HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 290/5/E940    most recent 00173.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (4) Citing Articles via Google Scholar Google Scholar Articles by Guinzberg, R. Articles by Piña, E. Search for Related Content PubMed PubMed Citation Articles by Guinzberg, R. Articles by Piña, E.

Inosine released after hypoxia activates hepatic glucose liberation through A₃ adenosine receptors

¹Departamentos de Bioquímica, Facultad de Medicina; ²Nutrición Animal y Bioquímica, Facultad de Medicina Veterinaria y Zootecnia; and ³Unidad de Biomedicina, Facultad de Estudios Superiores-Iztacala, Universidad Nacional Autónoma de México, Mexico City, Mexico

Submitted 20 April 2005 ; accepted in final form 3 December 2005

Inosine, an endogenous nucleoside, has recently been shown to exert potent effects on the immune, neural, and cardiovascular systems. This work addresses modulation of intermediary metabolism by inosine through adenosine receptors (ARs) in isolated rat hepatocytes. We conducted an in silico search in the GenBank and complete genomic sequence databases for additional adenosine/inosine receptors and for a feasible physiological role of inosine in homeostasis. Inosine stimulated glycogenolysis (40%, EC₅₀ 4.2 x 10^–9 M), gluconeogenesis (40%, EC₅₀ 7.8 x 10^–9 M), and ureagenesis (130%, EC₅₀ 7.0 x 10^–8 M) compared with basal values; these effects were blunted by the selective A₃ AR antagonist 9-chloro-2-(2-furanyl)-5-[(phenylacetyl)amino][1,2,4]-triazolo[1,5-c]quinazoline (MRS 1220) but not by selective A₁, A_2A, and A_2B AR antagonists. In addition, MRS 1220 antagonized inosine-induced transient increase (40%) in cytosolic Ca²⁺ and enhanced (90%) glycogen phosphorylase activity. Inosine-induced Ca²⁺ mobilization was desensitized by adenosine; in a reciprocal manner, inosine desensitized adenosine action. Inosine decreased the cAMP pool in hepatocytes when A₁, A_2A, and A_2B AR were blocked by a mixture of selective antagonists. Inosine-promoted metabolic changes were unrelated to cAMP decrease but were Ca²⁺ dependent because they were absent in hepatocytes incubated in EGTA- or BAPTA-AM-supplemented Ca²⁺-free medium. After in silico analysis, no additional cognate adenosine/inosine receptors were found in human, mouse, and rat. In both perfused rat liver and isolated hepatocytes, hypoxia/reoxygenation produced an increase in inosine, adenosine, and glucose release; these actions were quantitatively greater in perfused rat liver than in isolated cells. Moreover, all of these effects were impaired by the antagonist MRS 1220. On the basis of results obtained, known higher extracellular inosine levels under ischemic conditions, and inosine’s higher sensitivity for stimulating hepatic gluconeogenesis, it is suggested that, after tissular ischemia, inosine contributes to the maintainence of homeostasis by releasing glucose from the liver through stimulation of A₃ ARs.

ischemia; calcium; urea; phylogenetic analysis; homeostasis

This article has been cited by other articles:

				V. L. Kolachala, R. Bajaj, M. Chalasani, and S. V. Sitaraman Purinergic receptors in gastrointestinal inflammation Am J Physiol Gastrointest Liver Physiol, February 1, 2008; 294(2): G401 - G410. [Abstract] [Full Text] [PDF]