Backround: 

HCO₃^- secretion protects the proximal duodenum against damage by gastric acid. It is long known that a short contact of the duodenal mucosa with acid in vivo causes a long lasting stimulation of HCO₃^- secretion, and this stimulation involves sensory neurons, nitric oxide (NO) and prostaglandins (PGs), as elucidated by inhibitor experiments in vivo. A puzzling fact is that pharmacological blockade of each pathway results in complete inhibition of acid-stimulated duodenal HCO₃^- secretion, suggesting that these signalling events are sequentially arranged. However, the cellular location of these signalling events is unclear.

Aims and methods: 

In order to facilitate the identification of the cellular origin and targets of the signalling events involved in acid-activated HCO₃^- secretion in murine duodenum, acid-stimulated duodenal HCO₃^- secretory response was assessed in anesthetized mice deficient in the inducible NO-synthase (iNOS), the neuronal NO-synthase (nNOS), the endothelial NO-Synthase (eNOS), the cGMP-dependent kinase I (cGKI) as well as in epithelial-specific cGKI ko mice and cGKI ko mice with smooth muscle specific cGKI rescue. Immunohistochemistry was performed to elucidate the cellular location of duodenal nNOS and cGKI.

Results: 

Genetic ablation cGKI and nNOS completely abrogated the acid-induced HCO₃^- secretory response, and smooth-muscle specific rescue of cGKI did not restore it. Genetic ablation of iNOS and epithelial specific cGKI knockout did not alter acid-activated HCO₃^- secretory response, whereas ablation of eNOS caused a partial inhibition.

Conclusions: 

NO release secondary to a short contact of the duodenal epithelium with acid occurs predominantly in the neural system, and, via cGMP, stimulates cGKI in neighboring cells, most likely also of neural origin, both of which are essential in the downstream signalling events involved in eliciting the secretory response.