EFFECTS OF OKADAIC ACID ON RAT COLON

Effects of okadaic acid (OA) on mucosal damage were examined in rat co lon. OA was sprinkled on rat colon mucosa under observation with an el ectronic-endoscopic system, and OA was also applied to the in vivo mic roscopic field. The OA-induced changes in transepithelial conductance (G(t)) were measured by the Ussing voltage clamp technique. By endosco pic observation, the luminal sprinkling of OA (60 nmol/kg) evoked tran sient microthrombi in the submucosal venule, which was followed by muc osal edema. Histological study after endoscopic observation showed sub mucosal fluid retention, suggesting an increase of vascular permeabili ty. The microthrombi were also detected by in vivo microscopy. By elec trophysiological study after endoscopic observation with and without O A addition, the basal G(t) values were 54 +/- 6.2 and 36.2 +/- 4.2 mS/ cm(2), respectively (P < 0.01). Furthermore in control rats, the seros al addition of OA evoked an increase in G(t) in a concentration-depend ent manner without increasing lactate dehydrogenase release. 2,4,6-Tri aminopyrimidinium inhibited OA-induced G(t) change by 60%. These resul ts indicate that OA evokes an increase in paracellular permeability of epithelium. We conclude that the developed microthrombi are the first key event of OA-induced mucosal damage, followed by an increase in pe rmeability in the submucosal venule and in the paracellular pathway of the epithelium.