Altered cardiovascular responses in mice lacking the M1 muscarinic acetylcholine receptor
Altered cardiovascular responses in mice lacking the M1 muscarinic acetylcholine receptor
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DOI：
10.1124/jpet.301.1.129
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发表时间：
2002-04-01
影响因子：
3.5
通讯作者：
Nathanson, NM
中科院分区：
文献类型：
--
作者：
Hardouin, SN;Richmond, KN;Nathanson, NM
虽然M-2毒蕈碱型乙酰胆碱受体（mAChR）是心脏中主要的功能性mAChR亚型，但心血管系统对乙酰胆碱（ACh）的某些反应可能由其他mAChR亚型介导。使用M-1敲除（M-1-KO）小鼠研究M-1 mAChR对心脏功能的潜在作用。体内心脏动力学分析显示，野生型（WT）和M-1-KO小鼠之间的心率（HR）、左心室压力（DLVP）、左心室dP/dt（max）（LV dP/dt（max））和平均血压（MBP）的基础值相似。注射推定的M-1选择性激动剂4-（间氯苯基氨基甲酰氧基）-2-丁炔基三甲基铵（McN-A-343）可导致WT小鼠的LV dP/dt（max）、DLVP、HR和MBP增加，但不影响M-1-KO小鼠的血流动力学功能。WT小鼠中McN-A-343的刺激作用被普萘洛尔预处理阻断，表明M-1 mAChRs对交感节后神经元的刺激引起儿茶酚胺的释放。WT和M-1-KO小鼠静脉注射ACh均引起房室传导阻滞，但心房除极或房颤频率无显著变化。免疫沉淀和逆转录聚合酶链反应未能检测到M-1 mAChR在WT小鼠心肌组织中的表达。卡巴胆碱诱导的心脏组织中磷脂酶C活性增加在WT和M-1-KO小鼠之间没有差异。这些结果表明：1）交感节后细胞上M-1 mAChR亚型的激活导致儿茶酚胺介导的心脏刺激，2）M-1 mAChR在小鼠心脏中不表达，3）给予小鼠ACh诱导心律失常。
Although the M-2 muscarinic acetylcholine receptor (mAChR) is the predominant functional mAChR subtype in the heart, some responses of the cardiovascular system to acetylcholine (ACh) may be mediated by other mAChR subtypes. The potential effect of M-1 mAChR on heart function was investigated using M-1 knockout (M-1-KO) mice. In vivo cardiodynamic analysis showed that basal values of heart rate (HR), developed left ventricular pressure (DLVP), left ventricular dP/dt(max) (LV dP/dt(max)), and mean blood pressure (MBP) were similar between wild-type (WT) and M-1-KO mice. Injection of the putative M-1 selective agonist 4-(m-chlorophenyl-carbamoyloxy)-2-butynyltrimethylammonium (McN-A-343) produced an increase in LV dP/dt(max), DLVP, HR, and MBP in WT mice but did not affect hemodynamic function in the M-1-KO mice. The stimulatory effect of McN-A-343 in WT mice was blocked by pretreatment with propranolol, indicating that stimulation of the M-1 mAChRs on sympathetic postganglionic neurons evoked release of catecholamines. Intravenous injection of ACh in both WT and M-1-KO mice caused atrioventricular conduction block, without a significant change in the frequency of atrial depolarization, or atrial fibrillation. Immunoprecipitation and reverse transcriptase-polymerase chain reaction failed to detect the expression of M-1 mAChR in cardiac tissue from WT mice. The carbachol-induced increase of phospholipase C activity in cardiac tissues was not different between WT and M-1-KO mice. These results demonstrate that 1) activation of M-1 mAChR subtype on sympathetic postganglionic cells results in catecholamine-mediated cardiac stimulation, 2) M-1 mAChR is not expressed in mouse heart, and 3) administration of ACh to mice induces arrhythmia.