Osadchii Oleg E, Woodiwiss Angela J, Norton Gavin R
Cardiovascular Pathophysiology and Genomics Research Unit, School of Physiology, University of the Witwatersrand Medical School, 7 York Road, Parktown 2193, Johannesburg, South Africa.
Pflugers Arch. 2006 May;452(2):155-63. doi: 10.1007/s00424-005-0025-6. Epub 2005 Dec 17.
Contractile responses to phosphodiesterase (PDE) inhibitors are attenuated in heart failure, an effect limiting the clinical value of these agents. In this study, we sought to determine whether abnormalities in the beta-adrenoreceptor (beta-AR)-cyclic adenosine monophosphate (cAMP) signal transduction are sufficient to account for downregulation of PDE inhibitor-induced inotropic responses following chronic sympathetic activation. Sustained beta-AR activation produced by administration of isoproterenol (ISO) (50 microg kg(-1) day(-1) i.p. for 1 month) to rats resulted in cardiac hypertrophy, but did not affect baseline cardiac systolic function, as assessed in vivo by echocardiography and ex vivo under controlled loading conditions and heart rate (left ventricular systolic pressure-volume and stress-strain relations). Moreover, chronic ISO administration did not alter the baseline myocardial norepinephrine release or inotropic responses to incremental concentrations of Ca(2+) in isolated, perfused heart preparations. However, left ventricular contractile responses to ISO, the PDE III inhibitor amrinone, and the PDE IV inhibitor rolipram were attenuated following chronic beta-AR activation. Myocardial cAMP concentrations after stimulation with amrinone and rolipram were similar in ISO-treated and control rats. However, in ISO-treated rats, a marked decrease in contractile responsiveness to the cell-permeable, PDE-resistant cAMP analogue, 8-bromoadenosine cAMP, was noted. In conclusion, these data suggest that in cardiac disease, sustained beta-AR activation, without producing ventricular systolic dysfunction or enhanced myocardial norepinephrine release, is sufficient to account for the downregulation of contractile responses to PDE inhibitors. This effect appears to be largely mediated through abnormalities in signal transduction between cAMP and Ca(2+)-induced Ca(2+) release.
心力衰竭时对磷酸二酯酶（PDE）抑制剂的收缩反应减弱，这一效应限制了这些药物的临床价值。在本研究中，我们试图确定β-肾上腺素能受体（β-AR）-环磷酸腺苷（cAMP）信号转导异常是否足以解释慢性交感神经激活后PDE抑制剂诱导的正性肌力反应下调。给大鼠腹腔注射异丙肾上腺素（ISO）（50μg·kg⁻¹·天⁻¹，持续1个月）导致的持续β-AR激活会引起心脏肥大，但不影响基线心脏收缩功能，这在体内通过超声心动图评估，在体外通过控制负荷条件和心率（左心室收缩压-容积和应力-应变关系）评估。此外，慢性给予ISO并未改变离体灌注心脏标本中基线心肌去甲肾上腺素释放或对递增浓度Ca²⁺的正性肌力反应。然而，慢性β-AR激活后，左心室对ISO、PDE III抑制剂氨力农和PDE IV抑制剂咯利普兰的收缩反应减弱。氨力农和咯利普兰刺激后，ISO处理组和对照组大鼠的心肌cAMP浓度相似。然而，在ISO处理的大鼠中，观察到对细胞可渗透、PDE抗性的cAMP类似物8-溴腺苷cAMP的收缩反应性显著降低。总之，这些数据表明，在心脏疾病中，持续的β-AR激活，在不产生心室收缩功能障碍或增强心肌去甲肾上腺素释放的情况下，足以解释对PDE抑制剂收缩反应的下调。这种效应似乎主要是通过cAMP和Ca²⁺诱导的Ca²⁺释放之间信号转导异常介导的。
