5-HT4-elicited positive inotropic response is mediated by cAMP and regulated by PDE3 in failing rat and human cardiac ventricles
5-HT4-elicited positive inotropic response is mediated by cAMP and regulated by PDE3 in failing rat and human cardiac ventricles
复制标题
DOI：
10.1038/bjp.2008.339
复制
发表时间：
2008-12-01
影响因子：
7.3
通讯作者：
Qvigstad, E.
中科院分区：
文献类型：
--
作者：
Afzal, F.;Andressen, K. W.;Qvigstad, E.
背景和目的：衰竭心脏左心室对5-羟色胺敏感，这与功能性G(s)偶联5-羟色胺受体的出现并行。在这里，我们探讨了磷酸二酯酶在5-HT4受体介导的衰竭大鼠和人心脏心室肌功能作用中的调节功能。实验方法：Wistar大鼠冠状动脉结扎致大面积心肌梗死。术后6周测量大鼠左室乳头肌收缩力和移植心脏左室小梁收缩力。用RIA定量cAMP。关键结果：在大鼠心肌梗死后的乳头肌中，5-HT4刺激可产生正性肌力和弹力作用，并增加cAMP。非选择性抑制PDE （IBMX, 10 μ M）和选择性抑制PDE3（西洛胺，1 μ M）可增强肌力效应，但不抑制PDE2 （EHNA, 10 μ M）或PDE4（罗利普兰，10 μ M）。PDE3和PDE4联合抑制比单独抑制PDE3的作用更能增强肌力反应，增加了对5- HT的敏感性，并且在对照（假手术）大鼠心室中也显示出肌力反应。只有在PDE联合抑制时，lusitloicity效应才会增加。在衰竭的人心室中，PDEs以类似于梗死后大鼠心脏的方式调节5-HT4受体介导的正性肌力反应。结论和意义：衰竭大鼠心室5-HT4受体介导的正性肌力反应是camp依赖性的。PDE3是调节这种反应的主要PDE， PDE4的参与是通过梗死后大鼠和衰竭心脏中PDE3的伴随抑制来揭示的。5- HT、PDE3和PDE4在心力衰竭中可能具有病理生理功能。
Background and purpose: The left ventricle in failing hearts becomes sensitive to 5-HT parallelled by appearance of functional G(s)-coupled 5-HT4 receptors. Here, we have explored the regulatory functions of phosphodiesterases in the 5-HT4 receptor-mediated functional effects in ventricular muscle from failing rat and human heart.Experimental approach: Extensive myocardial infarctions were induced by coronary artery ligation in Wistar rats. Contractility was measured in left ventricular papillary muscles of rat, 6 weeks after surgery and in left ventricular trabeculae from explanted human hearts. cAMP was quantified by RIA.Key results: In papillary muscles from postinfarction rat hearts, 5-HT4 stimulation exerted positive inotropic and lusitropic effects and increased cAMP. The inotropic effect was increased by non-selective PDE inhibition (IBMX, 10 mu M) and selective inhibition of PDE3 (cilostamide, 1 mu M), but not of PDE2 (EHNA, 10 mu M) or PDE4 (rolipram, 10 mu M). Combined PDE3 and PDE4 inhibition enhanced inotropic responses beyond the effect of PDE3 inhibition alone, increased the sensitivity to 5- HT, and also revealed an inotropic response in control (sham-operated) rat ventricle. Lusitropic effects were increased only during combined PDE inhibition. In failing human ventricle, the 5-HT4 receptor-mediated positive inotropic response was regulated by PDEs in a manner similar to that in postinfarction rat hearts.Conclusions and implications: 5-HT4 receptor-mediated positive inotropic responses in failing rat ventricle were cAMP-dependent. PDE3 was the main PDE regulating this response and involvement of PDE4 was disclosed by concomitant inhibition of PDE3 in both postinfarction rat and failing human hearts. 5- HT, PDE3 and PDE4 may have pathophysiological functions in heart failure.