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TASK Potassium Channel Antagonists to Treat Opioid Depression of Breathing

TASK 钾通道拮抗剂治疗阿片类药物呼吸抑制

基本信息

批准号：
9264573
负责人：
Joseph F Cotten
金额：
$ 43.37万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-06-01 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9264573
关键词：
Absence of pain sensation Acute Adverse event Affect American Amino Acids Anatomy Apnea Area Bilateral Binding Blood Gas Analysis Brain Stem Breathing Carbon Dioxide Carotid Body Cells Chimera organism Chronic Obstructive Airway Disease Clinical Data Denervation Development Dimerization Disease Dose Doxapram Environmental air flow Foundations Hypercapnia Hypercapnic respiratory failure Hypoxia Intervention Intravenous Measures Mediating Morbidity - disease rate Morphine Neuromuscular Diseases Obesity Operative Surgical Procedures Opioid Oxygen Patients Perioperative Pharmaceutical Preparations Pharmacology Pharmacotherapy Plethysmography Potassium Potassium Channel Premature Infant Rattus Regulation Resistance Respiration Disorders Respiratory physiology Role Site Sleep Apnea Syndromes Structure-Activity Relationship Sudden infant death syndrome Techniques Testing Therapeutic Agents Ventilatory Depression dimer experience flopropione improved in vivo inhibitor/antagonist molecular site molecular targeted therapies mutant novel novel therapeutics patient safety premature pressure prevent public health relevance response therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Opioid drug-induced ventilatory depression is a common clinical problem and a significant cause of perioperative morbidity. The overall hypothesis of this proposal is that such respiratory depression may be overcome by pharmacological intervention. Specifically, we will test the hypothesis that inhibition of TASK-1 and TASK-3 tandem pore potassium channel function in the carotid body stimulates breathing and prevents morphine-induced ventilatory depression. The carotid body is essential for regulation of breathing by hypoxia and hypercarbia, and the TASK-1 and TASK-3 heterodimer potassium channel provides the predominant hypoxia-sensitive potassium conductance in carotid body chemosensing cells. The drug doxapram stimulates breathing through carotid body activation and is a potent TASK-1 and TASK-3 potassium channel antagonist. We have identified two additional TASK-1 and TASK-3 antagonist compounds that stimulate breathing with an efficacy, potency, and duration that markedly exceed that of doxapram. Our preliminary data also suggest these agents may prevent morphine-induced depression of breathing at supralethal doses. In Aims 1 and 2, we propose studies to determine if the carotid body and, more specifically, if TASK-1 and TASK-3 potassium channels within the carotid are the sites of action through which the TASK antagonist compounds stimulate breathing. We will quantify rat breathing before and after administration of the TASK antagonist compounds using plethysmography and blood gas analysis. We will study rats with and without surgically denervated carotid bodies, and we will study rats expressing antagonist-resistant mutant TASK-3 subunits in their carotid bodies. These antagonist-resistant TASK-3 mutants will be identified in our proposed studies. In Aim 3, we will use dynamic end-tidal forcing to characterize the effect of each TASK antagonist on breathing regulation by hypoxia and hypercarbia. Finally, in Aim 4, we will confirm the efficacy of TASK antagonists in reversing and preventing morphine-induced depression of breathing, and we will determine the effect of TASK antagonists on morphine analgesia. If our hypothesis is correct, these studies will validate TASK-1 and TASK-3 potassium channels as a therapeutic target for treatment of breathing disorders and will provide a novel pharmacologic strategy to improve patient safety during opioid administration.

