Submitted on June 12, 2007
Accepted on November 1, 2007
Pharmacological analysis of components of the change in transmural potential difference evoked by distension of rat proximal small intestine in vivo
Marie Helene Larsson1*, Maria Sapnara2, Evan A Thomas3, Joel Charles Bornstein3, Erik Lindstrom4, David J Svensson5, and Henrik Sjovall6
1 Integrative Pharmacology, AstraZeneca R&D Molndal, Molndal, Sweden
2 Internal medicine, Sahlgrenska university hospital, Goteborg, Sweden
3 Physiology, University of Melbourne, Parkville, Victoria, Australia
4 Integrative Pharmacology, AstraZeneca R&D, Molndal, Sweden
5 Biostatistics, Clinical Information Science, AstraZeneca, Molndal, Sweden
6 Internal Medicine, Sahlgren's Academy, Goteborg, Sweden
* To whom correspondence should be addressed. E-mail: marie.h.larsson{at}astrazeneca.com.
The reflex response to distension of the small intestine in vivo is complex and not well understood. The aim of this study was to characterize the neural mechanisms contributing to the complex time course of the intestinal secretory response to distension. Transmucosal potential difference (PD) was used as a marker for mucosal chloride secretion, which reflects the activity of the secretomotor neurons. Graded distensions (5, 10 and 20 mmHg) of distal rat duodenum with saline for 5 min induced a biphasic PD response with an initial peak (rapid response) followed by a plateau (sustained response). The rapid response was significantly reduced by the neural blockers tetrodotoxin and lidocaine (given serosally) and by i.v. administration of the ganglionic blocker hexamethonium and the NK1 receptor antagonist SR 140333. Serosal TTX and i.v. SR 140333 significantly reduced the sustained response, which was also reduced by the NK3 receptor antagonist talnetant and by the VPAC-antagonist [4Cl-D-Phe6, Leu17]-VIP. Serosal lidocaine and i.v. hexamethonium had no significant effect on this component. Inhibition of nitric oxide synthase had no effect on any of the components of the PD response to distension. The PD response to distension thus seems to consist of two components, a rapidly activating and adapting component operating via nicotinic transmission and NK1 receptors, and a slow component operating via VIP-ergic transmission and involving both NK1 and NK3 receptors.
