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Inhibitory Effect of Furosemide on Non-Selective Voltage-Independent Cation Channels in Human ErythrocytesKucherenko Y.V.a,b · Lang F.a
aDepartment of Physiology Institute I, Eberhard-Karls Universität Tübingen, bInstitute for Problems of Cryobiology and Cryomedicine of the Ukrainian National Academy of Sciences, Kharkov Corresponding Author
Department of Physiology, University of Tübingen
Gmelinstr. 5, D-72076 Tübingen (Germany)
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Background: Furosemide, a loop diuretic inhibiting the renal tubular Na+,K+,2Cl- cotransporter, has been shown to decrease cytosolic Ca2+ concentration ([Ca2+]i) in platelets and erythrocytes. [Ca2+]i in erythrocytes is a function of Ca2+ permeable cation channels. Activation of those channels e.g. by energy depletion or oxidative stress leads to increase of [Ca2+]i, which in turn triggers eryptosis, a suicidal erythrocyte death characterized by cell membrane scrambling. The present study was performed to explore whether furosemide influences the cation channels and thus influences eryptosis. Methods: Cation channel activity was determined by whole-cell patch clamp, [Ca2+]i utilizing Fluo3 fluorescence and annexin V binding to estimate cell membrane scrambling with phosphatidylserine exposure. Results: A 45 min exposure to furosemide (10 and 100 µM) slightly, but significantly decreased cation channel activity and [Ca2+]i in human erythrocytes drawn from healthy individuals. ATP-depletion (> 3 hours, +37°C, 6 mM ionosine and 6 mM iodoacetic acid) enhanced the non-selective cation channel activity, increased [Ca2+]i and triggered cell membrane scrambling, effects significantly blunted by furosemide (10 – 100 µM). Oxidative stress by exposure to tert-butylhydroperoxide (0.1 –1 mM) similarly enhanced the non-selective cation channels activity, increased [Ca2+]i and triggered cell membrane scrambling, effects again significantly blunted by furosemide (10 – 100 µM). Conclusions: The present study shows for the first time that the loop diuretic furosemide applied at micromolar concentrations (10 – 100 µM) inhibits non-selective cation channel activity in and eryptosis of human erythrocytes.
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