Effect of valproate, sodium 2-propyl-4-pentenoate and sodium 2-propyl-2-pentenoate on renal substrate uptake and ammoniagenesis in the rat.
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.
Elhamri
M
M
Laboratoire de Physiopathologie Métabolique et Rénale et de Spectroscopie RMN, Faculté de Médecine Alexis Carrel, Lyon, France.
Ferrier
B
B
Martin
M
M
Baverel
G
G
D000641:Ammonia / Q000378:metabolism*; D000818:Animals; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology*; D005230:Fatty Acids, Nonesterified / Q000493:pharmacokinetics; D005919:Glomerular Filtration Rate / Q000187:drug effects; D007657:Ketone Bodies / Q000493:pharmacokinetics; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D012079:Renal Circulation / Q000187:drug effects; D013268:Stimulation, Chemical; D014563:Urodynamics / Q000187:drug effects; D014635:Valproic Acid / Q000494:pharmacology*
D005229:Fatty Acids, Monounsaturated; D005230:Fatty Acids, Nonesterified; D007657:Ketone Bodies; C045022:2-propyl-4-pentenoic acid; C014168:2-propyl-2-pentenoic acid; D014635:Valproic Acid; D000641:Ammonia