Mechanisms of ATP conservation during ischemia in slow and fast heart rate hearts

Rouslin, William; Broge, Charles W.

doi:10.1152/ajpcell.1993.264.1.c209

Cited by 38 publications

(26 citation statements)

References 23 publications

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“…Opening mitochondrial K ATP channels results in a dissipation of the inner mitochondrial membrane potential (7), which leads to uncoupling of the oxidative phosphorylation and net oxidation of the mitochondria (7,9,10). Observations have suggested that mitochondrial K ATP channel activation may counteract ATP wastage and preserve cellular functions possibly through activation of endogenous mitochondrial ATPase inhibitor (IF 1 ), or blocking the Ca 2+ uniporter of the mitochondrion or changing the glycolytic pathways during ischemia (28).…”

Section: Discussionmentioning

confidence: 99%

“…Although the exact mechanism of this phenomenon is not understood, an opening of mitochondrial K + channels seems to be involved that results in dissipation of the inner mitochondrial membrane potential. This leads to net oxidation of the mitochondria with an apparent reduction in energy wastage (7,9,10).Diazoxide is known to act on K ATP channels in the plasma membrane of ␤-cells (11). It hyperpolarizes the membrane and inhibits the energy-consuming process of insulin secretion (12).…”

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confidence: 99%

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K(ATP) channel openers protect rat islets against the toxic effect of streptozotocin.

Kullin

Hansen

et al. 2000

Diabetes

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We examined the influence of two K ATP channel openers, diazoxide and an analog (NNC 55-0118), on experimental ␤-cell damage induced by streptozotocin (STZ; 0.5 mmol/l). Rat pancreatic islets were exposed to diazoxide or NNC 55-0118 for 30 min and were further incubated for 30 min after the addition of STZ. The islets were then washed and cultured for 24 h. Islets exposed to STZ alone showed extensive morphological damage, reduced glucose oxidation, low insulin content, and severely impaired glucose-stimulated insulin secretion and proinsulin biosynthesis. Islets treated with STZ in the presence of the channel openers (0.03-0.30 mmol/l) showed dose-dependent preservation of the morphology and improved glucose oxidation rates, insulin content, and secretion. NNC 55-0118 was capable of fully counteracting the STZ impairment, whereas diazoxide had a less protective effect. NNC 55-0118 did not counteract STZ-induced depression of islet NAD levels when examined 2 h after STZ exposure, which suggests that the mechanism of action by NNC 55-0118 is not through an inhibition of poly(ADP-ribose) polymerase. The results illustrate that K ATP channel openers can protect insulinproducing cells against toxic damage, an effect that may be of use in subjects with ongoing insulitis. Diabetes 49:1131-1136, 2000 I n human autoimmune diabetes, the insulin-producing ␤-cells are generally thought to be destroyed by cytotoxic T-cells that are driven by an antigen-specific process (1,2). In experiments with isolated islets, we have found that glucose increases the expression of ␤-cell autoantigens (3) and that diazoxide lowers the antigen amount (4). Against this background, we conducted a clinical trial and observed that a 3-month supplementary treatment with diazoxide had a beneficial effect on residual ␤-cell function in patients with new-onset type 1 diabetes (5). "␤-cell rest" may thus protect islet cells from autoimmune destruction (6) and may help to explain the remission phenomenon often noted subsequent to the initiation of insulin treatment.Diazoxide and other K ATP channel openers such as cromakalim and pinacidil have been used in experimental studies of the ischemic heart, and beneficial cardioprotective effects have been observed (7-9). Although the exact mechanism of this phenomenon is not understood, an opening of mitochondrial K + channels seems to be involved that results in dissipation of the inner mitochondrial membrane potential. This leads to net oxidation of the mitochondria with an apparent reduction in energy wastage (7,9,10).Diazoxide is known to act on K ATP channels in the plasma membrane of ␤-cells (11). It hyperpolarizes the membrane and inhibits the energy-consuming process of insulin secretion (12). Recently, exposure of ␤-cells to diazoxide has also been found to engage mitochondrial K ATP channels (13). In the present study, we examined the influence of diazoxide and NNC 55-0118, a new K ATP channel opener analog, on experimental ␤-cell damage induced by streptozotocin (STZ), an agent known to cause ene...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

K(ATP) channel openers protect rat islets against the toxic effect of streptozotocin.

