Schumacher C, Becker H, Conrads R, Schotten U, Pott S, Kellinghaus M, Sigmund M, Schöndube F, Preusse C, Schulte H D
Medizinische Klinik I, Rheinisch-Westfälische Technische Hochschule Aachen, Germany.
Naunyn Schmiedebergs Arch Pharmacol. 1995 Apr;351(4):398-407. doi: 10.1007/BF00169081.
Only few data are available concerning the biochemical and functional state of the beta-adrenergic system in hypertrophied human myocardium. The present study was to investigate the myocardial beta-adrenergic signal transduction system in hypertrophic obstructive cardiomyopathy (HOCM). Thin myocardial strips were prepared from surgically excised, septal myocardium from 7 patients with HOCM and their force of contraction was measured in vitro. The positive inotropic effects of calcium and dihydro-ouabain, both acting independently of beta-adrenoceptors and cAMP, were similar in these preparations to those, previously published, seen with nonfailing myocardium. In contrast, the beta-adrenoceptor agonist isoprenaline and the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX) had reduced positive inotropic effects. Their EC50-values were about 10 fold higher than the respective EC50-values published for nonfailing myocardium. The positive inotropic potencies of isoprenaline and IBMX were reduced in HOCM by as much as they were in the additionally investigated myocardium from 6 patients with severe mitral regurgitation (MR, NYHA III). In order to clarify whether the functional alterations are related to changes in the beta-adrenoceptors, beta-adrenoceptor density and beta 1: beta 2-adrenoceptor subtype distribution were determined in the same myocardium using 125I-Iodocyanopindolol saturation binding. Myocardial beta-adrenoceptor density was reduced to 68% in HOCM and to 56% in MR compared to nonfailing myocardium controls (NF: 64.8 +/- 6.5 fmol/mg protein). In HOCM, this reduction was due to a selective down regulation of beta 1-adrenoceptors (24.9 +/- 3.7 fmol/mg protein vs NF: 46.4 +/- 6.8 fmol/mg protein, P < 0.05), whereas beta 2-adrenoceptor density was unchanged (19.0 +/- 1.9 fmol/mg protein vs NF: 18.4 +/- 3.3 fmol/mg protein, n.s.). In MR both beta-adrenoceptor subtypes were reduced (beta 1: 26.9 +/- 1.4 fmol/mg protein, beta 2: 9.6 +/- 1.7 fmol/mg protein; both P < 0.05 vs NF). Electrochemically determined plasma catecholamine levels were elevated in MR. However, plasma catecholamine levels were normal or slightly below normal in HOCM. In summary, myocardial beta-adrenoceptors are downregulated and their function is impaired in HOCM. This desensitization is not caused by a negative feedback regulation due to increased plasma catecholamines. The present results show that the desensitizations of the beta-adrenergic system associated with HOCM has characteristics that indicate a major deviation in its development from that of the beta-adrenergic desensitization previously described to occur in congestive heart failure.
关于肥厚型人类心肌中β-肾上腺素能系统的生化和功能状态，仅有少量数据。本研究旨在调查肥厚型梗阻性心肌病（HOCM）中的心肌β-肾上腺素能信号转导系统。从7例HOCM患者手术切除的室间隔心肌制备薄心肌条，并在体外测量其收缩力。钙和二氢哇巴因的正性肌力作用均独立于β-肾上腺素能受体和环磷酸腺苷（cAMP），在这些制剂中，其作用与先前发表的正常心肌的作用相似。相比之下，β-肾上腺素能受体激动剂异丙肾上腺素和磷酸二酯酶抑制剂3-异丁基-1-甲基黄嘌呤（IBMX）的正性肌力作用减弱。它们的半数有效浓度（EC50）值比正常心肌公布的相应EC50值高约10倍。HOCM中异丙肾上腺素和IBMX的正性肌力效能降低程度与另外研究的6例严重二尖瓣反流（MR，纽约心脏协会III级）患者的心肌相同。为了阐明功能改变是否与β-肾上腺素能受体的变化有关，使用125I-碘氰吲哚洛尔饱和结合法在同一心肌中测定β-肾上腺素能受体密度和β1:β2-肾上腺素能受体亚型分布。与正常心肌对照（NF：64.8±6.5 fmol/mg蛋白）相比，HOCM中心肌β-肾上腺素能受体密度降至68%，MR中降至56%。在HOCM中，这种降低是由于β1-肾上腺素能受体的选择性下调（24.9±3.7 fmol/mg蛋白 vs NF：46.4±6.8 fmol/mg蛋白，P<0.05），而β2-肾上腺素能受体密度未改变（19.0±1.9 fmol/mg蛋白 vs NF：18.4±3.3 fmol/mg蛋白，无统计学意义）。在MR中，两种β-肾上腺素能受体亚型均降低（β1：26.9±1.4 fmol/mg蛋白，β2：9.6±1.7 fmol/mg蛋白；两者与NF相比P<0.05）。电化学测定的血浆儿茶酚胺水平在MR中升高。然而，HOCM中的血浆儿茶酚胺水平正常或略低于正常。总之，HOCM中心肌β-肾上腺素能受体下调且其功能受损。这种脱敏不是由血浆儿茶酚胺增加引起的负反馈调节所致。目前的结果表明，与HOCM相关的β-肾上腺素能系统脱敏具有一些特征，表明其发展过程与先前描述的发生在充血性心力衰竭中的β-肾上腺素能脱敏有很大差异。
