von der Leyen H
Abteilung Allgemeine Pharmakologie, Universitäts-Krankenhaus Eppendorf, Hamburg.
Klin Wochenschr. 1989 Jun 15;67(12):605-15. doi: 10.1007/BF01718141.
Cyclic AMP is known as a secondary messenger regulating the myocardial force of contraction. For the degradation of cAMP multiple forms of PDE within the cell are described, which vary according to substrate specificity, kinetic characterization, and cellular localization. One of these isoenzymes, the low Km cAMP-specific PDE (PDE III), which seems to be closely related to cardiotonic effects of PDE inhibitors, exists either in a particulate form (in dogs), probably associated with the sarcoplasmic reticulum, or in soluble form (in guinea pig). The existence of different forms of PDE III possibly reflects a different pooling or compartmentalization of cAMP. Many agents selectively inhibiting PDE III are described which potently increase the force of contraction and which exert vasodilatory effects. Besides PDE inhibition some of these agents possess additional cAMP-independent actions, e.g., sensitization of the contractile proteins to Ca2+, prolongation of the action potential, or prolongation of the open state of the Na+-channel. Since agents which nonselectively inhibit PDE are known as potent positive inotropic agents (e.g., IBMX), PDE III inhibition itself, but not a selectivity for PDE III inhibition, seems to be a prerequisite for this mechanism of action of cardiotonic drugs. Investigations with preparations from diseased human myocardium show that the beta-adrenoceptor agonist isoprenaline as well as the PDE inhibitor IBMX increase the force of contraction to only about one-third of the maximal effect of the cardiac glycoside dihydro-ouabain or Ca2+. In nonfailing human heart preparations all agents had equal activity. Possible reasons for these differences may be a decreased responsiveness to beta-adrenoceptor stimulation (beta-receptor down-regulation) or an inappropriate increase in cAMP levels due to increased activity of inhibitory Gi-proteins with resulting decrease of adenylate cyclase activity in the failing heart. Besides a short-term clinical and hemodynamic improvement of congestive heart failure, uncontrolled long-term administration of PDE III-inhibitor agents failed to produce sustained clinical benefit and had no effect on survival. Controlled long-term studies with new cardiotonic agents in patients with severe CHF are still lacking.
环磷酸腺苷（cAMP）作为调节心肌收缩力的第二信使已为人所知。细胞内存在多种形式的磷酸二酯酶（PDE）参与cAMP的降解，这些PDE根据底物特异性、动力学特性和细胞定位而有所不同。其中一种同工酶，即低Km的cAMP特异性PDE（PDE III），似乎与PDE抑制剂的强心作用密切相关，它在犬类中以颗粒形式存在（可能与肌浆网相关），而在豚鼠中以可溶性形式存在。PDE III不同形式的存在可能反映了cAMP的不同蓄积或分隔情况。已描述了许多选择性抑制PDE III的药物，它们能显著增强收缩力并发挥血管舒张作用。除了抑制PDE外，其中一些药物还具有其他不依赖cAMP的作用，例如使收缩蛋白对Ca2+敏感、延长动作电位或延长Na+通道的开放状态。由于非选择性抑制PDE的药物被认为是强效正性肌力药物（如异丁基甲基黄嘌呤，IBMX），因此PDE III抑制本身而非对PDE III抑制的选择性似乎是强心药物这种作用机制的先决条件。对病变人类心肌组织的研究表明，β肾上腺素能受体激动剂异丙肾上腺素以及PDE抑制剂IBMX只能将收缩力提高到强心苷类药物双氢哇巴因或Ca2+最大作用的约三分之一。在无心力衰竭的人类心脏组织中，所有药物的活性相同。这些差异的可能原因可能是对β肾上腺素能受体刺激的反应性降低（β受体下调），或者是由于衰竭心脏中抑制性Gi蛋白活性增加导致腺苷酸环化酶活性降低，从而使cAMP水平不适当升高。除了能短期改善充血性心力衰竭的临床症状和血流动力学外，不受控制地长期使用PDE III抑制剂未能产生持续的临床益处，对生存率也没有影响。目前仍缺乏针对重度慢性心力衰竭患者使用新型强心药物的对照长期研究。
