Abstract

Excessive Cl- secretion is the driving force for secretory diarrhea. 17 beta-Estradiol has been shown to inhibit Cl- secretion in rat distal colon through a nongenomic pathway. We examined whether 17 beta-estradiol inhibits Cl- secretion in an animal model of secretory diarrhea and the downstream effectors involved. The effect of 17 beta-estradiol on cholera toxin and heat-stable enterotoxin induced Cl- secretion in rat colonic mucosal sheets was studied by current-voltage clamping. Selective permeabilization of apical or basolateral membranes with amphotericin B or nystatin was used to isolate basolateral channel and apical Cl- channel activity, respectively. 17 beta-Estradiol dose-dependently inhibited secretory responses to both toxins with IC50 values of approximately 1 nM. This effect was female-gender specific, with no inhibition observed in male tissues. 17 beta-Estradiol responses were insensitive to the pure antiestrogen ICI 182,720. 17 beta-Estradiol exerted its effects downstream of enterotoxin-induced production of second messengers (cAMP and cGMP) but was dependent on PKCS activation. In nystatin-permeabilized tissues, apical Cl- currents were unaffected by 17 beta-estradiol treatment while basolateral le current was profoundly inhibited by the hormone. This current was sensitive to the specific KCNQ1 channel inhibitors chromanol 293B and HMR-1556. In conclusion, 17 beta-estradiol inhibits enterotoxin-induced Cl- secretion via a PKCS-dependent mechanism involving inhibition of basolateral KCNQ1 channels. These data elucidate mechanisms of 17 beta-estradiol inhibition of Cl- secretion induced by enterotoxins in intestinal epithelia, which may be relevant for the treatment of diarrheal diseases. (C) 2011 Elsevier Inc. All rights reserved.