Role Of Mitochondrial KATP Channels Research Articles

Role of mitochondrial KATP channels in increased ischemic tolerance of chronically hypoxic rat hearts

Role of mitochondrial KATP channels in increased ischemic tolerance of chronically hypoxic rat hearts

Cardiprotective effects of chronic hypoxia and preconditioning are not additive. Role of mitochondrial KATP channels

Cardiprotective effects of chronic hypoxia and preconditioning are not additive. Role of mitochondrial KATP channels

Failure to precondition pathological human myocardium

OBJECTIVESWe investigated the effects of ischemic preconditioning (PC) on diabetic and failing human myocardium and the role of mitochondrial KATPchannels on the response in these diseased tissues.BACKGROUNDThere is conflicting evidence to suggest that PC is a healthy heart phenomenon.METHODSRight atrial appendages were obtained from seven different groups of patients: nondiabetics, diet-controlled diabetics, noninsulin-dependent diabetics (NIDD) receiving KATPchannel blockers, insulin-dependent diabetics (IDD), and patients with left ventricular ejection fraction (LVEF) >50%, LVEF between 30% and 50% and LVEF <30%. After stabilization, the muscle slices were randomized into five experimental groups (n = 6/group): 1) aerobic control—incubated in oxygenated buffer for 210 min, 2) ischemia alone—90 min ischemia followed by 120 min reoxygenation, 3) preconditioning by 5 min ischemia/5 min reoxygenation before 90 min ischemia/120 min reoxygenation, 4) diazoxide (Mito KATPopener, 0.1 mm)—for 10 min before the 90 min ischemia/120 min reoxygenation and 5) glibenclamide (10 μm)—10 min exposure prior to PC (only in the diabetic patient groups). Creatine kinase leakage into the medium (CK, U/g wet wt) and MTT reduction (OD/mg wet wt), an index of cell viability, were assessed at the end of the experiment.RESULTSIschemia caused similar injury in both normal and diseased tissue. Preconditioning prevented the effects of ischemia in all groups except NIDD, IDD and poor cardiac function (<30%). In the diazoxide-treated groups, protection was mimicked in all groups except the NIDD and IDD groups. Interestingly, glybenclamide abolished protection in nondiabetic and diet-controlled NIDD groups and did not affect NIDD groups receiving KATPchannel blockers or IDD groups.CONCLUSIONSThese results show that failure to precondition the diabetic heart is due to dysfunction of the mitochondrial KATPchannels and that the mechanism of failure in the diabetic heart lies in elements of the signal transduction pathway different from the mitochondrial KATPchannels.

Mitochondrial ATP-sensitive K+ channels modulate cardiac mitochondrial function.

Discovered in the cardiac sarcolemma, ATP-sensitive K+ (KATP) channels have more recently also been identified within the inner mitochondrial membrane. Yet the consequences of mitochondrial KATP channel activation on mitochondrial function remain partially documented. Therefore, we isolated mitochondria from rat hearts and used K+ channel openers to examine the effect of mitochondrial KATP channel opening on mitochondrial membrane potential, respiration, ATP generation, Ca2+ transport, and matrix volume. From a mitochondrial membrane potential of -180 +/- 15 mV, K+ channel openers, pinacidil (100 microM), cromakalim (25 microM), and levcromakalim (20 microM), induced membrane depolarization by 10 +/- 7, 25 +/- 9, and 24 +/- 10 mV, respectively. This effect was abolished by removal of extramitochondrial K+ or application of a KATP channel blocker. K+ channel opener-induced membrane depolarization was associated with an increase in the rate of mitochondrial respiration and a decrease in the rate of mitochondrial ATP synthesis. Furthermore, treatment with a K+ channel opener released Ca2+ from mitochondria preloaded with Ca2+, an effect also dependent on extramitochondrial K+ concentration and sensitive to KATP channel blockade. In addition, K+ channel openers, cromakalim and pinacidil, increased matrix volume and released mitochondrial proteins, cytochrome c and adenylate kinase. Thus, in isolated cardiac mitochondria, KATP channel openers depolarized the membrane, accelerated respiration, slowed ATP production, released accumulated Ca2+, produced swelling, and stimulated efflux of intermembrane proteins. These observations provide direct evidence for a role of mitochondrial KATP channels in regulating functions vital for the cardiac mitochondria.