EFFECT OF PUTATIVE PHOSPHOLIPASE-A2 INHIBITORS ON ACETIC ACID-INDUCEDACUTE COLITIS IN THE RAT

Phospholipase activation may play an important role in ulcerative coli tis. This hypothesis was tested by evaluating the effect of two non-se lective phospholipase (PL) A2 inhibitors, quinacrine and p-bromophenac yl-bromide (pBPB), on acetic acid-induced colitis in the rat. The calc ium antagonist verapamil, which may also act as a PLA2 inhibitor, was also tested. Acute colitis was induced in an isolated colonic segment by instillation of 4 per cent acetic acid for 15 s; this induces a uni form colitis after 4 days. The severity of colitis was evaluated histo logically, by measuring myeloperoxidase (MPO) activity and by determin ing plasma exudation into the lumen of the colon (permeability) with I -125-labelled albumin given intravenously. All three putative PLA2 inh ibitors tested were found to prevent the development of colitis. Intra venous administration of quinacrine 10 mg kg-1 at 30 min before instil lation of acetic acid resulted in a normal mucosal appearance, normal MPO activity and a significantly reduced increase in plasma exudation into the colon. A similar effect was achieved using verapamil. Intraco lonic administration of either quinacrine or pBPB also prevented aceti c acid-induced colitis. However, three doses, starting immediately aft er acetic acid administration and repeated on the first and second day s, were needed to achieve this, whereas one dose produced only a parti al effect. PLA2 may play an important role in acetic acid-induced coli tis and inhibition of its activity may offer an alternative mode of tr eatment in ulcerative colitis.