Kullin

Hansen

et al. 2000

Diabetes

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“…On the other hand, several groups have shown that preconditioning can be independent of mitochondrial F 1 F 0 -ATPase inhibition [79–80]. However, this inhibitor protein is much more active in slow heart rate species such as rabbits and pigs, and has lower activity in mouse and rat heart [81–82]. This inhibitor may account for the much slower rate of ATP depletion in slow heart rate species than high heart rate species during ischemia, but since ischemic preconditioning is equally effective in rats, rabbits, and pigs, it is unlikely that this inhibitor is solely responsible for the effect of ischemic preconditioning on ATP consumption.…”

Section: Other Factors In Mitochondrial Adenine Nucleotide Metabolismmentioning

confidence: 99%

Mitochondrial adenine nucleotide transport and cardioprotection

Das

Steenbergen

2012

Journal of Molecular and Cellular Cardiology

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Mitochondria are highly metabolically active cell organelles that not only act as the powerhouse of the cell by supplying energy through ATP production, but also play a destructive role by initiating cell death pathways. Growing evidence recognizes that mitochondrial dysfunction is one of the major causes of cardiovascular disease. Under de-energized conditions, slowing of adenine nucleotide transport in and out of the mitochondria significantly attenuates myocardial ischemia-reperfusion injury. The purpose of this review is to elaborate on and update the mechanistic pathways which may explain how altered adenine nucleotide transport can influence cardiovascular function.

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“…However, the question regarding how opening the mitochondrial K ATP channel protects the myocyte against ischemic insult still remains unclear. The function of the mitochondrial K ATP channel was shown to include modulation of the mitochondrial volume [18] and energy possibly by inhibiting ATP wastage [19] as opposed to electrical activity for the sarcolemmal K ATP channel [20]. Since the K ATP channel opener-treated hearts have been shown to maintain higher ATP levels and exhibit reduced infarct size and enhanced postischemic recovery upon reperfusion, opening the mitochondrial K ATP channel may be a necessary component in myoprotective mechanisms.…”

Section: Role Of Mitochondrial K Atp Channel In Ipcmentioning

confidence: 99%

Mitochondrial ATP-Sensitive Potassium Channel Plays a Dominant Role in Ischemic Preconditioning of Rabbit Heart

Nakai

Horimoto²,

Mieno³

et al. 2001

Eur Surg Res

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Background: The ATP-sensitive potassium (K_ATP) channel has been shown to be important in the ischemic preconditioning (IPC) response. Recently, the mitochondrial rather than the sarcolemmal K_ATP channel has been focused on due to its energy-modulating property. Hence, this study was undertaken to elucidate the role of the mitochondrial K_ATP channel in IPC by modulating the mitochondrial K_ATP channel in isolated perfused rabbit hearts. Methods: Seven hearts served as a control with no interventions. Seven hearts underwent IPC consisting of two 5-min cycles of global ischemia followed by 5 min of reperfusion. Seven hearts received the selective mitochondrial K_ATP channel blocker 5-dehydroxydecanoate (5-HD, 100 µM) for 5 min before IPC, and 7 hearts received the selective mitochondrial K_ATP channel opener diazoxide (50 µM) for 5 min. Then, all hearts were subjected to 1 h of left anterior descending coronary artery ischemia and 1 h of reperfusion. Left ventricular pressures, monophasic action potentials and coronary flow were measured throughout the experiment and infarct size was detected at the end of experiment. Results: (1) The mitochondria-selective K_ATP channel opener diazoxide reduced infarct size as compared to control (p < 0.05); (2) IPC reduced infarct size and preserved postischemic diastolic function as compared to control (p < 0.05), and (3) the mitochondria-selective K_ATP channel blocker 5-HD reversed these effects. Conclusion: The mitochondrial ATP-sensitive potassium channel may be a potential site of cardioprotection.

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Mechanisms of ATP conservation during ischemia in slow and fast heart rate hearts

Cited by 38 publications

References 23 publications

K(ATP) channel openers protect rat islets against the toxic effect of streptozotocin.

K(ATP) channel openers protect rat islets against the toxic effect of streptozotocin.

Mitochondrial adenine nucleotide transport and cardioprotection

Mitochondrial ATP-Sensitive Potassium Channel Plays a Dominant Role in Ischemic Preconditioning of Rabbit Heart

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