Phosphodiesterase isozymes involved in regulation of HCO3- secretion in isolated mouse duodenum in vitro

We examined the effects of various isozyme-selective PDE inhibitors on HCO(3)(-) secretion in the mouse duodenum in vitro and investigated which type(s) of phosphodiesterase (PDE) isozymes are involved in the response to PGE(2) and NO. The duodenal mucosa of male DDY mice was stripped of the muscle layer and mounted on an Ussing chamber, and HCO(3)(-) secretion was measured at pH 7.0 by a pH-stat method using 2mM HCl. Both PGE(2) and NOR-3 (NO donor) increased HCO(3)(-) secretion in the mouse duodenum in vitro, and the response to PGE(2) was inhibited by both EP3 and EP4 antagonists but not EP1 antagonist, while that to NOR-3 was inhibited by methylene blue. IBMX, a nonselective PDE inhibitor, significantly increased basal HCO(3)(-) secretion and potentiated the responses to both PGE(2) and NOR-3. Likewise, vinpocetine (PDE1 inhibitor) and cilostamide (PDE3 inhibitor) also increased the basal secretion at high doses and potentiated the HCO(3)(-) response to PGE(2) at doses that had no effect by themselves on the basal secretion. By contrast, the HCO(3)(-) stimulatory action of NOR-3 was significantly potentiated by vinpocetine but not cilostamide. Inhibitors of other PDE subtypes had no effect on the HCO(3)(-) secretion under basal or stimulated conditions. Both PDE1 and PDE3 mRNAs were expressed in the duodenal mucosa. These results suggested that PDE1 and PDE3 are involved in the regulation of duodenal HCO(3)(-) secretion and that the response to PGE(2) is associated with both PDE1 and PDE3, while the response to NO is mainly modulated by PDE1.