Effect of putative phospholipase A2 inhibitors on acetic acid-induced acute colitis in the rat.
Phospholipase activation may play an important role in ulcerative colitis. This hypothesis was tested by evaluating the effect of two non-selective phospholipase (PL) A2 inhibitors, quinacrine and p-bromophenacyl-bromide (pBPB), on acetic acid-induced colitis in the rat. The calcium 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 uniform colitis after 4 days. The severity of colitis was evaluated histologically, by measuring myeloperoxidase (MPO) activity and by determining plasma exudation into the lumen of the colon (permeability) with 125I-labelled albumin given intravenously. All three putative PLA2 inhibitors tested were found to prevent the development of colitis. Intravenous administration of quinacrine 10 mg kg-1 at 30 min before instillation 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. Intracolonic administration of either quinacrine or pBPB also prevented acetic acid-induced colitis. However, three doses, starting immediately after acetic acid administration and repeated on the first and second days, were needed to achieve this, whereas one dose produced only a partial effect. PLA2 may play an important role in acetic acid-induced colitis and inhibition of its activity may offer an alternative mode of treatment in ulcerative colitis.
Fabia
R
R
Department of Surgery, Lund University, Sweden.
Ar'Rajab
A
A
Willén
R
R
Andersson
R
R
Bengmark
S
S
D000085:Acetates; D019342:Acetic Acid; D000098:Acetophenones / Q000627:therapeutic use; D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D003106:Colon / Q000201:enzymology / Q000473:pathology; D004789:Enzyme Activation; D005260:Female; D007413:Intestinal Mucosa / Q000473:pathology; D009195:Peroxidase / Q000378:metabolism; D010741:Phospholipases A / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D054467:Phospholipases A2; D011796:Quinacrine / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D014700:Verapamil / Q000627:therapeutic use
D000085:Acetates; D000098:Acetophenones; D014700:Verapamil; D009195:Peroxidase; D010741:Phospholipases A; D054467:Phospholipases A2; D011796:Quinacrine; C006821:4-bromophenacyl bromide; D019342:Acetic Acid