Dexmedetomidine Pretreatment Protects Against Myocardial Ischemia/Reperfusion Injury by Activating STAT3 Signaling

Anesthesia & Analgesia, Journal Year: 2023, Volume and Issue: unknown

Published: May 5, 2023

BACKGROUND: Myocardial infarction is a common perioperative complication, and blood flow restoration causes ischemia/reperfusion injury (IRI). Dexmedetomidine (DEX) pretreatment can protect against cardiac IRI, but the mechanism still insufficiently understood. METHODS: In vivo, myocardial (30 minutes/120 minutes) was induced via ligation then reperfusion of left anterior descending coronary artery (LAD) in mice. Intravenous infusion 10 μg/kg DEX performed 20 minutes before ligation. Moreover, α2-adrenoreceptor antagonist Yohimbine STAT3 inhibitor Stattic were applied 30 ahead infusion. vitro, hypoxia/reoxygenation (H/R) with for 1 hour isolated neonatal rat cardiomyocytes. addition, pretreatment. RESULTS: mouse model, lowered serum creatine kinase-MB isoenzyme (CK-MB) levels (2.47 ± 0.165 vs 1.55 0.183; P < .0001), downregulated inflammatory response ( ≤ .0303), decreased 4-hydroxynonenal (4-HNE) production cell apoptosis = .0074), promoted phosphorylation (4.94 0.690 6.68 0.710, which could be blunted by Stattic. The bioinformatic analysis differentially expressed mRNAs further confirmed that signaling might involved cardioprotection DEX. Upon H/R treatment cardiomyocytes, 5 μM improved viability .0005), inhibited reactive oxygen species (ROS) calcium overload (both .0040), .0470), at Tyr705 (0.102 0.0224 0.297 0.0937; .0001) Ser727 (0.586 0.177 0.886 0.0546; .0157), abolished CONCLUSIONS: protects presumably promoting vivo vitro.

Language: Английский

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Review of clinical pharmacokinetics and pharmacodynamics of clonidine as an adjunct to opioids in palliative care

Basic & Clinical Pharmacology & Toxicology, Journal Year: 2024, Volume and Issue: 134(4), P. 485 - 497

Published: Jan. 26, 2024

Abstract Clonidine is an α‐adrenoceptor agonist acting on receptors in the brain and peripheral tissues, leading to a reduction sympathetic outflow release of certain neurotransmitters. has multiple uses across various medical conditions. One its as adjuvant anaesthetic analgesic agents specially opioids, mostly administered through intravenous epidural routes. The effective cancer pain management, are associated with side effects such sedation, pruritus, constipation, nausea, respiratory depression, tolerance dependence. Combination clonidine opioids seems help achieve better management less need opioids. Use palliative care been common, but it gradually gaining recognition for potential benefits managing symptoms like agitation. This combination approach explored settings, including agitation, where patients experience complex refractory symptoms. It be well tolerated gives symptom relief. available literature clonidine's use agitation especially subcutaneous form, limited outdated. Therefore, optimal dosing, safety profile overall effectiveness requires further exploration prospective research studies.

Language: Английский

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Dexmedetomidine and Perioperative Arrhythmias

Journal of Cardiothoracic and Vascular Anesthesia, Journal Year: 2024, Volume and Issue: 38(5), P. 1221 - 1227

Published: Jan. 10, 2024

Language: Английский

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Additive Effects of Clonidine Used in Propofol Sedation in Colonoscopy

Anesthesiology and Pain Medicine, Journal Year: 2025, Volume and Issue: 15(1)

Published: Feb. 25, 2025

Background: Propofol is commonly used for sedation during colonoscopy but often requires high doses. Objectives: This study aimed to compare the outcomes of propofol alone versus combined with clonidine sedation. Methods: In this randomized, double-blind controlled trial, 60 adult patients scheduled elective were enrolled. Patients divided into two groups: Group 1 (G1) received alone, while group 2 (G2) plus μg/kg intravenously over 10 minutes. infusion was initiated at 25 - 75 μg/kg/min IV first 15 minutes, then titrated 50 based on clinical response. Results: Sedation onset significantly faster in G2 than G1 (P = 0.001). The total requirement 22% lower Heart rate (HR) and mean arterial pressure (MAP) induction end procedure < 0.05). Patient satisfaction scores higher 0.042). observer's assessment alertness/sedation (OAA/S) score after 0.015), indicating deeper However, Aldrete post-anesthesia care unit (PACU) 0.001), suggesting a slower recovery. Conclusions: addition led onset, reduced requirements, improved patient satisfaction, sedation, potentially prolonged recovery times.

Language: Английский

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Comprehensive mini-review: therapeutic potential of cannabigerol – focus on the cardiovascular system

Frontiers in Pharmacology, Journal Year: 2025, Volume and Issue: 16

Published: March 26, 2025

Backgrounds Cannabigerol (CBG) is a non-psychoactive phytocannabinoid with broad spectrum of biological effects. However, there still too little research on its safety especially effects the cardiovascular system. Due to agonist alpha-2-adrenergic receptors (α 2 AR), it speculated that may have applications in pharmacotherapy metabolic syndrome, particularly hypertension. Thus, aim our review was analyse therapeutic potential CBG diseases. Methods The based searches PubMed and Web Science databases. Keywords were used identify literature containing mechanistic information Results A shows exhibits hypotensive mice probably through α AR agonism. Other numerous vitro vivo studies show has anti-inflammatory, antioxidant also regulates cell apoptosis. improved tissue sensitivity insulin, showed efficacy inhibiting platelet aggregation. are reports adverse high doses liver architecture function, which calls into question usefulness profile. Conclusion Above mentioned beneficial properties suggest be useful treating hypertension syndrome. lack chronic administration parameters condition, necessary determine need for future other indications.

