Eicosanoids and histamine mediate C5a-induced electrolyte secretion in guinea pig ileal mucosa

Abstract

C5a is a biologically active polypeptide formed during the course of complement activation and is known to possess histamine-releasing and neutrophil chemotactic properties. In the present study, we have demonstrated that C5a can regulate electrolyte transport across guinea pig ileum, and we have investigated its mechanism of action. Segments of ileum stripped of longitudinal muscle were mounted in Ussing chambers (Krebs' buffer, 37 degrees C, 95% O2/5% CO2) for monitoring short-circuit current (Isc). Serosal application of C5a evoked a transient increase in Isc with an EC50 value of 5.0 nM indicating a potent effect. The C5a-induced increase in Isc was abolished by elimination of both Cl- and HCO3- from the Krebs' solution. Pretreatment with the cyclooxygenase inhibitor indomethacin (5 microM), the neurotoxin tetrodotoxin (0.5 microM) and the H1 receptor antagonist pyrilamine (0.5 microM) reduced the effect of C5a, but the muscarinic antagonist atropine (0.5 microM) was without effect. C5a (100 nM) also evoked the release of histamine (measured by radioimmunoassay in the serosal bathing fluid) by 282% of the control value. In conclusion, in the guinea pig ileum C5a stimulates mucosal anion secretion by releasing histamine and cyclooxygenase products of arachidonic acid. The response is also mediated, in part, via non-chloinergic enteric nerves.