MitoK<sub>ATP</sub> opener, diazoxide, reduces neuronal damage  after middle cerebral artery occlusion in the rat

Shimizu, Katsuyoshi; Lacza, Zsombor; Rajapakse, Nishadi; Horiguchi, Takashi; Snipes, James A.; Busija, David W.

doi:10.1152/ajpheart.00054.2002

Cited by 104 publications

(76 citation statements)

References 42 publications

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“…An effect on these channels has been suggested to mediate the protection conferred by this potassium channel opener against toxins in the heart (21,22) and the central nervous system (23)(24)(25). In ␤-cells, on the other hand, diazoxide has been suggested to act on K ATP channels in both plasma membrane (26) and mitochondria (27).…”

Section: Discussionmentioning

confidence: 99%

KATP Channels and Pancreatic Islet Blood Flow in Anesthetized Rats

et al. 2003

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K ATP channels are important for insulin secretion and depolarization of vascular smooth muscle. In view of the importance of drugs affecting K ATP channels in the treatment of diabetes, we investigated the effects of these channels on splanchnic blood perfusion in general and pancreatic islet blood flow in particular. We treated anesthetized Sprague-Dawley rats with the K ATP channel openers diazoxide or NNC 55-0118 or the K ATP channel closer glipizide. Both diazoxide and NNC 55-0118 dose-dependently increased total pancreatic and islet blood flow in the presence of moderate hyperglycemia, but had no effects on the blood perfusion of other splanchnic organs. Diazoxide markedly lowered the mean arterial blood pressure and thus increased vascular conductance in all organs studied. NNC 55-0118 had much smaller effects on the blood pressure. Glipizide did not affect total pancreatic blood flow, but decreased islet blood flow by 50% in the presence of hypoglycemia. We conclude that K ATP channels actively participate in the blood flow regulation of the pancreatic islets and that substances affecting such channels may also influence islet blood flow.

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Section: Discussionmentioning

confidence: 99%

KATP Channels and Pancreatic Islet Blood Flow in Anesthetized Rats

et al. 2003

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“…In adult animals, application of mitochondrial K ATP openers, such as diazoxide or BMS-191095, reduces neuronal death (rats: [116,[119][120][121] ; mice: [122] ), whereas a selective mitochondrial K ATP channel blocker, 5-hydroxydecanoate, prevents preconditioning-induced neuronal protection in middle cerebral artery occlusion (MCAO) focal cerebral ischemia [123] . In contrast, xenon-induced preconditioning is not associated with the mitochondrial channels, but rather, is mediated by plasmalemma K ATP channels [124] .…”

Section: K Atp Channels and Their Neuroprotective Role In Cerebral Ismentioning

confidence: 99%

Neuroprotective role of ATP-sensitive potassium channels in cerebral ischemia

Sun

Feng

2012

Acta Pharmacol Sin

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ATP-sensitive potassium (K ATP ) channels are weak, inward rectifiers that couple metabolic status to cell membrane electrical activity, thus modulating many cellular functions. An increase in the ADP/ATP ratio opens K ATP channels, leading to membrane hyperpolarization. K ATP channels are ubiquitously expressed in neurons located in different regions of the brain, including the hippocampus and cortex. Brief hypoxia triggers membrane hyperpolarization in these central neurons. In vivo animal studies confirmed that knocking out the Kir6.2 subunit of the K ATP channels increases ischemic infarction, and overexpression of the Kir6.2 subunit reduces neuronal injury from ischemic insults. These findings provide the basis for a practical strategy whereby activation of endogenous K ATP channels reduces cellular damage resulting from cerebral ischemic stroke. K ATP channel modulators may prove to be clinically useful as part of a combination therapy for stroke management in the future.

