EICOSANOIDS AND HISTAMINE MEDIATE C5A-INDUCED ELECTROLYTE SECRETION IN GUINEA-PIG ILEAL MUCOSA

C5a is a biologically active polypeptide formed during the course of c omplement activation and is known to possess histamine-releasing and n eutrophil chemotactic properties. In the present study, we have demons trated that C5a can regulate electrolyte transport across guinea pig i leum, and we have investigated its mechanism of action. Segments of il eum stripped of longitudinal muscle were mounted in Ussing chambers (K rebs' buffer, 37 degrees C, 95% O-2/5% CO2) for monitoring short-circu it current (Isc). Serosal application of C5a evoked a transient increa se in Isc with an EC(50) value of 5.0 nM indicating a potent effect. T he C5a-induced increase in Isc was abolished by elimination of both Cl - and HCO3- from the Krebs' solution. Pretreatment with the cyclooxyge nase inhibitor indomethacin (5 mu M), the neurotoxin tetrodotoxin (0.5 mu M) and the H-1 receptor antagonist pyrilamine (0.5 mu M) reduced t he effect of C5a, but the muscarinic antagonist atropine (0.5 mu M) wa s without effect. C5a (100 nM) also evoked the release of histamine (m easured by radioimmunoassay in the serosal bathing fluid) by 282% of t he control value. In conclusion. in the guinea pig ileum C5a stimulate s mucosal anion secretion by releasing histamine and cyclooxygenase pr oducts of arachidonic acid. The response is also mediated, in part, vi a non-chloinergic enteric nerves.