Surg Res. 1995 Dec;59(6):631-5. doi: 10.1006/jsre.1995.1216.
Octreotide (SMS, synthetic miniature somatostatin) effectively alleviates the secretory diarrhea of the malignant carcinoid syndrome. Although SMS inhibits tumor release of serotonin (5HT) and other bioactive agents, it also inhibits the diarrhea in patients who continue to exhibit elevated serum levels of 5HT. This observation suggest that SMS may directly inhibit mediator-stimulated intestinal ion secretion at the mucosal level. To test this hypothesis, intestinal ion secretion was studied in rabbit ileal mucosa mounted in Ussing chambers. Maximal changes in short circuit current (delta Isc) were observed as an indicator of mucosal ion secretion. The application of pathophysiologic concentrations of 5HT (10(-5) M) to the mucosal preps resulted in a delta Isc of 52 +/- 6 microA/cm2. This 5HT-stimulated delta Isc was significantly inhibited by serosal furosemide (10(-3) M) or use of a chloride-depleted medium, indicating that 5HT stimulates electrogenic chloride secretion in the rabbit ileum. Pretreatment with a therapeutic concentration of SMS (10(-8) M) resulted in a significant inhibition of 5HT-stimulated electrogenic Cl- secretion (9 +/- 1 microA/cm2) (P < 0.005). This inhibitory effect of SMS was not seen in tissue pretreated with pertussis toxin. The results of these experiments demonstrate that octreotide inhibits 5HT-stimulated electrogenic chloride secretion at the mucosal level. Additionally this inhibitory effect of octreotide is likely mediated by activation of the inhibitory subunit of membrane-bound GTP-binding regulatory proteins. These results thus provide experimental evidence in support of the ability of SMS to ameliorate the carcinoid diarrhea by a direct effect on stimulated mucosal ion secretion.
奥曲肽（SMS，合成型微小生长抑素）能有效缓解恶性类癌综合征的分泌性腹泻。尽管SMS能抑制肿瘤释放血清素（5-羟色胺，5HT）及其他生物活性物质，但对于血清5HT水平持续升高的患者，它也能抑制腹泻。这一观察结果提示，SMS可能在黏膜水平直接抑制介质刺激的肠道离子分泌。为验证这一假说，我们在置于尤斯灌流小室的兔回肠黏膜中研究了肠道离子分泌。观察短路电流（ΔIsc）的最大变化作为黏膜离子分泌的指标。将病理生理浓度的5HT（10⁻⁵ M）应用于黏膜制剂，导致ΔIsc为52±6微安/平方厘米。这种5HT刺激的ΔIsc被浆膜侧呋塞米（10⁻³ M）或使用无氯培养基显著抑制，表明5HT刺激兔回肠中的电中性氯分泌。用治疗浓度的SMS（10⁻⁸ M）预处理导致5HT刺激的电中性Cl⁻分泌显著抑制（9±1微安/平方厘米）（P<0.005）。在百日咳毒素预处理的组织中未观察到SMS的这种抑制作用。这些实验结果表明，奥曲肽在黏膜水平抑制5HT刺激的电中性氯分泌。此外，奥曲肽的这种抑制作用可能是由膜结合鸟苷酸结合调节蛋白抑制亚基的激活介导的。因此，这些结果提供了实验证据，支持SMS通过直接作用于刺激的黏膜离子分泌来改善类癌腹泻的能力。