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“…Our observation of increased astrocyte density in the WM after CPB, which was not present in non-CPB lambs, reflects the impact of an inflammatory insult of CPB on the immature brain. Surprisingly, however, given that stimulation of mitochondrial ATP-sensitive K channels in the brain is considered to confer neuroprotection (12,22), CPB+Levo lambs exhibited a raised microglial density within WM that was not seen with CPB alone. We have previously shown a strong correlation between the intensity of microgliosis and the extent of brain injury in an ovine model of endotoxin exposure (23) suggesting a substantial role for microglial activation in the manifestation of and/or response to injury or other adverse events in this species.…”

Section: Discussionmentioning

confidence: 97%

“…Mitochondria play a major role in cellular responses to ischemic injury, and the activation of mitochondrial ATP-sensitive K + channels confers neuroprotection in models of CPB and in models of cerebral ischemia-reperfusion (11,12). More recently, the action of Levo on mitochondrial ATP-sensitive K + channels in the heart has been shown to protect the heart against ischemia-reperfusion injury and to limit myocyte apoptosis (13).…”

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confidence: 99%

Impact of levosimendan on brain injury patterns in a lamb model of infant cardiopulmonary bypass

et al. 2014

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Background:The effects of levosimendan (Levo) on injury patterns in the immature brain following cardiopulmonary bypass (CPB) are unknown. Methods: Eighteen 3-to 4-wk-old anesthetized lambs, instrumented with vascular catheters and aortic and right carotid artery flow probes, were allocated to non-CPB, CPB, or CPB+Levo groups (each n = 6). After 120 min CPB with 90 min aortic cross-clamp, CPB animals received dopamine, and CPB+Levo animals both dopamine and Levo, for 4 h. All lambs then underwent brain magnetic resonance imaging, followed by postmortem brain perfusion fixation for immunohistochemical studies. results: In CPB lambs, aortic (P < 0.05) and carotid artery (P < 0.01) blood flows fell by 29 and 30%, respectively, between 2 and 4 h after cross-clamp removal but were unchanged in the CPB+Levo group. No brain injury was detectable with magnetic resonance imaging in either CPB or CPB+Levo lambs. However, on immunohistochemical analysis, white matter astrocyte density of both groups was higher than in non-CPB lambs (P < 0.05), while white matter microglial density was higher (P < 0.05), but markers of cortical oxidative stress were less prevalent in CPB+Levo than CPB lambs. conclusion: While Levo prevented early postoperative falls in cardiac output and carotid artery blood flow in a lamb model of infant CPB, this was associated with heterogeneous neuroglial activation and manifestation of markers of oxidative stress. n eurodevelopmental impairment affects up to one half of all survivors of infant heart surgery, with the spectrum ranging from gross and fine motor deficits, visuospatial difficulties, and impaired cognition to delay in speech and language development (1-5). The mechanisms contributing to brain injury in infants with congenital heart disease are complex and multifactorial, with no consistent improvement in neurodevelopmental outcomes achieved despite major advances in pediatric cardiac surgery and survival. A recent report from the Pediatric Heart Network and the National Heart, Lung, and Blood Institute working group reaffirmed the importance of trials aimed at evaluating novel therapies to address this problem (6).Younger infants undergoing surgery for congenital heart disease are most susceptible to developing brain injury (7,8).The perioperative interval represents a high-risk period with often extended duration of cardiopulmonary bypass (CPB) at the time of the first surgical procedure, as well as significant circulatory disturbance postoperatively. The avoidance of a low cardiac output (CO) state, which can complicate the postoperative course of a proportion of infants after cardiac surgery and which may contribute to later impairment, is a major focus of postoperative care after infant heart surgery. The PRIMACORP study demonstrated the efficacy of intravenous milrinone in preventing this phenomenon in a cohort of children undergoing intracardiac repairs (9). Our laboratory subsequently demonstrated that the inodilator levosimendan (Levo) (Simdax, Abbott, Botany, Australia) was at leas...

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MitoK_ATP opener, diazoxide, reduces neuronal damage after middle cerebral artery occlusion in the rat

Abstract: . MitoKATP opener, diazoxide, reduces neuronal damage after middle cerebral artery occlusion in the rat. Am

Cited by 104 publications

References 42 publications

KATP Channels and Pancreatic Islet Blood Flow in Anesthetized Rats

KATP Channels and Pancreatic Islet Blood Flow in Anesthetized Rats

Neuroprotective role of ATP-sensitive potassium channels in cerebral ischemia

Impact of levosimendan on brain injury patterns in a lamb model of infant cardiopulmonary bypass

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