Dexmedetomidine protects the heart against ischemia-reperfusion injury by an endothelial eNOS/NO dependent mechanism

Riquelme, Jaime A.; Westermeier, Francisco; Hall, Andrew; Vicencio, José M.; Pedrozo, Zully; Ibacache, Mauricio; Fuenzalida, Bárbara; Sobrevía, Luis; Davidson, Sean M.; Yellon, Derek M.; Pecchi, Gina; Lavandero, Sergio

doi:10.1016/j.phrs.2015.11.004

Cited by 73 publications

(41 citation statements)

References 68 publications

(85 reference statements)

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“…Some possible mechanisms may underlie the DEX-induced protective effects against myocardial I/R injury, including inhibition of inflammation, activation of the eNOS/NO signaling, and maintaining a direct action. 15,30,31 It is also highlighted that disordered Ca 2+ homeostasis is a leading cause of For personal use only. myocardial I/R injury.…”

Section: Discussionmentioning

confidence: 99%

<p>Dexmedetomidine protects H9c2 cardiomyocytes against oxygen-glucose deprivation/reoxygenation-induced intracellular calcium overload and apoptosis through regulating FKBP12.6/RyR2 signaling</p>

Yuan¹,

Meng²,

Ma³

et al. 2019

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Purpose Intracellular calcium ([Ca 2+ ]i) overload is a major cause of cell injury during myocardial ischemia/reperfusion (I/R). Dexmedetomidine (DEX) has been shown to exert anti-inﬂammatory and organ protective effects. This study aimed to investigate whether pretreatment with DEX could protect H9c2 cardiomyocytes against oxygen-glucose deprivation/reoxygenation (OGD/R) injury through regulating the Ca 2+ signaling. Methods H9c2 cardiomyocytes were subjected to OGD for 12 h, followed by 3 h of reoxygenation. DEX was administered 1 h prior to OGD/R. Cell viability, lactate dehydrogenase (LDH) release, level of [Ca 2+ ]i, cell apoptosis, and the expression of 12.6-kd FK506-binding protein/ryanodine receptor 2 (FKBP12.6/RyR2) and caspase-3 were assessed. Results Cells exposed to OGD/R had decreased cell viability, increased LDH release, elevated [Ca 2+ ]i level and apoptosis rate, down-regulated expression of FKBP12.6, and up-regulated expression of phosphorylated-Ser2814-RyR2 and cleaved caspase-3. Pretreatment with DEX significantly blocked the above-mentioned changes, alleviating the OGD/R-induced injury in H9c2 cells. Moreover, knockdown of FKBP12.6 by small interfering RNA abolished the protective effects of DEX. Conclusion This study indicates that DEX pretreatment protects the cardiomyocytes against OGD/R-induced injury by inhibiting [Ca 2+ ]i overload and cell apoptosis via regulating the FKBP12.6/RyR2 signaling. DEX may be used for preventing cardiac I/R injury in the clinical settings.

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Section: Discussionmentioning

confidence: 99%

<p>Dexmedetomidine protects H9c2 cardiomyocytes against oxygen-glucose deprivation/reoxygenation-induced intracellular calcium overload and apoptosis through regulating FKBP12.6/RyR2 signaling</p>

Yuan¹,

Meng²,

Ma³

et al. 2019

DDDT

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“…In addition, neuro- and cardioprotective properties have been described. Several mechanisms are reported to be involved, such as activation of pro-survival kinases [135], modification of oxidative and inflammatory responses [136], and activation of the endothelial nitric oxide synthase [137]. In animal studies, it was found that dexmedetomidine potentially protects against neuro-apoptosis caused by other agents [138–140].…”

