Proceedings of The Physiological Society
University College London (2011) Proc Physiol Soc 24, C12 and PC12
Loss of neuronal cGMP kinase I abolishes acid-induced HCO3- secretion and predisposes mice to bleeding duodenal ulcers
A. K. Singh1, B. Spiessberger2, W. Zheng1, F. Xiao1, R. Lukowski2, J. W. Wegener2, P. Weinmeister2, D. Saur3, S. Klein3, M. Schemann4, D. Krueger4, U. E. Seidler1, F. Hofmann2
1. Dept. of Gastroenterology, Hannover Medical School, Hannover, Germany. 2. Institute of Pharmacology, Technical University of Munich, Munich, Germany. 3. Dept. of Internal Medicine II, Technical University of Munich, Munich, Germany. 4. Human Biology, Technical University of Munich, Munich, Germany.
Background and Aims: Brief contact of the duodenal mucosa with luminal acid elicits a long lasting HCO3- secretory response, which is thought to be one of the major protective mechanisms of the duodenal mucosa against acid damage. The H+-induced signaling pathways are not fully understood, and direct experimental evidence for a direct link between disturbed H+-induced HCO3- secretory response and duodenal ulcer development is lacking. Here we describe the spontaneous development of bleeding ulcers and early death in cGMP kinase type I knockout (cGKI-/-) mice that is amenable to proton pump inhibitor treatment, and investigate the underlying signaling defect. Methods and Results: Anesthetized, luminally perfused cGKI-/- mice were unable to respond to a physiological H+ stimulus with a HCO3- secretory response. Smooth-muscle selective cGKI knockin rescued the motility disturbance but not the defective HCO3- secretion or the ulcus phenotype. H+-induced HCO3- secretion was not attenuated by selective inactivation of the cGKI gene in interstitial cells of Cajal or in enterocytes, but was abolished by inactivation of cGKI in nestin-expressing cells, demonstraing that cGKI in the central nervous system is required for sensing luminal acid and responding to it with increased duodenal bicarbonate output. cGKI was found to be strongly expressed in the brainstem nucleus tractus solitarius. Accordingly, truncation of the subdiaphragmal N. vagus (under isoflurane inhalation anaesthesia: 1.2-2.2% in 30% O2-70% N2) significantly diminished H+-induced HCO3- secretion in WT mice, whereas stimulation of the subdiaphragmal N. vagus elicited a similar HCO3- secretory response in cGKI-/- ,nestin-cGKI-/- and WT mice. Gastric acidity did not differ between cGKI-/- and WT mice. Conclusions: These findings show that protection of the duodenum from acid injury requires neuronal cGKI, and that its lack results in the formation of duodenal ulcers.
Where applicable, experiments conform with Society ethical requirements