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MEMBRANE TRANSPORTERS, ION CHANNELS, AND PUMPS

Genistein stimulates electrogenic Cl^– secretion via phosphodiesterase modulation in the mouse jejunum

Department of Physiology, School of Medical Sciences, University of Otago, Dunedin, New Zealand

Submitted 22 May 2009 ; accepted in final form 15 June 2009

Previously, we demonstrated that genistein stimulated Cl^– secretion in the mouse jejunum (Baker MJ and Hamilton KL, Am J Physiol Cell Physiol 287: C1636–C1645, 2004); however, the mode of action of genistein still remains unclear. Here, we examined the activation of Cl^– secretion by the modulation of phosphodiesterases (PDEs) by genistein (75 µM) in the mouse jejunum with the Ussing short-circuit current (I_sc) technique. Drugs tested included theophylline (10 mM), a nonspecific PDE inhibitor; 8-methoxymethyl-3-isobutyl-1-methylxanthine (8-MM-IBMX; 100 µM), erythro-9-(2-hydroxyl-3-nonyl)-adenine (EHNA; 40 µM), milrinone (100 µM), and rolipram (40 and 100 µM), which are specific inhibitors of PDE1–PDE4, respectively. Theophylline stimulated a bumetanide-sensitive I_sc, indicative of Cl^– secretion, and abolished genistein's stimulatory action on I_sc. Neither 8-MM-IBMX nor EHNA altered the basal I_sc nor did these PDE inhibitors affect the stimulatory action of genistein on the I_sc of the mouse jejunum. Rolipram had no effect on basal I_sc, but it reduced the genistein-stimulated I_sc compared with time-matched control tissues. Milrinone stimulated a concentration-dependent increase in I_sc. Bumetanide (10 µM) inhibited 60 ± 4% of milrinone-induced I_sc. Pretreating tissues with milrinone prevented genistein from stimulating I_sc, and pretreatment with genistein reduced the effect of milrinone on I_sc. H89 (50 µM), a PKA inhibitor, reduced the milrinone-stimulated I_sc. Likewise, H89 reduced the genistein-stimulated I_sc. Here, we demonstrate, for the first time, that genistein activates Cl^– secretion of the mouse jejunum via inhibition of a PDE3-dependent pathway.

PDE3; cystic fibrosis transmembrane conductance regulator; Ca²⁺-activated Cl^– channels; milrinone