Effects of ATP-sensitive potassium channel activators diazoxide and BMS-191095 on membrane potential and reactive oxygen species production in isolated piglet mitochondria

Busija, David W.; Katakam, Prasad V. G.; Rajapakse, Nishadi; Kis, Béla; Grover, Gary J.; Domoki, Ferenc; Bari, Ferenc

doi:10.1016/j.brainresbull.2005.03.022

Cited by 61 publications

(64 citation statements)

References 23 publications

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“…Previous studies have found that 3-nitropropionic acid (3-NPA), a specific inhibitor of succinate dehydrogenase, also protected neurons both in vivo and in vitro. It is not known whether effects of succinate dehydrogenase inhibition were additive or counterproductive to channel-related cellular protection, but neuroprotective effects of 3-NPA were substantially less than those reported with diazoxide alone in that study (Riepe et al, 1992, Busija et al, 2005.…”

Section: Discussionmentioning

confidence: 69%

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ɛPKC phosphorylates the mitochondrial K+ATP channel during induction of ischemic preconditioning in the rat hippocampus

et al. 2007

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Neuroprotection against cerebral ischemia conferred by ischemic preconditioning (IPC) requires translocation of epsilon protein kinase C (εPKC). A major goal in our laboratory is to define the cellular targets by which εPKC confers protection. We tested the hypothesis that εPKC targets the mitochondrial channel ( ) after IPC. Our results demonstrated a rapid translocation of εPKC to rat hippocampal mitochondria after IPC. Because in other tissues εPKC targets channels, but its presence in brain mitochondria is controversial, we determined the presence of the channel-specific subunits (Kir6.1 and Kir6.2) in mitochondria isolated from rat hippocampus. Next, we determined whether channels play a role in the IPC induction. In hippocampal organotypic slice cultures, IPC and lethal ischemia were induced by oxygen-glucose deprivation. Subsequent cell death in the CA1 region was quantified using propidium iodide staining. Treatment with the channel openers diazoxide or pinacidil 48 h prior to lethal ischemia protected hippocampal CA1 neurons, mimicking the induction of neuroprotection conferred by either IPC or εPKC agonist-induced preconditioning. Blockade of channels using 5-hydroxydecanoic acid abolished the neuroprotection due to either IPC or εPKC preconditioning. Both ischemic andεPKC agonist-mediated preconditioning resulted in phosphorylation of the channel subunit Kir6.2. After IPC, selective inhibition of εPKC activation prevented Kir6.2 phosphorylation, consistent with Kir6.2 as a phosphorylation target of εPKC or its downstream effectors. Our results support the hypothesis that the brain channel is an important target of IPC and the signal transduction pathways initiated by εPKC.

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Section: Discussionmentioning

confidence: 69%

“…It is well documented in heart that the increased channel activity leads to the generation of reactive oxygen species (ROS) (Busija et al, 2005, Roth et al, 2006. ROS are important intracellular signaling molecules and are increased during sublethal oxidative stress (a preconditioning stimulus).…”

Section: Discussionmentioning

confidence: 99%

ɛPKC phosphorylates the mitochondrial K+ATP channel during induction of ischemic preconditioning in the rat hippocampus

et al. 2007

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“…In contrast to endothelium and neurons, the predominant early event following mitochondrial depolarization in vascular smooth muscle cells is the localized generation of calcium sparks from sarcoplasmic reticulum resulting in a decrease in [Ca 2ϩ ] i (20,42). BMS has selective effects on mitoK ATP channels; however, it appears that diazoxide has dual effects on mitochondria, which involve activation of mitoK ATP channels as well as generation of ROS from inhibition of complex II (2). We have documented that mitochondria are the source of superoxide anion in response to diazoxide application using the selective fluoroprobe MitoSOX.…”

Section: Discussionmentioning

confidence: 99%

“…MITOCHONDRIAL MEMBRANE POTENTIAL is a critical regulator of cellular activity and survival and is controlled by a variety of factors including the ATP-sensitive potassium (mitoK ATP ) channels located on the inner mitochondrial membrane (2). Pharmacological activators of mitoK ATP channels, such as BMS-191095 (BMS) and diazoxide, decrease the mitochondrial membrane potential by facilitating the influx of potassium from cytosol into the matrix (2).…”

Section: The Current Study Provides Evidence That Pharmacological Depmentioning

confidence: 99%

“…Pharmacological activators of mitoK ATP channels, such as BMS-191095 (BMS) and diazoxide, decrease the mitochondrial membrane potential by facilitating the influx of potassium from cytosol into the matrix (2). Signaling events following mitochondrial depolarization appear to be diverse in the various cell types comprising the neurovascular unit (cerebral vascular endothelium and smooth muscle, perivascular neurons, parenchymal neurons, and glia).…”

Section: The Current Study Provides Evidence That Pharmacological Depmentioning

confidence: 99%

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Depolarization of mitochondria in neurons promotes activation of nitric oxide synthase and generation of nitric oxide

