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International Journal of Physiology and Pathophysiology

Publication de 4  numéros par an

ISSN Imprimer: 2155-014X

ISSN En ligne: 2155-0158

SJR: 0.116

New Fluorine-Containing Openers of ATP-sensitive Potassium Channels Flocalin and Tioflocalin Inhibit Calcium-Induced Mitochondrial Pore Opening in Rat Hearts

Volume 5, Numéro 4, 2014, pp. 333-343
DOI: 10.1615/IntJPhysPathophys.v5.i4.60
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RÉSUMÉ

In vitro experiments on the mitochondria isolated from the rat's heart, we studied the effects of flocalin and tioflocalin, the openers of ATP-sensitive potassium channels (KATP-channels), on the calcium-induced mitochondrial permeability transition pore (MPTP) opening. Both flocalin and tioflocalin caused moderate calcium-independent mitochondria swelling, typical of an activation of KATP-channels, which was prevented by 5-hydroxydecanoate (5-HD), a specific inhibitor of the latter. It allowed us to attribute those compounds to pharmacological openers of just mitochondrial KATP-channels. The concentration-dependent effects of both flocalin and tioflocalin (10−7 to 10−4 M) on Ca2+-induced mitochondrial swelling (MPTP opening) in the heart have been shown, with IC50 = 50 µM and IC50 = 2.7 µM, respectively, and more powerful cardioprotective action of the latter. Administration of those compounds in vivo experiments decreased the sensitivity of the MPTP opening to Ca2+. In particular, flocalin (10−5, 510−5, and 10−4 M) prevented Ca2+-induced MPTP opening by 23.9%, 50.5%, and 100%, while tioflocalin (10−6, 510−6 i 10−5 M) - by 20.2%, 69% and 100%, respectively. Thus, under physiological conditions, the openers of KATP-channels are likely to exert the membrane-stabilizing effects, thereby effectively increasing organelle resistance to Ca2+, the MPTP inductor. The results obtained testify that KATP-channels have importance as cardioprotectors and regulators of MPTP formation in the heart, and they exert anti-ischemic and anti-apoptotic effects, which can be used in correction of mitochondrial dysfunction under pathological conditions of the cardiovascular system.

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