Laboratory of Gastrointestinal Physiology, School of Life Sciences, College of Medical, Veterinary & Life Sciences, Glasgow University, Glasgow G12 8QQ, Scotland, United Kingdom.
Med Hypotheses. 2013 Oct;81(4):601-6. doi: 10.1016/j.mehy.2013.07.010. Epub 2013 Aug 3.
Secretory diarrhoeal disease due to enterotoxins is thought to arise from the enhancement to pathologically high rates of normally occurring chloride ion and therefore fluid secretion from enterocytes. In support of this concept, many enterotoxins increase intestinal short-circuit current, regarded now as faithfully reflecting the increased chloride ion secretion. Contradicting this assumption, STa reduces absorption but does not cause secretion in vivo although short-circuit current is increased in vitro. There is therefore a mismatch between an assumed enterocyte mediated secretory event that should but does not cause net fluid secretion and an undoubtedly increased short-circuit current. It is proposed here that short-circuit current increases are not themselves secretory events but result from interrupted fluid absorption. A noteworthy feature of compounds that inhibit the increase in short-circuit current is that the majority are vasoactive, neuroactive or both. In general, vasodilator substances increase current. An alternative hypothesis for the origin of short-circuit current increases is that these result from reflex induction of electrogenic fluid absorption. This reflex enhances a compensatory response that is also present at a cellular level. An intestinal reflex is therefore proposed by which decreases in interstitial and intravascular volume or pressure within the intestine initiate an electrogenic fluid absorption mechanism that compensates for the loss of electrically neutral fluid absorption. This hypothesis would explain the apparently complex pharmacology of short-circuit current increases since many depressor substances have receptors in common with enterocytes and enteric nerves. The proposed alternative view of the origin of short-circuit current increases assumes that these do not represent chloride secretion from the enterocytes. This view may therefore aid the successful development of anti-diarrhoeal drugs to overcome a major cause of infant mortality worldwide, if short-circuit current data are being persistently misinterpreted. The putative but testable link between interstitial volume or pressure and fluid absorption also provides support for the alternative view of secretion; namely, that enhanced capillary and epithelial cell tight junctional permeability together with increased intracapillary pressure may cause secretion and not chloride exit from the enterocytes.
肠毒素引起的分泌性腹泻病被认为是由于病理上高浓度的正常氯离子以及因此从肠细胞分泌的液体而增强的。支持这一概念，许多肠毒素增加肠短路电流，现在被认为忠实地反映了氯离子分泌的增加。与这一假设相反，STa 在体内减少吸收但不引起分泌，尽管体外短路电流增加。因此，在假定的肠细胞介导的分泌事件与不引起净液体分泌但无疑增加短路电流之间存在不匹配。这里提出的是，短路电流的增加本身不是分泌事件，而是由于中断的液体吸收而导致的。抑制短路电流增加的化合物的一个显著特征是，大多数是血管活性的、神经活性的或两者兼有。一般来说，血管扩张物质增加电流。短路电流增加的另一种假设是，这些是由电致液体吸收的反射诱导引起的。这种反射增强了一种代偿性反应，这种反应也存在于细胞水平。因此，提出了一种肠反射，其中肠内间质和血管内体积或压力的减少会引发一种电致液体吸收机制，补偿电中性液体吸收的损失。这个假设可以解释短路电流增加的复杂药理学，因为许多降压物质与肠细胞和肠神经有共同的受体。增加短路电流的替代观点假设这些并不代表肠细胞的氯离子分泌。如果持续错误地解释短路电流数据，那么这种观点可能有助于成功开发抗腹泻药物来克服全球范围内婴儿死亡率的主要原因。假设但可测试的间质体积或压力与液体吸收之间的联系也为分泌的替代观点提供了支持；即，增强的毛细血管和上皮细胞紧密连接通透性以及增加的毛细血管内压可能导致分泌而不是氯离子从肠细胞中排出。
