Nicorandil protects ATP-sensitive potassium channels against oxidation-induced dysfunction in cardiomyocytes of aging rats

Raveaud, Stéphanie; Verdetti, Jean; Faury, Gilles

doi:10.1007/s10522-008-9196-9

Cited by 17 publications

(12 citation statements)

References 43 publications

(53 reference statements)

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“…In addition to the robust cardioprotection derived from direct targeting of mitochondria to modulate electron transport in the present study, mitochondria from aged hearts remain responsive to direct manipulation of the K ATP channel by nicorandil 46 or diazoxide treatment. 47 Direct modulation of permeability transition pore susceptibility 48–50 also limits damage in the aged heart.…”

Section: Discussionmentioning

confidence: 72%

Blockade of electron transport before ischemia protects mitochondria and decreases myocardial injury during reperfusion in aged rat hearts

Tanaka-Esposito

Chen

Lesnefsky

2012

Translational Research

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Myocardial injury is increased in the aged heart following ischemia and reperfusion (I-R) in both humans and experimental models. Hearts from aged 24 mo. old Fischer 344 rats sustain greater cell death and decreased contractile recovery after I-R compared to 6 mo. adult controls. Cardiac mitochondria incur damage during I-R contributing to cell death. Aged rats have a defect in complex III of the mitochondrial electron transport chain (ETC) localized to the interfibrillar population of cardiac mitochondria (IFM), situated in the interior of the cardiomyocyte among the myofibrils. The defect involves the quinol oxidation site (Qo) and increases the production of reactive oxygen species (ROS) in the baseline state. Ischemia further decreases complex III activity via functional inactivation of the iron-sulfur subunit. We studied the contribution of ischemia-induced defects in complex III to the increased cardiac injury in the aged heart. The reversible blockade of the ETC proximal to complex III during ischemia using amobarbital protects mitochondria against ischemic damage, removing the ischemia component of mitochondrial dysfunction. Reperfusion of the aged heart in the absence of ischemic mitochondrial damage decreases net ROS production from mitochondria and reduces cell death. Thus, even despite the persistence of the age-related defects in electron transport, protection against ischemic damage to mitochondria can reduce injury in the aged heart. The direct therapeutic targeting of mitochondria protects against ischemic damage and decreases cardiac injury during reperfusion in the high risk elderly heart.

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Section: Discussionmentioning

confidence: 72%

Blockade of electron transport before ischemia protects mitochondria and decreases myocardial injury during reperfusion in aged rat hearts

Tanaka-Esposito

Chen

Lesnefsky

2012

Translational Research

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“…However, cardiac fibroblasts pretreated with nicorandil (3 mol/l, 30 min) had significantly decreased levels of Ang-II-induced ERK phosphorylation. Studies on the antioxidative effect of nicorandil in inhibiting radical production revealed that it possesses a certain degree of protective effects in vitro [13,21,22] and in vivo [23] . The protective characteristics may be associated with their antioxidant activity.…”

Section: Discussionmentioning

confidence: 99%

Nicorandil Inhibits Angiotensin-II-Induced Proliferation of Cultured Rat Cardiac Fibroblasts

Liou

Hong²,

Sung

et al. 2011

Pharmacology

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Background/Aims: Nicorandil, an ATP-sensitive potassium (K_ATP) channel opener, nitric oxide (NO) donor and antioxidant, was shown to exert a variety of pharmacological effects including cardioprotective properties. However, its mechanisms of action are not completely understood. The aims of this study were to examine whether nicorandil may alter angiotensin-II (Ang II)-induced cell proliferation and to identify the putative underlying signaling pathways in rat cardiac fibroblasts. Methods: Cultured rat cardiac fibroblasts were pretreated with nicorandil, then stimulated with Ang II, and cell proliferation and endothelin-1 (ET-1) expression were examined. The effects of nicorandil on Ang-II-induced reactive oxygen species (ROS) formation and extracellular signal-regulated kinase (ERK) phosphorylation were also examined. In addition, the effects of nicorandil on NO production and endothelial nitric oxide synthase (eNOS) phosphorylation were tested to elucidate the intracellular mechanism. Results: Nicorandil (0.1–10 µmol/l) caused a concentration-dependent inhibition of Ang-II-increased cell proliferation and ET-1 expression which were prevented by the K_ATP channel blocker glibenclamide (1 µmol/l). Nicorandil also inhibited Ang-II-increased ROS and ERK phosphorylation. In addition, nicorandil was found to increase the NO and eNOS phosphorylation. N-nitro-L-arginine methyl ester, an inhibitor of NOS, and the short interfering RNA transfection for eNOS markedly attenuated the inhibitory effect of nicorandil on Ang-II-induced cell proliferation. Conclusion: Our results suggest that nicorandil prevents cardiac fibroblast proliferation, and the inhibitory effect might be associated with the opening K_ATP channels, by interfering with the generation of ROS, and the activation of the eNOS-NO pathway.

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“…Moreover, increased intracellular Ca2+ for a prolonged period causes increased Ca2+ uptake by mitochondria, which further leads to mitochondrial dysfunction and cardiomyocyte death. Similarly, expression and/or function of ATP sensitive K+ (KATP) channels decreases with advanced age affecting the electrical activities of cardiomyocytes [47]–[49]. Decreased KATP channel density represents a possible mechanism for decreased tolerance of aged heart against ischemic injury [47],[48].…”

Section: Aging and The Heartmentioning

confidence: 99%

Mitochondria and the aging heart

Chaudhary¹,

El‐Sikhry²,

Seubert³

2011

Journal of Geriatric Cardiology

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The average human life span has markedly increased in modern society largely attributed to advances in medical and therapeutic sciences that have successfully reduced important health risks. However, advanced age results in numerous alterations to cellular and subcellular components that can impact the overall health and function of an individual. Not surprisingly, advanced age is a major risk factor for the development of heart disease in which elderly populations observe increased morbidity and mortality. Even healthy individuals that appear to have normal heart function under resting conditions, actually have an increased susceptibility and vulnerability to stress. This is confounded by the impact that stress and disease can have over time to both the heart and vessels. Although, there is a rapidly growing body of literature investigating the effects of aging on the heart and how age-related alterations affect cardiac function, the biology of aging and underlying mechanisms remain unclear. In this review, we summarize effects of aging on the heart and discuss potential theories of cellular aging with special emphasis on mitochondrial dysfunction.

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Nicorandil protects ATP-sensitive potassium channels against oxidation-induced dysfunction in cardiomyocytes of aging rats

Cited by 17 publications

References 43 publications

Blockade of electron transport before ischemia protects mitochondria and decreases myocardial injury during reperfusion in aged rat hearts

Blockade of electron transport before ischemia protects mitochondria and decreases myocardial injury during reperfusion in aged rat hearts

Nicorandil Inhibits Angiotensin-II-Induced Proliferation of Cultured Rat Cardiac Fibroblasts

Mitochondria and the aging heart

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