Histamine-induced ion secretion across rat distal colon: Involvement of histamine H1 and H2 receptors

The aim of the present study was to investigate the effect of histamine, a product of e.g. mast cells, on short-circuit current (Isc) across rat distal colon. Histamine concentration-dependently stimulated an increase in Isc, 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 Isc was blocked by the histamine H1 antagonist, pyrilamine, but was resistant against the histamine H2 antagonist, cimetidine. Conversely, the histamine H1 agonist, TMPH (2-(3-trifluoromethylphenyl)histamine), exclusively evoked an increase in Isc, whereas the histamine H2 agonist, amthamine, evoked only a decrease in Isc 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 Isc evoked by histamine was blocked after depletion of intracellular Ca2+ stores with cyclopiazonic acid and after blockade of inositol 1,4,5-trisphosphate (IP3) receptors, suggesting a release of stored Ca2+. This was confirmed by the observation that the histamine H1 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 H1 and H2 receptors, from which the former seems to be prominently involved in the induction of epithelial chloride secretion.