STEREOSPECIFIC ACTIONS OF MISOPROSTOL ON RAT COLONIC ELECTROLYTE TRANSPORT

Misoprostol (Miso) produces a mild, transient diarrhea in some patient s, which is believed to be partly due to intraluminal fluid accumulati on. To better understand this diarrheagenic action, were compared the effects of Miso, its 4 stereoisomers (11R16R, 11R16S, 11S16S, 11S16R), misoprostol free acid (Miso-FA), and 16,16-dimethyl PGE2 (dmPGE2) on rat colonic electrolyte transport in vitro. Increases in short-circuit current (Isc) were measured (after serosal addition) in segments of m ucosa stripped of muscularis and mounted in Ussing chambers. The rank order of apparent potencies, in terms of threshold, were (muM): 11R, 1 6S (1.2) almost-equal-to dmPGE2 (1.0) > Miso-FA (10.0) approximately M iso > > 11R, 16R; 11S, 16R; 11S, 16S (all inactive at 100 muM). The re sponse to dmPGE2 and Miso was attenuated in the presence of the Na+/K/Cl- co-transport inhibitor bumetanide (100 muM). Pretreatment with at ropine (0.1 muM) did not affect the Isc response to Miso, Miso-FA, or dmPGE2. Tetrodotoxin partially attenuated (39+/-9% inhibition) the res ponse to Miso-FA, but did not affect Miso or dmPGE2. In conclusion, Mi so increases Cl- secretion across rat colonic mucosa through a direct action on epithelial cells. The activity resides in the 11R,16S isomer , thus implying a stereospecific interaction at PGE receptors. The eff ect of Miso to stimulate epithelial Cl-secretion might contribute to i ts diarrheagenic action in vivo.