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

• 批准号: 8843947
• 负责人: Joseph F Cotten
• 金额: $ 42.72万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8843947
• 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; Disease; Dose; Doxapram; Environmental air flow; Foundations; Health; Hypercapnia; Hypercapnic respiratory failure; Hypoxia; Intervention; Intravenous; Measures; Mediating; Molecular; Morbidity - disease rate; Morphine; Neuromuscular Diseases; Obesity; Opioid; Oxygen; Patients; Perioperative; Pharmaceutical Preparations; Pharmacotherapy; Plethysmography; Potassium; Potassium Channel; Premature Infant; Rattus; Regulation; Resistance; Respiratory physiology; Role; Site; Sleep Apnea Syndromes; Structure-Activity Relationship; Sudden infant death syndrome; Techniques; Testing; Therapeutic Agents; Ventilatory Depression; experience; flopropione; improved; in vivo; inhibitor/antagonist; molecular site; mutant; novel; patient safety; premature; pressure; prevent; response; therapeutic target

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）：阿片类药物引起的通气抑制是常见的临床问题，也是围手术期发病的重要原因。该提案的总体假设是，这种呼吸抑制可以通过药物干预来克服。具体来说，我们将测试以下假设：抑制颈动脉体中的 TASK-1 和 TASK-3 串联孔钾通道功能会刺激呼吸并防止吗啡引起的通气抑制。颈动脉体对于缺氧和高碳酸血症调节呼吸至关重要，TASK-1 和 TASK-3 异二聚体钾通道在颈动脉体化学传感细胞中提供主要的缺氧敏感钾电导。药物多沙普兰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。我们已经鉴定出另外两种 TASK-1 和 TASK-3 拮抗剂化合物，它们刺激呼吸的功效、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，这些药物可以预防吗啡在超致死剂量时引起的呼吸抑制。在目标 1 和 2 中，我们建议进行研究以确定颈动脉体，更具体地说，颈动脉内的 TASK-1 和 TASK-3 钾通道是否是 TASK 拮抗剂化合物刺激呼吸的作用位点。我们将使用体积描记法和血气分析来量化施用 TASK 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去神经颈动脉体的大鼠，我们将研究在其颈动脉体中表达拮抗剂抗性突变体TASK-3亚基的大鼠。这些拮抗剂抗性 TASK-3 突变体将在我们提出的研究中被鉴定。在目标 3 中，我们将使用动态潮气末强迫来表征每种 TASK 拮抗剂对缺氧和高碳酸血症呼吸调节的影响。最后，在目标4中，我们将确认TASK拮抗剂在逆转和预防吗啡引起的呼吸抑制方面的功效，并且我们将确定TASK拮抗剂对吗啡镇痛的作用。如果我们的假设正确，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，以提高阿片类药物给药期间患者的安全性。