Schultheiss Gerhard, Hennig Britta, Schunack Walter, Prinz Gundula, Diener Martin
Institut für Veterinär-Physiologie, Justus-Liebig-Universität Giessen, Frankfurter Str. 100, D-35392 Giessen, Germany.
Eur J Pharmacol. 2006 Sep 28;546(1-3):161-70. doi: 10.1016/j.ejphar.2006.07.047. Epub 2006 Aug 1.
The aim of the present study was to investigate the effect of histamine, a product of e.g. mast cells, on short-circuit current (I(sc)) across rat distal colon. Histamine concentration-dependently stimulated an increase in I(sc), which often was preceded by a transient negative current. Neither a release of neurotransmitters nor a release of prostaglandins contributed to the histamine response. The histamine-induced increase in I(sc) was blocked by the histamine H(1) antagonist, pyrilamine, but was resistant against the histamine H(2) antagonist, cimetidine. Conversely, the histamine H(1) agonist, TMPH (2-(3-trifluoromethylphenyl)histamine), exclusively evoked an increase in I(sc), whereas the histamine H(2) agonist, amthamine, evoked only a decrease in I(sc) suggesting that stimulation of different types of histamine receptors is responsible for the two phases of the response evoked by native histamine. Histamine induces the opening of glibenclamide-sensitive Cl(-) channels and of charybdotoxin-sensitive K(+) channels in the apical membrane as demonstrated by experiments at basolaterally depolarized epithelia. A further action site is the basolateral membrane, because histamine stimulates a charybdotoxin- and tetrapentylammonium-sensitive K(+) conductance in this membrane as observed in tissues, in which the apical membrane was permeabilized with an ionophore, nystatin. The increase in I(sc) evoked by histamine was blocked after depletion of intracellular Ca(2+) stores with cyclopiazonic acid and after blockade of inositol 1,4,5-trisphosphate (IP(3)) receptors, suggesting a release of stored Ca(2+). This was confirmed by the observation that the histamine H(1) agonist TMPH induced an increase in the fura-2 ratio signal of epithelial cells within isolated colonic crypts. Consequently, the mediator histamine seems to stimulate both histamine H(1) and H(2) receptors, from which the former seems to be prominently involved in the induction of epithelial chloride secretion.
本研究的目的是探究组胺（如肥大细胞产生的一种产物）对大鼠远端结肠短路电流（I(sc)）的影响。组胺浓度依赖性地刺激I(sc)增加，且这一过程通常先出现短暂的负电流。神经递质的释放和前列腺素的释放均与组胺反应无关。组胺诱导的I(sc)增加被组胺H(1)拮抗剂吡苄明阻断，但对组胺H(2)拮抗剂西咪替丁具有抗性。相反，组胺H(1)激动剂TMPH（2-(3-三氟甲基苯基)组胺）仅引起I(sc)增加，而组胺H(2)激动剂氨他明仅引起I(sc)降低，这表明刺激不同类型的组胺受体是天然组胺诱发反应两个阶段的原因。如在基底外侧去极化上皮细胞上进行的实验所示，组胺诱导顶端膜上格列本脲敏感的Cl(-)通道和卡律蝎毒素敏感的K(+)通道开放。另一个作用位点是基底外侧膜，因为在顶端膜用离子载体制霉菌素通透的组织中观察到，组胺刺激该膜上卡律蝎毒素和四戊铵敏感的K(+)电导。用环匹阿尼酸耗尽细胞内Ca(2+)储存后以及阻断肌醇1,4,5-三磷酸（IP(3)）受体后，组胺诱发的I(sc)增加被阻断，提示储存的Ca(2+)释放。这一点通过观察组胺H(1)激动剂TMPH诱导分离结肠隐窝内上皮细胞中fura-2比率信号增加得到证实。因此，介质组胺似乎刺激组胺H(1)和H(2)受体，其中前者似乎在诱导上皮氯化物分泌中起主要作用。
