Herz- und Diabeteszentrum NRW, Klinik f. Thorax- und Kardiovaskularchirurgie, E. & H. Klessmann-Institut f. Kardiovaskuläre Forschung und Entwicklung, Bad Oeynhausen, Germany.
J Heart Lung Transplant. 2012 Oct;31(10):1127-35. doi: 10.1016/j.healun.2012.07.005.
Response to catecholamines is blunted in terminal heart failure due to β-receptor downregulation and uncoupling from adenylyl cyclase (AC). Improved myocardial responsiveness to catecholamines after ventricular assist device (VAD) support is associated with upregulation of β1-adrenergic receptors (β1-ARs). Little is known about the regulation of AC and β2-AR coupling after VAD; moreover β2-AR stimulation during VAD was claimed to induce myocardial recovery.
We analyzed in VAD-supported human myocardium the regulation of AC activity upon β1-AR and selective β2-AR stimulation in 8 non-failing hearts (NF) and 17 paired samples of VAD patients. AC messenger RNA was measured by TaqMan. AC was stimulated via β2-AR using clenbuterol (β2-AR agonist) and bisoprolol (β1-AR blocker). Organ bath experiments were done with trabeculae from both ventricles. Samples were stratified according to chronic or acute heart failure history.
Isoprenaline-induced AC activity was downregulated (p < 0.001) pre-VAD and increased significantly (p < 0.05) after unloading (mean ± standard deviation pmole/mg/min) in NF (47.9 ± 14.9), pre-VAD (24.35 ± 13.3), and post-VAD (50.04 ± 50.25). Forskolin stimulation revealed significant (p < 0.05) upregulation of AC activity during VAD, especially in acutely failing hearts (NF, 192.1 ± 68.7; pre-VAD, 191.1 ± 60.4; post-VAD, 281.5 ± 133). However, forskolin stimulation relative to isoprenaline-induced inotropy remained reduced before and after VAD compared with NF. The selective stimulation of β2-AR did not reveal influence of VAD support on β2-AR-AC coupling. Stimulation of ventricular trabeculae by > 100 μmole/liter clenbuterol revealed negative inotropic responses.
VAD does not influence β2-AR coupling to AC stimulation. Elevated response to catecholamines after VAD support is influenced by β1-AR upregulation and modulation of AC activity. Restoration of β-adrenergic responsiveness was restricted to acutely failing hearts.
由于β受体下调和与腺苷酸环化酶（AC）解偶联，终末期心力衰竭对儿茶酚胺的反应减弱。心室辅助装置（VAD）支持后儿茶酚胺对心肌的反应性提高与β1-肾上腺素能受体（β1-AR）的上调有关。关于 VAD 后 AC 和β2-AR 偶联的调节知之甚少;此外，据称 VAD 期间β2-AR 刺激可诱导心肌恢复。
我们分析了在 VAD 支持的人类心肌中，在 8 个非衰竭心脏（NF）和 17 对 VAD 患者的配对样本中，β1-AR 和选择性β2-AR 刺激对 AC 活性的调节。通过 TaqMan 测量 AC 信使 RNA。通过克仑特罗（β2-AR 激动剂）和比索洛尔（β1-AR 阻滞剂）刺激β2-AR 来刺激 AC。使用来自两个心室的小梁进行器官浴实验。根据慢性或急性心力衰竭病史对样本进行分层。
异丙肾上腺素诱导的 AC 活性在 VAD 前下调（p <0.001），在卸载后显着增加（p <0.05）（平均±标准偏差 pmole/mg/min）在 NF（47.9 ± 14.9），VAD 前（24.35 ± 13.3）和 VAD 后（50.04 ± 50.25）。Forskolin 刺激显示 VAD 期间 AC 活性显着增加（p <0.05），尤其是在急性衰竭心脏中（NF，192.1 ± 68.7; VAD 前，191.1 ± 60.4; VAD 后，281.5 ± 133）。然而，与 NF 相比，VAD 前后异丙肾上腺素诱导的变力刺激后，Forskolin 刺激的 AC 活性相对上调仍然减少。β2-AR 的选择性刺激并未显示 VAD 支持对β2-AR-AC 偶联的影响。> 100 μmol/L 克仑特罗刺激心室小梁可引起负性变力反应。
VAD 不影响β2-AR 对 AC 刺激的偶联。VAD 支持后儿茶酚胺反应的升高受β1-AR 上调和 AC 活性调节的影响。β-肾上腺素能反应性的恢复仅限于急性衰竭的心脏。
