Kinin-induced anion-dependent secretion in porcine ileum: Characterization and involvement of opioid- and cannabinoid-sensitive enteric neural circuits

The intestinal secretory actions of the proinflammatory peptide kallidin ( lysyl-bradykinin) are mediated partially by enteric neurons. We hypothesized that kallidin produces neurogenic anion secretion through opioid- and cannabinoid-sensitive enteric neural pathways. Changes in short-circuit current (I-sc) across sheets of porcine ileal mucosa-submucosa mounted in Ussing chambers were measured in response to kallidin (1 muM) or drugs added to the contraluminal bathing medium. Kallidin transiently increased I-sc, an effect reduced after inhibition of neuronal conduction by 0.1 muM saxitoxin, cyclooxygenase inhibition by 10 muM indomethacin, or kinin B-2 receptor blockade by 1 muM D-arginyl-L-arginyl-L-prolyltrans-4- hydroxy-L-prolylglycyl-3-(2-thienyl)-L-alanyl-L-seryl-D-1,2,3,4- tetrahydro-3-isoquinolinecarbonyl-L-(2alpha,3beta,7alphabeta)-octahydro-1H- indole-2-carbonyl-L-arginine (HOE-140). Its action was dependent upon extracellular Cl- or HCO3- ions, but was resistant to 10 muM bumetanide or 0.3 mM 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid, and seemed to involve luminal alkalinization as measured by pH-stat titration. Kallidin-induced I-sc elevations were sensitive to saxitoxin in tissues bathed in Cl--, but not HCO3--deficient media. Tissues pretreated with 0.1 muM [D-Pen(2,5)]enkephalin, a selective delta-opioid agonist, displayed reduced I-sc responses to kallidin; this effect was prevented by the delta-opioid antagonist naltrindole. At a contraluminal concentration of 1 muM, the cannabinoid receptor agonist (6aR)-trans-3-(1,1-dimethylheptyl)6a, 7,10,10a-tetrahydro-1-hydroxy-6,6-dimethyl-6H-dibenzo[ b,d] pyran-9-methanol (HU-210) also attenuated responses to kallidin. Proinflammatory kinins seem to stimulate neurogenic anion secretion in porcine ileum by activating enteric neural circuits expressing inhibitory opioid and possibly cannabinoid receptors.