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

摘要

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 transitionpore (MPTP) opening. Both flocalin and tioflocalin caused moderate calcium-independent mitochondria swelling, typical of an activation of KAXp-channels, which was prevented by 5-hydroxydecanoate (5-HD), a specific inhibitor of the latter. It allowed us to attribute those compoimds to pharmacological openers of just mitochondrial KATP-channels. The concentration-dependent effects of both flocalin and tioflocalin (10~(-7)to 10M) on Ca~(2+)-induced mitochondrial swelling (MPTP opening) in the heart have been shown, with IC50 = 50 nM and IC50 = 2.7 nM, respectively, and more powerful cardioprotective action of the latter. Administration of those compounds in vivo experiments decreased the sensitivity of the MPTP opening to Ca~(2+) In particular, flocalin (10~(-5) 10~(-5)and 10~(-4)M) prevented Ca~(2+)-induced MPTP opening by 23.9%, 50.5%, and 100%, while tioflocalin (10~(-6)10~(-6)l0~(-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 Ca~(2+), the MPTP inductor. The results obtained testify that KAXp-channels have importance as cardioprotectors and regulators of MPTP formation in the heart, and they exert anli-ischemic and anti-apoptotic effects, which can be used in correction of mitochondrial dysfunc-tion under pathological conditions of the cardiovascular system.