Section: New Clinical Applicationsmentioning

confidence: 99%

Clinical Pharmacokinetics and Pharmacodynamics of Dexmedetomidine

et al. 2017

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Dexmedetomidine is an α2-adrenoceptor agonist with sedative, anxiolytic, sympatholytic, and analgesic-sparing effects, and minimal depression of respiratory function. It is potent and highly selective for α2-receptors with an α2:α1 ratio of 1620:1. Hemodynamic effects, which include transient hypertension, bradycardia, and hypotension, result from the drug’s peripheral vasoconstrictive and sympatholytic properties. Dexmedetomidine exerts its hypnotic action through activation of central pre- and postsynaptic α2-receptors in the locus coeruleus, thereby inducting a state of unconsciousness similar to natural sleep, with the unique aspect that patients remain easily rousable and cooperative. Dexmedetomidine is rapidly distributed and is mainly hepatically metabolized into inactive metabolites by glucuronidation and hydroxylation. A high inter-individual variability in dexmedetomidine pharmacokinetics has been described, especially in the intensive care unit population. In recent years, multiple pharmacokinetic non-compartmental analyses as well as population pharmacokinetic studies have been performed. Body size, hepatic impairment, and presumably plasma albumin and cardiac output have a significant impact on dexmedetomidine pharmacokinetics. Results regarding other covariates remain inconclusive and warrant further research. Although initially approved for intravenous use for up to 24 h in the adult intensive care unit population only, applications of dexmedetomidine in clinical practice have been widened over the past few years. Procedural sedation with dexmedetomidine was additionally approved by the US Food and Drug Administration in 2003 and dexmedetomidine has appeared useful in multiple off-label applications such as pediatric sedation, intranasal or buccal administration, and use as an adjuvant to local analgesia techniques.

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“…The authors concluded that independently from autonomic nervous system modulation, DEX cardioprotective effects are mediated by activation of prosurvival PI3K/Akt signaling pathway after cardiac a2-adrenergic receptor stimulation. More recent studies have demonstrated the role of endothelial a2-adrenergic receptors with beneficial effects on DEX against I/R injury (Riquelme et al, 2016;Deng et al, 2019), activating the eNOS/NO cardioprotective signaling pathways (Kim et al, 2009).…”

Section: Dex Molecular Pathwaysmentioning

confidence: 99%

“…Currently, the biological functions of DEX have been demonstrated in different animal models through several signaling pathways. Some studies demonstrate the beneficial effects of DEX against ischemia-reperfusi0on (I/R) injury (Riquelme et al, 2016;Deng et al, 2019), activating the eNOS/ NO cardioprotective signaling pathways. In vivo mechanistic studies are needed to determine the effects of DEX in clinical events that are associated with I/R.…”

Section: Introductionmentioning

confidence: 99%

Dexmedetomidine Improves Cardiovascular and Ventilatory Outcomes in Critically Ill Patients: Basic and Clinical Approaches

et al. 2020

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Dexmedetomidine (DEX) is a highly selective a2-adrenergic agonist with sedative and analgesic properties, with minimal respiratory effects. It is used as a sedative in the intensive care unit and the operating room. The opioid-sparing effect and the absence of respiratory effects make dexmedetomidine an attractive adjuvant drug for anesthesia in obese patients who are at an increased risk for postoperative respiratory complications. The pharmacodynamic effects on the cardiovascular system are known; however the mechanisms that induce cardioprotection are still under study. Regarding the pharmacokinetics properties, this drug is extensively metabolized in the liver by the uridine diphosphate glucuronosyltransferases. It has a relatively high hepatic extraction ratio, and therefore, its metabolism is dependent on liver blood flow. This review shows, from a basic clinical approach, the evidence supporting the use of dexmedetomidine in different settings, from its use in animal models of ischemia-reperfusion, and cardioprotective signaling pathways. In addition, pharmacokinetics and pharmacodynamics studies in obese subjects and the management of patients subjected to mechanical ventilation are described. Moreover, the clinical efficacy of delirium incidence in patients with indication of non-invasive ventilation is shown. Finally, the available evidence from DEX is described by a group of Chilean pharmacologists and clinicians who have worked for more than 10 years on DEX.

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Dexmedetomidine protects the heart against ischemia-reperfusion injury by an endothelial eNOS/NO dependent mechanism

Abstract: .Dexmedetomidine protects the heart against ischemia-reperfusion injury by an endothelial eNOS/NO dependent mechanism.Pharmacological Research http://dx

Cited by 73 publications

References 68 publications

<p>Dexmedetomidine protects H9c2 cardiomyocytes against oxygen-glucose deprivation/reoxygenation-induced intracellular calcium overload and apoptosis through regulating FKBP12.6/RyR2 signaling</p>

<p>Dexmedetomidine protects H9c2 cardiomyocytes against oxygen-glucose deprivation/reoxygenation-induced intracellular calcium overload and apoptosis through regulating FKBP12.6/RyR2 signaling</p>

Clinical Pharmacokinetics and Pharmacodynamics of Dexmedetomidine

Dexmedetomidine Improves Cardiovascular and Ventilatory Outcomes in Critically Ill Patients: Basic and Clinical Approaches

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