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Abstract: SA-PO260

Torasemide Decreases Kynurenic Acid Production in Rat Kidney In Vitro

Session Information

Category: Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

  • 2000 Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

Authors

  • Zakrocka, Izabela, Uniwersytet Medyczny w Lublinie, Lublin, Lubelskie, Poland
  • Zaluska, Wojciech T., Uniwersytet Medyczny w Lublinie, Lublin, Lubelskie, Poland
Background

Loop diuretics are one of the most widely used agents in the treatment of congestive heart failure or arterial hypertension and related edemas. Torasemide is known to have longer time of action compared to other class representatives and thus more often chosen to stimulate diuresis. It was speculated that torasemide by volume depletion can be responsible for impaired kidney function, however direct nephrotoxic effect cannot be excluded.
Tryptophan metabolites are well described uremic toxins. Among them kynurenic acid (KYNA) presents ambiguous effects. KYNA is a broad spectrum glutamatergic receptors antagonist, an agonist of cholinergic alpha-7-nicotinic receptors and a ligand of aryl hydrocarbon receptors. Direct precursor of KYNA, kynurenine (KYN) is metabolized through kynurenine aminotransferases (KATs). In animal models of hypertension KYNA was reported to cause natriuresis and lower the heart rate. On the other hand, it was observed that KYNA accumulated in the body proportionally to kidney function decline in animal and human studies.
The aim of our study was to examine the influence of torasemide on KYNA synthesis and KATs isoenzymes activity, KAT I and KAT II, in rat kidney in vitro.

Methods

KYNA production and enzymes activity was analyzed in kidney homogenates and on purified enzymes after 2 hours incubation in the presence of L-KYN and torasemide in 6 different concentrations (1 µM, 10 µM, 50 µM, 100 µM, 500 µM, 1 mM). Due to limited drug’s solubility torasemide was tested in kidney homogenates up to 500 µM concentration, whereas enzymes activity was analyzed up to 1 mM concentration. The amount of formed KYNA was quantified by high-performance liquid chromatography.

Results

Torasemide at 500 µM concentration decreased KYNA production to 68 % (p < 0.05) of control value. At 500 µM and 1 mM concentration torasemide inhibited KAT I activity to 78 % (p < 0.05) and 43 % (p < 0.05) of control value, respectively. Only at 1 mM concentration torasemide lowered KAT II activity to 17 % (p < 0.01) of control value.

Conclusion

We show for the first time that torasemide inhibits KYNA production and KATs activity in rat kidney in vitro. Further studies are warranted to investigate the impact of presented results on kidney function.