Neuromuscular blocker-induced asthma during anesthesia

描述（由申请人提供）：Rapacuronium是一种新的快速作用非去极化神经肌肉阻断药物，于1999年发布使用。它是专门用于在全身麻醉诱导期间促进气管插管的，但与危及生命的支气管痉挛有关。至少有5名患者死亡，该药最近已停止临床使用。这种气道收缩的机制目前尚不清楚。可能的机制包括组胺释放、胆碱酯酶抑制、M3毒蕈碱受体激动作用和M2毒蕈碱受体拮抗作用。了解这种药物诱导气道收缩的机制以防止新引入的神经肌肉阻滞剂再次发生这种情况是非常重要的。迫切需要一种安全有效的超短效非去极化神经肌肉阻滞剂用于常规临床应用，直到找到一种为止，研究将继续进行。我们假设具有选择性M2拮抗特性的神经肌肉阻滞剂可增强副交感神经释放乙酰胆碱介导支气管收缩。气管插管时，副交感神经释放乙酰胆碱，作用于气道平滑肌上的M3毒蕈碱受体，促进支气管收缩。初步数据表明，雷帕库溴铵诱导致死性支气管痉挛的机制是选择性抑制M2毒蕈碱受体。我们将使用体内和体外方法来确定神经肌肉阻滞剂诱导支气管收缩增强的机制。M2和M3毒蕈碱受体的神经肌肉亲和性将通过放射配体结合和功能测定（腺苷酸环化酶和肌醇磷酸测定）来确定。神经肌肉阻滞剂对乙酰胆碱酯酶活性的影响也将被测量。神经肌肉阻滞剂增强副交感神经乙酰胆碱释放的能力将在器官浴中用豚鼠气管进行测量。神经肌肉阻滞剂增强迷走神经介导的支气管收缩或通过组胺释放增加气道压力的能力将在体内使用特征良好的豚鼠模型进行测量。这一机制需要明确地描述，以便它可以作为临床实践中开发的新药的金标准筛选。必须了解神经肌肉阻滞剂诱发支气管痉挛的潜在机制，以便每年接受全身麻醉的数百万患者不会遭受不必要的危及生命的支气管痉挛。

DESCRIPTION (provided by applicant): Rapacuronium, a new rapidly acting nondepolarizing neuromuscular blocking drug, was released for use in 1999. It was developed specifically to facilitate tracheal intubation during the induction of general anesthesia, but has been associated with life threatening bronchospasm. At least five patients have died and the drug was recently withdrawn from clinical use. The mechanism underlying this airway constriction is not currently known. Possible mechanisms include histamine release, cholinesterase inhibition, M3 muscarinic receptor agonism and M2 muscarinic receptor antagonism. It is extremely important that we understand the mechanism by which this drug induces airway constriction to prevent this from ever occurring again with newly introduced neuromuscular blocking agents. A safe and effective ultra-short acting nondepolarizing neuromuscular blocker is urgently needed for routine clinical use, and until one is found the search will continue. We hypothesize that neuromuscular blocking agents that have selective M2 antagonistic properties potentiate parasympathetic release of acetylcholine mediating bronchoconstriction. During intubation of the trachea, parasympathetic nerves release acetylcholine that act on M3 muscarinic receptors on airway smooth muscle to promote bronchoconstriction. Preliminary data generated from this proposal strongly suggest that the mechanism by which rapacuronium induced fatal bronchospasm is by selective inhibition of M2 muscarinic receptors. We will use in vivo and in vitro approaches to define the mechanism of neuromuscular blocking agent-induced potentiation of bronchoconstriction. Neuromuscular affinities for M2 and M3 muscarinic receptors will be defined by radioligand binding and functional assays (adenylyl cyclase and inositol phosphate assays). Neuromuscular blocking agents effects on acetyl cholinesterase activity will also be measured. The ability of neuromuscular blocking agents to enhance acetylcholine release from parasympathetic nerves will be measured using guinea pig trachea in organ baths. The ability of neuromuscular blocking agents to potentiate vagal nerve mediated bronchoconstriction or to increase airway pressure via histamine release will be measured in vivo using a well-characterized guinea pig model. This mechanism needs to be clearly characterized so that it can serve as a gold standard screen for new agents developed for clinical practice. It is imperative that the mechanism of neuromuscular blocking agents potential to induce bronchospasm be understood so that the millions of patients who undergo general anesthesia on a yearly basis are not subjected to unnecessary life threatening bronchospasm.