Background & Aim: 

Dopamine is produced in large quantities in the upper GI tract, and dopamine deficiency causes severe GI dysfunction. However, the origin and the molecular modes of dopamine action in the GI tract are incompletely understood. Aim: Elucidation of the molecular mode of action of dopamine on duodenal bicarbonate secretion (DBS).

Methods: 

HCO₃^- secretory (JHCO₃^-) rate was measured by single-pass perfusion in anesthetized mice. Immunohistochemical staining was performed to localize the membrane expression of the transporters involved.

Results: 

Because luminally applied dopamine elicited a HCO₃^- secretory response in vivo only in supraphysiologically high concentrations, we applied catechol-o-methyltransferase inhibitors (COMT-inhibitor). Luminal application of 50 mM 3,5-dinitrocatechol (3,5-DNC) just for 10 min. resulted in a biphasic JHCO₃^- response. In CFTR-deficient mice, only the delayed J HCO₃^- response was observed, while mice deficient for the luminal Na+/H+ exchanger (NHE3) displayed only the fast JHCO3- response. Inhibiting a1, a2, and b1 receptors each caused a stimulation of JHCO₃^- in WT mice, possibly reflecting the known inhibition of duodenal HCO₃^- secretion by sympaticoadrenergic stimulation. D1 receptor inhibition inhibited the fast JHCO3- response to 3.5-DNC, while b2 receptor inhibition inhibited both fast and delayed JHCO₃^- response to 3,5-DNC. PDZ-domain adaptor protein NHERF1 (EBP50) expression was important for both the b2-AR mediated translocation of CFTR into the plasma membrane and the 3,5-DNC induced internalization of NHE3.

Conclusions: 

Catecholamines have complex actions on duodenal HCO₃^- secretion. Via D1 receptor and b2-AR, CFTR is activated. NHE3 is internalized via b2-AR activation. Both these effect require NHERF1. These effects likely contribute to the mucosal protective effect of dopamine.