心脏停搏后β-肾上腺素能信号传导的下游缺陷及其与心肌收缩力的关系。

Downstream defects in beta-adrenergic signaling and relation to myocyte contractility after cardioplegic arrest.

作者信息

Houck W V, Thomas C V, Doscher M A, Wang Y H, Hebbar L, Joshi J D, Mukherjee R, Crawford F A, Spinale F G

机构信息

Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston 29425, USA.

出版信息

J Thorac Cardiovasc Surg. 1998 Jan;115(1):190-9. doi: 10.1016/s0022-5223(98)70457-x.

DOI:10.1016/s0022-5223(98)70457-x

PMID:9451063

Abstract

OBJECTIVE

Transient left ventricular dysfunction can occur after hypothermic, hyperkalemic cardioplegic arrest and is associated with decreased beta-adrenergic receptor responsiveness. Occupancy of the beta-adrenergic receptor activates adenylate cyclase, which phosphorylates the L-type Ca2+ channel-enhancing myocyte contractility. The goal of this study was to identify potential mechanisms that contribute to the defects in the beta-adrenergic receptor signaling cascade after cardioplegic arrest.

METHODS

Isolated left ventricular porcine myocytes were assigned to one of two treatment groups: (1) cardioplegic arrest (24 mEq/L K+, 4 degrees C x 2 hours, then 5 minutes in 37 degrees C cell media; n = 130) or (2) normothermic control (cell media, 37 degrees C x 2 hours; n = 222). Myocyte contractility was assessed at baseline and after either beta-adrenergic receptor occupancy (25 nmol/L isoproterenol [INN: isoprenaline]), activation of adenylate cyclase (0.5 mumol forskolin), or direct activation of the L-type Ca(2+)-channel (10 nmol/L or 100 nmol/L (-)BayK 8644).

RESULTS

Myocyte velocity of shortening (micron/sec) was increased with beta-adrenergic receptor occupancy or direct adenylate cyclase stimulation compared with baseline in the normothermic group (187.3 +/- 6.9, 181.7 +/- 10.2, and 73.9 +/- 2.9, respectively; p < 0.0001) and after cardioplegic arrest (128.6 +/- 8.9, 124.3 +/- 9.4, and 46.1 +/- 2.6, respectively; p < 0.0001). However, the response after cardioplegic arrest was significantly reduced compared with normothermic values under all conditions (p = 0.012). Direct activation of the L-type Ca(2+)-channel, which eliminates beta-adrenergic receptor-dependent events, increased myocyte contractility in the normothermic group (161.90 +/- 12.0, p < 0.0001) and after cardioplegic arrest (92.78 +/- 6.8, p < 0.0001), but the positive inotropic response appeared reduced compared with normothermic control values (p = 0.003).

CONCLUSION

These findings suggest that contributory mechanisms for the reduced beta-adrenergic receptor-mediated response after hypothermic, hyperkalemic cardioplegic arrest lie downstream from these specific components of the transduction pathway and likely include defects in Ca2+ homeostasis, myofilament Ca2+ sensitivity, or both.

摘要

目的

低温、高钾停搏后可发生短暂性左心室功能障碍，且与β-肾上腺素能受体反应性降低有关。β-肾上腺素能受体被占据会激活腺苷酸环化酶，后者使L型钙通道磷酸化，增强心肌细胞收缩力。本研究的目的是确定导致停搏后β-肾上腺素能受体信号级联缺陷的潜在机制。

方法

将分离的猪左心室肌细胞分为两个治疗组之一：（1）停搏组（24 mEq/L钾，4℃×2小时，然后在37℃细胞培养基中放置5分钟；n = 130）或（2）常温对照组（细胞培养基，37℃×2小时；n = 222）。在基线时以及β-肾上腺素能受体被占据（25 nmol/L异丙肾上腺素[国际非专利药品名称：异丙肾]）、腺苷酸环化酶激活（0.5 μmol福司可林）或L型钙通道直接激活（10 nmol/L或100 nmol/L（-）BayK 8644）后评估心肌细胞收缩力。

结果

与常温组基线相比（分别为187.3±6.9、181.7±10.2和73.9±2.9；p < 0.0001）以及停搏后（分别为128.6±8.9、124.3±9.4和46.1±2.6；p < 0.0001），β-肾上腺素能受体被占据或腺苷酸环化酶直接刺激后心肌细胞缩短速度（微米/秒）增加。然而，在所有条件下，停搏后的反应与常温值相比均显著降低（p = 0.012）。L型钙通道的直接激活消除了β-肾上腺素能受体依赖性事件，使常温组（161.90±12.0，p < 0.0001）和停搏后（92.78±6.8，p < 0.0001）的心肌细胞收缩力增加，但正性肌力反应与常温对照组值相比似乎降低（p = 0.003）。