Abstract
Abstract Background and Aims Loop diuretics are highly potent agents, particularly beneficial in patients with impaired kidney function or heart failure exacerbation. Furosemide, due to fast onset and short time of action, remains the most commonly used drug from this class of diuretics. Inhibition of sodium-potassium-chloride cotransporter (NKCC2) in the thick ascending limb of Henle's loop is the main mechanism of furosemide's action. Other effects of furosemide, like modulation of potassium channels activity or activation of prostaglandin synthesis, were previously described. It was postulated that furosemide may exacerbate kidney injury in a dose dependent manner. Kynurenic acid (KYNA) is a tryptophan derivative synthesized from L-kynurenine (L-KYN) by kynurenine aminotransferases (KATs). KAT I and KAT II are the main KAT isoenzymes. Non-selective antagonism towards ionotropic glutamatergic receptors, as well as activation of aryl hydrocarbon receptors and the α7 nicotinic acetylcholine receptors are known mechanisms of KYNA’s action. KYNA was shown to regulate water and electrolyte balance through natriuretic effect. By some researchers KYNA, together with other tryptophan metabolites, is classified as uremic toxin. We aimed to analyze the influence of furosemide, widely used loop diuretic, on KYNA’s synthesis and the activity of both KATs in rat kidney in vitro. Method The influence of furosemide on KYNA’s production with KAT I and KAT II activity was tested in rat kidney homogenates in vitro after 2 hours incubation in the presence of KYNA precursor L-KYN and furosemide. Diuretic was examined at increasing concentrations: 1 μM, 10 μM, 50 μM, 100 μM, 500 μM and 1 mM. Enzymatic KYNA’s production was measured by high performance liquid chromatography (HPLC) with fluorometric detector. All applicable international, national and institutional guidelines for the care and use of animals were followed. Results Furosemide at 500 μM and 1 mM lowered KYNA formation in kidney homogenates in vitro to 80% (p < 0.05) and 70% (p < 0.05) of control value, respectively. At 1 mM concentration furosemide inhibited kidney KAT I activity in vitro to 38% (p < 0.01) of control value. Similarly, furosemide at 500 μM and 1 mM concentration decreased kidney KAT II activity in vitro to 53% (p < 0.01) and 18% (p < 0.001) of control value, respectively. Conclusion Our study presents a novel mechanism of action of furosemide. Inhibition of KYNA synthesis in the kidney by furosemide may have influence on kidney function.
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