Metabolic fate of orally administered cGMP in rats
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POSTER PRESENTATION Open Access Metabolic fate of orally administered cGMP in rats Elaine Liong * , Christopher Graul, Samuel Rivers, Marco Kessler, Gerhard Hannig, Inmaculada Silos-Santiago From 6th International Conference on cGMP: Generators, Effectors and Therapeutic Implications Erfurt, Germany. 28-30 June 2013 Background Activation of membrane guanylate cyclase type C (GC-C) on the luminal surface of the intestinal epithelium by GC- C agonists results in an increase in both intracellular and extracellular levels of cyclic guanosine monophosphate (cGMP). Elevation in intracellular cGMP results in the secretion of chloride and bicarbonate anions into the intestinal lumen through the activation of the cystic fibro- sis transmembrane conductance regulator (CFTR) ion channel. Physiologically, this results in increased intestinal fluid and accelerated transit. Furthermore, an accompany- ing increase in the luminal and submucosal concentration of cGMP is observed as intracellular cGMP is transported out of epithelial cells. In animal models, decreased activity of pain-sensing afferent fibers is likely mediated by increased extracellular cGMP in the submucosa [1]. Compared to the pharmacological effects elicited by the increase in cGMP, less is known about the distribution and metabolic fate of this second messenger that is trans- ported out into the luminal space. Results and conclusion We used radiolabeled 14C-cGMP to assess the presence and metabolism of cGMP following oral administration in different regions of the gastrointestinal tract in rats, as well as in plasma and urine. In tracking the levels of 14C- cGMP and its metabolites we developed a better under- standing of the fate of orally dosed cGMP in the intestinal tract, which has implications for the mechanism of action of cGMP in decreasing gastrointestinal pain. Specifically, we hypothesize that cGMP may act on intestinal afferent fibers while travelling along the small intestine whose pro- jections converge on second order neurons that also receive input from colonic afferents, thus affecting their function. In this context, we showed that more than 50% of the dosed cGMP is available in the small intestine 2 hours after dosing. Little/no 5’GMP or other metabolites were detected in the luminal contents. In contrast, 40-50% of cGMP metabolites were found in tissue samples. Published: 29 August 2013 Reference 1. Castro J, Martin C, Hughes PA, Silos-Santiago A, Kurtz CB, Blackshaw LA, Brierley SM: A novel role of cyclic GMP in colonic sensory neurotransmission in healthy and TNBS-treated mice. Gastroenterology 2011, 140:538. doi:10.1186/2050-6511-14-S1-P39 Cite this article as: Liong et al.: Metabolic fate of orally administered cGMP in rats. BMC Pharmacology and Toxicology 2013 14(Suppl 1):P39. Submit your next manuscript to BioMed Central and take full advantage of: • Convenient online submission • Thorough peer review • No space constraints or color figure charges • Immediate publication on acceptance • Inclusion in PubMed, CAS, Scopus and Google Scholar • Research which is freely available for redistribution Submit your manuscript at www.biomedcentral.com/submit * Correspondence: [email protected] Ironwood Pharmaceuticals, Cambridge, MA 02142, USA Liong et al. BMC Pharmacology and Toxicology 2013, 14(Suppl 1):P39 http://www.biomedcentral.com/2050-6511/14/S1/P39 © 2013 Liong et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Transcript of Metabolic fate of orally administered cGMP in rats
POSTER PRESENTATION Open Access
Metabolic fate of orally administered cGMP in ratsElaine Liong*, Christopher Graul, Samuel Rivers, Marco Kessler, Gerhard Hannig, Inmaculada Silos-Santiago
From 6th International Conference on cGMP: Generators, Effectors and Therapeutic ImplicationsErfurt, Germany. 28-30 June 2013
BackgroundActivation of membrane guanylate cyclase type C (GC-C)on the luminal surface of the intestinal epithelium by GC-C agonists results in an increase in both intracellular andextracellular levels of cyclic guanosine monophosphate(cGMP). Elevation in intracellular cGMP results in thesecretion of chloride and bicarbonate anions into theintestinal lumen through the activation of the cystic fibro-sis transmembrane conductance regulator (CFTR) ionchannel. Physiologically, this results in increased intestinalfluid and accelerated transit. Furthermore, an accompany-ing increase in the luminal and submucosal concentrationof cGMP is observed as intracellular cGMP is transportedout of epithelial cells. In animal models, decreased activityof pain-sensing afferent fibers is likely mediated byincreased extracellular cGMP in the submucosa [1].Compared to the pharmacological effects elicited by theincrease in cGMP, less is known about the distributionand metabolic fate of this second messenger that is trans-ported out into the luminal space.
Results and conclusionWe used radiolabeled 14C-cGMP to assess the presenceand metabolism of cGMP following oral administration indifferent regions of the gastrointestinal tract in rats, aswell as in plasma and urine. In tracking the levels of 14C-cGMP and its metabolites we developed a better under-standing of the fate of orally dosed cGMP in the intestinaltract, which has implications for the mechanism of actionof cGMP in decreasing gastrointestinal pain. Specifically,we hypothesize that cGMP may act on intestinal afferentfibers while travelling along the small intestine whose pro-jections converge on second order neurons that alsoreceive input from colonic afferents, thus affecting theirfunction. In this context, we showed that more than 50%of the dosed cGMP is available in the small intestine2 hours after dosing. Little/no 5’GMP or other metabolites
were detected in the luminal contents. In contrast, 40-50%of cGMP metabolites were found in tissue samples.
Published: 29 August 2013
Reference1. Castro J, Martin C, Hughes PA, Silos-Santiago A, Kurtz CB, Blackshaw LA,
Brierley SM: A novel role of cyclic GMP in colonic sensoryneurotransmission in healthy and TNBS-treated mice. Gastroenterology2011, 140:538.
doi:10.1186/2050-6511-14-S1-P39Cite this article as: Liong et al.: Metabolic fate of orally administeredcGMP in rats. BMC Pharmacology and Toxicology 2013 14(Suppl 1):P39.
Submit your next manuscript to BioMed Centraland take full advantage of:
• Convenient online submission
• Thorough peer review
• No space constraints or color figure charges
• Immediate publication on acceptance
• Inclusion in PubMed, CAS, Scopus and Google Scholar
• Research which is freely available for redistribution
Submit your manuscript at www.biomedcentral.com/submit* Correspondence: [email protected]
Ironwood Pharmaceuticals, Cambridge, MA 02142, USA
Liong et al. BMC Pharmacology and Toxicology 2013, 14(Suppl 1):P39http://www.biomedcentral.com/2050-6511/14/S1/P39
© 2013 Liong et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative CommonsAttribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction inany medium, provided the original work is properly cited.