描述（由申请人提供）：阿片类药物诱导的抑郁症是一种常见的临床问题，也是围手术期发病的重要原因。这一建议的总体假设是，这种呼吸抑制可以通过药物干预来克服。具体来说，我们将测试的假设，即在颈动脉体中的ASK-1和ASK-3串联孔钾通道功能的抑制刺激呼吸，防止吗啡诱导的抑郁症。颈动脉体对于通过缺氧和高碳酸血症调节呼吸是必不可少的，并且在颈动脉体化学传感细胞中，ASK-1和ASK-3异二聚体钾通道提供了主要的缺氧敏感性钾电导。药物doxapram通过颈动脉体激活刺激呼吸，是一种有效的TASK-1和TASK-3钾通道拮抗剂。我们已经鉴定了另外两种ASK-1和ASK-3拮抗剂化合物，其刺激呼吸的功效、效力和持续时间明显超过多沙普仑。我们的初步数据还表明，这些药物可以防止吗啡诱导的呼吸抑制在超致死剂量。在目的1和2中，我们提出研究以确定颈动脉体，更具体地说，颈动脉内的ASK-1和ASK-3钾通道是否是ASK拮抗剂化合物刺激呼吸的作用部位。我们将使用体积描记法和血气分析来量化在施用ASK拮抗剂化合物之前和之后的大鼠呼吸。我们将研究有和没有手术失神经支配颈动脉体的大鼠，我们将研究在颈动脉体中表达拮抗剂抗性突变体ASK-3亚基的大鼠。这些拮抗剂耐药的ASK-3突变体将在我们提出的研究中鉴定。在目标3中，我们将使用动态潮气末强迫来表征每种ASK拮抗剂对缺氧和高碳酸血症呼吸调节的影响。最后，在目的4中，我们将确认ASK拮抗剂在逆转和预防吗啡诱导的呼吸抑制中的功效，并且我们将确定ASK拮抗剂对吗啡镇痛的作用。如果我们的假设是正确的，这些研究将验证TASK-1和TASK-3钾通道作为治疗呼吸障碍的治疗靶点，并将提供一种新的药理学策略，以改善阿片类药物给药期间的患者安全性。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A Novel Strategy to Reverse General Anesthesia by Scavenging with the Acyclic Cucurbit[n]uril-type Molecular Container Calabadion 2.

DOI：
10.1097/aln.0000000000001199
发表时间：
2016-08
期刊：
Anesthesiology
影响因子：
8.8
作者：
Diaz-Gil D;Haerter F;Falcinelli S;Ganapati S;Hettiarachchi GK;Simons JC;Zhang B;Grabitz SD;Moreno Duarte I;Cotten JF;Eikermann-Haerter K;Deng H;Chamberlin NL;Isaacs L;Briken V;Eikermann M
通讯作者：
Eikermann M

Anesthetic pretreatment confers thermotolerance on Saccharomyces cerevisiae yeast.

DOI：
10.1016/j.bbrc.2019.11.083
发表时间：
2020-02-05
期刊：
Biochemical and biophysical research communications
影响因子：
3.1
作者：
Luethy A;Kindler CH;Cotten JF
通讯作者：
Cotten JF

The effect of atomoxetine, a selective norepinephrine reuptake inhibitor, on respiratory arrest and cardiorespiratory function in the DBA/1 mouse model of SUDEP.

托莫西汀（一种选择性去甲肾上腺素再摄取抑制剂）对 SUDEP DBA/1 小鼠模型呼吸骤停和心肺功能的影响。

DOI：
10.1016/j.eplepsyres.2017.08.005
发表时间：
2017
期刊：
Epilepsy research
影响因子：
2.2
作者：
Zhao,Haiting;Cotten,JosephF;Long,Xiaoyan;Feng,Hua-Jun
通讯作者：
Feng,Hua-Jun

Etomidate and Ketamine: Residual Motor and Adrenal Dysfunction that Persist beyond Recovery from Loss of Righting Reflex in Rats.

依托咪酯和氯胺酮：大鼠翻正反射丧失后持续存在的残余运动和肾上腺功能障碍。

DOI：
10.3390/ph8010021
发表时间：
2014
期刊：
Pharmaceuticals (Basel, Switzerland)
影响因子：
0
作者：
Diaz-Gil,Daniel;Mueller,Noomi;Moreno-Duarte,Ingrid;Lin,Hsin;Ayata,Cenk;Cusin,Cristina;Cotten,JosephF;Eikermann,Matthias
通讯作者：
Eikermann,Matthias

The latest pharmacologic ventilator.

最新的药理呼吸机。