Pivotal effects of phosphodiesterase inhibitors on myocyte contractility and viability in normal and ischemic hearts

Phosphodiesterases (PDEs) are enzymes that degrade cellular cAMP and cGMP and are thus essential for regulating the cyclic nucleotides. At least 11 families of PDEs have been identified, each with a distinctive structure, activity, expression, and tissue distribution. The PDE type-3, -4, and -5 (PDE3, PDE4, PDE5) are localized to specific regions of the cardiomyocyte, such as the sarcoplasmic reticulum and Z-disc, where they are likely to influence cAMP/cGMP signaling to the end effectors of contractility. Several PDE inhibitors exhibit remarkable hemodynamic and inotropic properties that may be valuable to clinical practice. In particular, PDE3 inhibitors have potent cardiotonic effects that can be used for short-term inotropic support, especially in situations where adrenergic stimulation is insufficient. Most relevant to this review, PDE inhibitors have also been found to have cytoprotective effects in the heart. For example, PDE3 inhibitors have been shown to be cardioprotective when given before ischemic attack, whereas PDE5 inhibitors, which include three widely used erectile dysfunction drugs (sildenafil, vardenafil and tadalafil), can induce remarkable cardioprotection when administered either prior to ischemia or upon reperfusion. This article provides an overview of the current laboratory and clinical evidence, as well as the cellular mechanisms by which the inhibitors of PDE3, PDE4 and PDE5 exert their beneficial effects on normal and ischemic hearts. It seems that PDE inhibitors hold great promise as clinically applicable agents that can improve cardiac performance and cell survival under critical situations, such as ischemic heart attack, cardiopulmonary bypass surgery, and heart failure.

磷酸二酯酶（PDEs）是降解细胞内cAMP和cGMP的酶，因此对调节环核苷酸至关重要。目前已鉴定出至少11个PDE家族，每个家族都具有独特的结构、活性、表达和组织分布。PDE3型、 -4型和 -5型（PDE3、PDE4、PDE5）定位于心肌细胞的特定区域，如肌浆网和Z盘，它们可能影响cAMP/cGMP向收缩性终末效应器的信号传导。几种PDE抑制剂表现出显著的血流动力学和正性肌力特性，可能对临床实践有价值。特别是，PDE3抑制剂具有强大的强心作用，可用于短期正性肌力支持，尤其是在肾上腺素能刺激不足的情况下。与本综述最相关的是，PDE抑制剂也被发现对心脏有细胞保护作用。例如，已表明PDE3抑制剂在缺血发作前给药具有心脏保护作用，而PDE5抑制剂（包括三种广泛使用的治疗勃起功能障碍的药物：西地那非、伐地那非和他达拉非）在缺血前或再灌注时给药均可诱导显著的心脏保护作用。本文综述了当前的实验室和临床证据，以及PDE3、PDE4和PDE5抑制剂对正常和缺血心脏发挥有益作用的细胞机制。似乎PDE抑制剂作为可在缺血性心脏病发作、心肺转流手术和心力衰竭等危急情况下改善心脏功能和细胞存活的临床适用药物具有很大的应用前景。