Effect of valproate, sodium 2-propyl-4-pentenoate and sodium 2-propyl-2-pentenoate on renal substrate uptake and ammoniagenesis in the rat.

Abstract

Experiments were carried out in the intact functioning rat kidney to study the effect of valproate (VPA), a widely used antiepileptic drug and an hyperammonemic agent, but usually without clinical relevance, and of two of its metabolites, sodium 2-propyl-4-pentenoate (4-en-VPA) and sodium 2-propyl-2-pentenoate (2-en-VPA), on the renal production of ammonia and on the renal uptake of glutamine, glutamate and of inhibitors of renal ammoniagenesis; mainly lactate, fatty acids, ketone bodies and alpha-ketoglutarate. Administration of VPA and 4-en-VPA stimulated the uptake of glutamine and glutamate and the production of ammonia by the rat kidney, resulting in an increase in the renal venous release of ammonia and in a hyperammonemia. By contrast, no hyperammonemia was observed after the administration of 2-en-VPA which stimulated renal ammoniagenesis to a lesser extent than VPA and 4-en-VPA, resulting in no stimulation of the renal venous release of ammonia. The three compounds tested caused, in a qualitatively different but, in terms of substrate carbons, in a quantitatively similar manner, a significant diminution of the renal uptake of fatty acids, ketone bodies and alpha-ketoglutarate. These results suggest that, in the rat kidney, VPA, 4-en-VPA and 2-en-VPA stimulate the production of ammonia at least in part by reducing the renal uptake and metabolism of ammoniagenesis inhibitors; the more potent stimulation of renal ammoniagenesis caused by VPA and 4-en-VPA also suggest that these compounds exert their stimulatory effect by an additional mechanism.

• Authors: M Elhamri, B Ferrier, M Martin, G Baverel
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 266 Issue 1 Pg. 89-96 (Jul 1993) ISSN: 0022-3565 [Print] United States
• PMID: 8331578 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Fatty Acids, Monounsaturated
• Fatty Acids, Nonesterified
• Ketone Bodies
• 2-propyl-4-pentenoic acid
• 2-propyl-2-pentenoic acid
• Valproic Acid
• Ammonia

Topics

• Ammonia (metabolism)
• Animals
• Fatty Acids, Monounsaturated (pharmacology)
• Fatty Acids, Nonesterified (pharmacokinetics)
• Glomerular Filtration Rate (drug effects)
• Ketone Bodies (pharmacokinetics)
• Kidney (drug effects, metabolism)
• Male
• Rats
• Rats, Wistar
• Renal Circulation (drug effects)
• Stimulation, Chemical
• Urodynamics (drug effects)
• Valproic Acid (pharmacology)