Impaired cardiac muscarinic receptor function in dogs with heart failure.
Impaired cardiac muscarinic receptor function in dogs with heart failure.
复制标题
患有心力衰竭的狗的心脏毒蕈碱受体功能受损。
DOI：
10.1172/jci113528
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发表时间：
1988
期刊：
影响因子：
--
通讯作者：
Homcy,CJ
中科院分区：
文献类型：
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作者：
Vatner,DE;Lee,DL;Schwarz,KR;Longabaugh,JP;Fujii,AM;Vatner,SF;Homcy,CJ
先前的生理学研究表明，在心力衰竭时，副交感神经控制会发生改变。我们研究的目的是探讨心力衰竭对M受体的影响及其与腺苷环化酶的偶联。用[~3H]苯甲酸奎宁酯和丰富的左心室(LV)肌膜进行的配基结合研究表明，心力衰竭患者的M受体密度从对照的5.6+/-0.6pmol/mg下降了36%，而拮抗剂亲和力没有变化。然而，与卡巴胆碱和氧托莫林的激动剂竞争研究表明，导致这种差异的原因是左心衰时肌膜上高亲和力激动剂结合位点的丢失。同时还检测了M受体的功能效应。当在0.1 mM GTP和0.1 mM异丙肾上腺素中加入1微米乙酰甲胆碱时，正常左心室腺苷环化酶激活活性被抑制15%，而心力衰竭动物左心室肌膜腺苷环化酶激活活性仅被抑制5%，即使考虑到这些心力衰竭动物腺苷环化酶的降低。即使在乙酰甲胆碱浓度增加100倍的情况下，与正常左心室肌膜相比，左心室衰竭时对腺苷环化酶活性的抑制也明显较少。用百日咳毒素标记法测定，已知的将M受体偶联到腺苷环化酶上的GTP抑制蛋白的水平在左心衰患者中并未受到抑制。因此，在心力衰竭时，调节LV腺苷环化酶活性的抑制通路是有缺陷的。M受体密度的降低，特别是高亲和力激动剂结合成分的特异性丢失，似乎是导致这种异常的主要因素。
Prior physiological studies have suggested that parasympathetic control is altered in heart failure. The goal of our studies was to investigate the influence of heart failure on the muscarinic receptor, and its coupling to adenylate cyclase. Ligand binding studies using [3H]quinuclidinyl benzilate and enriched left ventricular (LV) sarcolemma, demonstrated that muscarinic receptor density in heart failure declined 36% from a control of 5.6 +/- 0.6 pmol/mg, with no change in antagonist affinity. However, agonist competition studies with both carbachol and oxotremorine showed that it was a loss of high affinity agonist binding sites in the sarcolemma from failing LV that accounted for this difference. The functional efficacy of the muscarinic receptor was also examined. When 1 microM methacholine was added to 0.1 mM GTP and 0.1 mM isoproterenol, adenylate cyclase stimulated activity was inhibited by 15% in normal LV but only 5% in LV sarcolemma from animals with heart failure even when the reduced adenylate cyclase in these heart failure animals was taken into account. Even at 100-fold greater concentrations of methacholine, significantly less inhibition of adenylate cyclase activity was observed in LV failure as compared with normal LV sarcolemma. Levels of the GTP-inhibitory protein known to couple the muscarinic receptor to adenylate cyclase, as measured with pertussis toxin labeling, were not depressed in LV failure. Thus, the inhibitory pathway regulating LV adenylate cyclase activity is defective in heart failure. The decrease in muscarinic receptor density, and in particular the specific loss of the high affinity agonist binding component of this receptor population, appears to be the major factor underlying this abnormality.Images