Katakam

Dutta

Sure

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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-The diverse signaling events following mitochondrial depolarization in neurons are not clear. We examined for the first time the effects of mitochondrial depolarization on mitochondrial function, intracellular calcium, neuronal nitric oxide synthase (nNOS) activation, and nitric oxide (NO) production in cultured neurons and perivascular nerves. Cultured rat primary cortical neurons were studied on 7-10 days in vitro, and endothelium-denuded cerebral arteries of adult Sprague-Dawley rats were studied ex vivo. Diazoxide and BMS-191095 (BMS), activators of mitochondrial K ATP channels, depolarized mitochondria in cultured neurons and increased cytosolic calcium levels. However, the mitochondrial oxygen consumption rate was unaffected by mitochondrial depolarization. In addition, diazoxide and BMS not only increased the nNOS phosphorylation at positive regulatory serine 1417 but also decreased nNOS phosphorylation at negative regulatory serine 847. Furthermore, diazoxide and BMS increased NO production in cultured neurons measured with both fluorescence microscopy and electron spin resonance spectroscopy, which was sensitive to inhibition by the selective nNOS inhibitor 7-nitroindazole (7-NI). Diazoxide also protected cultured neurons against oxygen-glucose deprivation, which was blocked by NOS inhibition and rescued by NO donors. Finally, BMS induced vasodilation of endothelium denuded, freshly isolated cerebral arteries that was diminished by 7-NI and tetrodotoxin. Thus pharmacological depolarization of mitochondria promotes activation of nNOS leading to generation of NO in cultured neurons and endothelium-denuded arteries. Mitochondrial-induced NO production leads to increased cellular resistance to lethal stress by cultured neurons and to vasodilation of denuded cerebral arteries. MITOCHONDRIAL MEMBRANE POTENTIAL is a critical regulator of cellular activity and survival and is controlled by a variety of factors including the ATP-sensitive potassium (mitoK ATP ) channels located on the inner mitochondrial membrane (2). Pharmacological activators of mitoK ATP channels, such as BMS-191095 (BMS) and diazoxide, decrease the mitochondrial membrane potential by facilitating the influx of potassium from cytosol into the matrix (2). Signaling events following mitochondrial depolarization appear to be diverse in the various cell types comprising the neurovascular unit (cerebral vascular endothelium and smooth muscle, perivascular neurons, parenchymal neurons, and glia). Both BMS and diazoxide applications result in dilation of isolated cerebral arteries; however, individual effects on vascular smooth muscle and endothelium, which contribute to the overall vascular effect, are completely different (20,22,35,42). Thus BMS and diazoxide relax cerebral vascular smooth muscle cells via generation of localized calcium sparks by sarcoplasmic reticulum linked to mitochondrial depolarization, resulting in decreased global intracellular Ca 2ϩ ([Ca 2ϩ ] i ) (20, 42). Conversely, mitochondrial depolarization in cerebral endothe...

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Role of Mitochondria in Cerebral Vascular Function: Energy Production, Cellular Protection, and Regulation of Vascular Tone

Busija

Rutkai

Dutta

et al. 2016

Comprehensive Physiology

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Mitochondria not only produce energy in the form of ATP to support the activities of cells comprising the neurovascular unit, but mitochondrial events, such as depolarization and/or ROS release, also initiate signaling events which protect the endothelium and neurons against lethal stresses via pre-/postconditioning as well as promote changes in cerebral vascular tone. Mitochondrial depolarization in vascular smooth muscle (VSM), via pharmacological activation of the ATP-dependent potassium channels on the inner mitochondrial membrane (mitoKATP channels), leads to vasorelaxation through generation of calcium sparks by the sarcoplasmic reticulum and subsequent downstream signaling mechanisms. Increased release of ROS by mitochondria has similar effects. Relaxation of VSM can also be indirectly achieved via actions of nitric oxide (NO) and other vasoactive agents produced by endothelium, perivascular and parenchymal nerves, and astroglia following mitochondrial activation. Additionally, NO production following mitochondrial activation is involved in neuronal preconditioning. Cerebral arteries from female rats have greater mitochondrial mass and respiration and enhanced cerebral arterial dilation to mitochondrial activators. Preexisting chronic conditions such as insulin resistance and/or diabetes impair mitoKATP channel relaxation of cerebral arteries and preconditioning. Surprisingly, mitoKATP channel function after transient ischemia appears to be retained in the endothelium of large cerebral arteries despite generalized cerebral vascular dysfunction. Thus, mitochondrial mechanisms may represent the elusive signaling link between metabolic rate and blood flow as well as mediators of vascular change according to physiological status. Mitochondrial mechanisms are an important, but underutilized target for improving vascular function and decreasing brain injury in stroke patients. © 2016 American Physiological Society. Compr Physiol 6:1529-1548, 2016.

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Effects of ATP-sensitive potassium channel activators diazoxide and BMS-191095 on membrane potential and reactive oxygen species production in isolated piglet mitochondria

Cited by 61 publications

References 23 publications

ɛPKC phosphorylates the mitochondrial K+ATP channel during induction of ischemic preconditioning in the rat hippocampus

ɛPKC phosphorylates the mitochondrial K+ATP channel during induction of ischemic preconditioning in the rat hippocampus

Depolarization of mitochondria in neurons promotes activation of nitric oxide synthase and generation of nitric oxide

Role of Mitochondria in Cerebral Vascular Function: Energy Production, Cellular Protection, and Regulation of Vascular Tone

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