Language: Английский

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The signaling and selectivity of α‐adrenoceptor agonists for the human α2A, α2B and α2C‐adrenoceptors and comparison with human α1 and β‐adrenoceptors

Pharmacology Research & Perspectives, Journal Year: 2022, Volume and Issue: 10(5)

Published: Sept. 13, 2022

α2-adrenoceptors, (α2A, α2B and α2C-subtypes), are Gi-coupled receptors. Central activation of brain α2A α2C-adrenoceptors is the main site for α2-agonist mediated clinical responses in hypertension, ADHD, muscle spasm ITU management sedation, reduction opiate requirements, nausea delirium. However, despite having same Gi-potency functional assays, some α2-agonists also stimulate Gs-responses whilst others do not. This was investigated. Agonist to 49 different α-agonists were studied (CRE-gene transcription, cAMP, ERK1/2-phosphorylation binding affinity) CHO cells stably expressing human α2A, or α2C-adrenoceptor, enabling ligand intrinsic efficacy be determined (binding K

Language: Английский

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Novel Scaffold Agonists of the α2A Adrenergic Receptor Identified via Ensemble-Based Strategy

Molecules, Journal Year: 2024, Volume and Issue: 29(5), P. 1097 - 1097

Published: Feb. 29, 2024

The α2A adrenergic receptor (α2A-AR) serves as a critical molecular target for sedatives and analgesics. However, α2A-AR ligands with an imidazole ring also interact imidazoline well other proteins lead to undesirable effects, motivating us develop more novel scaffold ligands. For this purpose, we employed ensemble-based ligand discovery strategy, integrating long-term dynamics (MD) simulations virtual screening, identify new potential agonists scaffold. Our results showed that compounds SY-15 SY-17 exhibited significant biological effects in the preliminary evaluation of protein kinase A (PKA) redistribution assays. They reduced levels intracellular cyclic adenosine monophosphate (cAMP) dose-dependent manner. Upon treatment cells 100 μM concentrations SY-17, there was respective decrease cAMP by 63.43% 53.83%. Subsequent computational analysis conducted elucidate binding interactions α2A-AR. free energies calculated MD were −45.93 −71.97 kcal/mol. revealed both act bitopic agonists, occupying orthosteric site exosite simultaneously. findings integrative experimental approaches could offer enhance affinity selectivity through dual-site occupancy provide direction rational design

Language: Английский

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Alpha-2-adrenergic agonists reduce resting energy expenditure in humans during external cooling

Temperature, Journal Year: 2024, Volume and Issue: 11(3), P. 280 - 298

Published: April 21, 2024

Intravenous alpha-2-adrenergic receptor agonists reduce energy expenditure and lower the temperature when shivering begins in humans, allowing a decrease core body temperature. Because there are few data about similar effects from oral drugs, we tested whether single doses of sedative dexmedetomidine (1 µg/kg sublingual or 4 swallowed) muscle relaxant tizanidine (8 mg 16 mg), combined with surface cooling, humans. A total 26 healthy participants completed 41 one-day laboratory studies measuring using an ingested telemetry capsule indirect calorimetry for up to 6 hours after drug ingestion. Dexmedetomidine induced median 13% – 19% peak reduction 15% 22% relative baseline. Core decreased 0.5°C 0.6°C 0.7°C respectively. Decreases occurred reductions expenditure. Energy increased control but did not occur tizanidine. Plasma levels were related mean change. heart rate, blood pressure, respiratory cardiac stroke volume index, index associated change metabolic rate higher doses. We conclude that both allow

Language: Английский

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Adrenoceptors: Receptors, Ligands and Their Clinical Uses, Molecular Pharmacology and Assays

Handbook of experimental pharmacology, Journal Year: 2024, Volume and Issue: unknown, P. 55 - 145

Published: Jan. 1, 2024

Language: Английский

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The α₂ Adrenoceptor Agonist and Sedative/Anaesthetic Dexmedetomidine Excites Diverse Neuronal Types in the Ventrolateral Preoptic Area of Male Mice

ASN NEURO, Journal Year: 2023, Volume and Issue: 15

Published: Jan. 1, 2023

The unique sedative activities with rapid arousal of dexmedetomidine (Dex) are not fully understood. Growing evidence suggests the involvement ventrolateral preoptic area (VLPO) in sleep–wake cycle. major type VLPO is sleep-active neurons, inhibited by noradrenaline (NA(−) neurons). other neurons activated NA (NA(+) neurons), which wake-active. Previous research showed that Dex-induced sedation and sleep homeostasis likely share common mechanisms. To explore underlying mechanisms Dex VLPO, vivo polysomnography recording vitro electrophysiological were used our study. Bath application (2 μM) increased firing rate both NA(−) NA(+) neurons. Compared to control group, there was no difference after RS79948 (1 mM) administration, an α 2 receptor antagonist. No detected regarding resting membrane potential (RMP) amplitude (−) μM). Moreover, significantly reduced frequency miniature inhibitory postsynaptic currents (mIPSCs) These electrophysiology results consistent behavioral sedation, nonrapid eye movement (NREM sleep) expression c-Fos during dark phase intraperitoneal injection (80 μg/kg). In conclusion, activates via presynaptic receptors. This mechanism may explain properties arousal. Summary Statement Dexmedetomidine important ICU sedative. Activating using recording, this

Language: Английский

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