ASSESSMENT OF THE BETA-ADRENERGIC-RECEPTOR PATHWAY IN THE INTACT FAILING HUMAN-HEART - PROGRESSIVE RECEPTOR DOWN-REGULATION AND SUBSENSITIVITY TO AGONIST RESPONSE
ASSESSMENT OF THE BETA-ADRENERGIC-RECEPTOR PATHWAY IN THE INTACT FAILING HUMAN-HEART - PROGRESSIVE RECEPTOR DOWN-REGULATION AND SUBSENSITIVITY TO AGONIST RESPONSE
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DOI：
10.1161/01.cir.74.6.1290
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发表时间：
1986-12-01
期刊：
影响因子：
37.8
通讯作者：
BRISTOW, MR
中科院分区：
文献类型：
--
作者：
FOWLER, MB;LASER, JA;BRISTOW, MR
我们开发了识别。beta的方法。-肾上腺素能受体与放射性配体（-）[125I]iodocyanopindolol （ICYP）在人右心室心肌内膜活检组织中的表达。在源自心内膜活检组织的粗制、高产膜制剂中，ICYP结合的特异性高（特异性约为90%）、高亲和力（Kd约为20 pM）、可饱和且对异丙肾上腺素（-）和（+）异构体具有立体特异性。轻度-中度和重度双心室功能不全的受试者的β分别下降。a-肾上腺素能受体密度分别为38.2%和57.7%，ICYP解离常数差异有统计学意义。根据左心室射血分数（LVEF）将受试者细分为轻度心功能障碍（LVEF < 0.50 > 0.40）和重度心力衰竭（LVEF < 0.20），并给予分级顺序输注多巴酚丁胺和葡萄糖酸钙。严重心功能障碍患者多巴酚丁胺dP/dt和卒中工作指数反应明显受损，而两组对钙的反应没有差异。这些数据表明，在完整的人心脏中(1)心内膜活检可用于直接分析。-肾上腺素能受体，(2)心力衰竭相关心肌。-肾上腺素能下调始于轻中度心室功能障碍；(3)心肌β降低。-受体密度与心力衰竭程度有关，(4)。-受体下调与- β细胞的药理学特异性损伤有关。-激动剂介导的收缩反应。
We developed methods for identifying .beta.-adrenergic receptors in human right ventricular endomyocardial biopsy tissue with the radioligand (-)[125I]iodocyanopindolol (ICYP). Specific ICYP binding in a crude, high-yield membrane preparation derived from endomyocardial biopsy tissue was high (specificity > 90%), of high affinity (Kd around 20 pM), saturable and stereospecific for the (-) vs the (+) isomer of isoproterenol. Subjects with mild-moderate and severe biventricular dysfunction had respective decreases in .beta.a-adrenergic receptor density of 38.2% and 57.7% when normalization methods were averaged, with so significant differences in ICYP dissociation constant. A subgroup of subjects was subdivided by left ventricular ejection fraction (LVEF) into those with mild cardiac dysfunction (LVEF < 0.50 > 0.40) and severe heart failure (LVEF < 0.20) and given graded sequential infusions of dobutamine and calcium gluconate. Those with severe cardiac dysfunction had marked impairment of the dobutamine dP/dt and stroke work index response, whereas these responses to calcium did not differ in the two groups. These data indicate that in the intact human heart (1) endomyocardial biopsy may be used for direct analysis of .beta.-adrenergic receptors, (2) heart failure-associated myocardial .beta.-adrenergic down-regulation begins with mild-moderate ventricular dysfunction, (3) reduction in myocardial .beta.-receptor density is related to degree of heart failure, and (4) .beta.-receptor down-regulation is associated with pharmacologically specific impairment of the .beta.-agonist-mediated contractile response.