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J. Biol. Chem., Vol. 283, Issue 22, 15063-15071, May 30, 2008

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3-Isobutylmethylxanthine Inhibits Hepatic Urea Synthesis

PROTECTION BY AGMATINE^*

From the Children's Hospital of Philadelphia, Division of Child Development, Rehabilitation Medicine, and Metabolic Disease, Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104

We previously showed that agmatine stimulated hepatic ureagenesis. In this study, we sought to determine whether the action of agmatine is mediated via cAMP signaling. A pilot experiment demonstrated that the phosphodiesterase inhibitor, 3-isobutylmethylxanthine (IBMX), inhibited urea synthesis albeit increased [cAMP]. Thus, we hypothesized that IBMX inhibits hepatic urea synthesis independent of [cAMP]. We further theorized that agmatine would negate the IBMX action and improve ureagenesis. Experiments were carried out with isolated mitochondria and ¹⁵NH₄Cl to trace [¹⁵N]citrulline production or [5-¹⁵N]glutamine and a rat liver perfusion system to trace ureagenesis. The results demonstrate that IBMX induced the following: (i) inhibition of the mitochondrial respiratory chain and diminished O₂ consumption during liver perfusion; (ii) depletion of the phosphorylation potential and overall hepatic energetic capacity; (iii) inhibition of [¹⁵N]citrulline synthesis; and (iv) inhibition of urea output in liver perfusion with little effect on [N-acetylglutamate]. The results indicate that IBMX directly and specifically inhibited complex I of the respiratory chain and carbamoyl-phosphate synthase-I (CPS-I), with an EC₅₀ about 0.6 mM despite a significant elevation of hepatic [cAMP]. Perfusion of agmatine with IBMX stimulated O₂ consumption, restored hepatic phosphorylation potential, and significantly stimulated ureagenesis. The action of agmatine may signify a cascade effect initiated by increased oxidative phosphorylation and greater ATP synthesis. In addition, agmatine may prevent IBMX from binding to one or more active site(s) of CPS-I and thus protect against inhibition of CPS-I. Together, the data may suggest a new experimental application of IBMX in studies of CPS-I malfunction and the use of agmatine as intervention therapy.

Received for publication, January 8, 2008 , and in revised form, March 27, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants DK-53761 (to I. N.), DK047870, U54RR019453, and HD26971. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Division of Child Development, Abramson Pediatrics Research Center, Rm. 510C, 34th St. and Civic Center Blvd., Philadelphia, PA 19104-4318. Fax: 215-590-5199.

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