Opening of mitochondrial K_ATPchannels enhances cardioprotection through the modulation of mitochondrial matrix volume, calcium accumulation, and respiration

Abstract

Previously, we have shown that the pharmacological opening of the mitochondrial ATP-sensitive K channels with diazoxide (DZX) enhances the cardioprotection afforded by magnesium-supplemented potassium (K/Mg) cardioplegia. To determine the mechanisms involved in the cardioprotection afforded by K/Mg + DZX cardioplegia, rabbit hearts (n=24) were subjected to isolated Langendorff perfusion. Control hearts were perfused for 75 min. Global ischemia (GI) hearts were subjected to 30 min of equilibrium, 30 min of GI, and 15 min of reperfusion. K/Mg and K/Mg + DZX cardioplegia hearts received either K/Mg or K/Mg + DZX for 5 min before GI and reperfusion. Tissue was harvested for mitochondrial isolation and transmission electron microscopy (TEM). Mitochondrial structure, area, matrix volume, free calcium, and oxygen consumption were determined. TEM demonstrated that GI mitochondria were damaged and that K/Mg and K/Mg + DZX preserved mitochondrial structure. TEM and light scattering demonstrated separately that mitochondrial matrix and cristae area and matrix volume were significantly increased after GI and reperfusion with GI > K/Mg + DZX > K/Mg hearts (P <0.05 vs. control). Mitochondrial free calcium was significantly increased in GI and K/Mg hearts. K/Mg + DZX significantly decreased mitochondrial free calcium accumulation (P <0.05 vs. GI and K/Mg). State 3 oxygen consumption and respiratory control index in malate (complex I substrate)- and succinate (complex II substrate)-energized mitochondria were significantly decreased (P <0.05 vs. control) in the GI and K/Mg + DZX groups. These data indicate that the enhanced cardioprotection afforded by K/Mg + DZX cardioplegia occurs through the preservation of mitochondrial structure and the significant decrease in mitochondrial free calcium accumulation and mitochondrial state 3 oxygen consumption.

Tryptamine-Gallic Acid Hybrid Prevents Non-steroidal Anti-inflammatory Drug-induced Gastropathy

“…Oxygen Consumption-Mitochondrial oxygen consumption was measured using a Clark-type electrode in a liquid phase oxygen measurement system (Oxygraph, Hansatech, Norfolk, UK) (46). Complex I (state 3)-mediated oxygen consumption was initiated by the incorporation of glutamate and malate (5 mM each) to 1 ml of respiratory medium (250 mM sucrose, 5 mM KH 2 PO 4 , 5 mM MgCl 2 , 0.1 mM EDTA, and 0.1% BSA in 20 mM HEPES, pH 7.2).…”

Modulation of mitochondrial respiratory function and ROS production by novel benzopyran analogues

“…Also, our data regarding the effect of 5-HD are in agreement with the previous reports showing that the mK ATP blocker had no effect on the activation of the basal mitochondrial respiration by diazoxide and pinacidil applied in similar concentrations (Kopustinskiene et al 2010;Korotkov et al 2006). Furthermore, all four compounds significantly decreased State 3 respiration as was earlier demonstrated for diazoxide (Kopustinskiene et al 2002;Rousou et al 2004) and pinacidil (Kopustinskiene et al 2010).…”

Cardioprotective Effects of Sarcolemmal and Mitochondrial K-ATP Channel Openers in an Experimental Model of Autoimmune Myocarditis

“…13,14) It has been reported that acute inflammation causes myocardial damage, apoptosis, or necrosis and results in an intracellular and mitochondrial calcium overload similar to acute ischemia. [7][8][9][10] Therefore, a cardioprotective effect would be expected with a treatment which would reduce the calcium overload in the myocardium or its mitochondria. In the present study, we used two different clinically available K-ATP channel openers.…”

“…[3][4][5][6][7] However, K-ATP channels are found not only in the sarcolemma of myocytes, but also in the mitochondrial membrane, and openers of these mitochondrial K-ATP channels, such as nicorandil, have been proven to play an important role in its cardioprotective effect by protecting mitochondrial function, especially in short-term acute ischemia. [8][9][10] It has been reported that an increase in ventricular wall stress causes prolongation of the action potential duration, particularly in damaged myocardium with heart failure. 11) This prolongation of the action potential duration may increase transient calcium and may exaggerate intracellular calcium overload, resulting in the deterioration of myocardial dysfunction.…”