Acute Enhancement of Cardiac Function by Phosphodiesterase Type 1 Inhibition.
Acute Enhancement of Cardiac Function by Phosphodiesterase Type 1 Inhibition.
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DOI：
10.1161/circulationaha.117.030490
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发表时间：
2018-10-30
期刊：
影响因子：
37.8
通讯作者：
Kass DA
中科院分区：
文献类型：
--
作者：
Hashimoto T;Kim GE;Tunin RS;Adesiyun T;Hsu S;Nakagawa R;Zhu G;O'Brien JJ;Hendrick JP;Davis RE;Yao W;Beard D;Hoxie HR;Wennogle LP;Lee DI;Kass DA
磷酸二酯酶1型（PDE1）水解环AMP和cGMP，并在心脏中组成性表达，但其体内急性抑制对心脏的影响在很大程度上是未知的。现有数据仅限于主要表达有利于cGMP的PDE1A亚型的啮齿动物。人心脏主要表达PDE1C，对cAMP和cGMP具有平衡的选择性。在这里，我们确定了PDE1抑制在表达PDE1C的哺乳动物，狗和兔子，在正常和衰竭的心脏中的急性作用，并探讨了其调节途径。清醒的狗长期仪器的压力-容量关系进行了研究之前和之后的快速起搏诱导的心力衰竭（HF）。选择性PDE1抑制剂（ITI-214）经口或静脉±多巴酚丁胺给药。麻醉兔的压力-容积分析测试了β-肾上腺素能和腺苷受体信号传导对ITI-214效应的作用。本文对家兔左心室肌细胞肌节和钙动力学进行了研究。在正常和HF犬中，ITI-214增加了负荷非依赖性收缩力，改善了舒张，降低了全身动脉阻力，提高了心输出量而不改变收缩压。心率增加，但在HF犬中较少。ITI-214的作用与β-肾上腺素能受体（β-AR）激动作用（多巴酚丁胺）相加。多巴酚丁胺而不是ITI-214增加血浆cAMP。ITI-214在家兔中诱导了类似的心血管效应，而小鼠仅显示出轻度血管舒张，无收缩效应。在兔中，β-AR阻断剂（艾司洛尔）阻止了ITI-214介导的变时性，但变力性和血管舒张保持不变。相比之下，腺苷A2B受体阻断剂（MRS-1754）抑制ITI-214的心血管效应。添加固定速率心房起搏并没有改变结果。单独使用ITI-214不影响肌节或全细胞钙动力学，而β-AR激动（异丙肾上腺素）或PDE3抑制（西洛酰胺，CIL）均增加。与CIL不同，当与异丙肾上腺素结合时，CIL进一步增强缩短和峰值钙，ITI-214对这些反应没有影响。PDE1和PDE3抑制剂增加缩短和加速钙衰变时，结合毛喉素，但只有CIL增加钙瞬变。ITI-214在体内对PDE1的抑制作用可在伴有和不伴有HF的表达PDE1C的哺乳动物中产生急性正性肌力、负性肌力和动脉血管舒张作用。这些效应似乎与cAMP信号传导有关，这与通过β-AR受体或PDE3调节提供的信号传导不同。ITI-214已完成I期临床试验，可能为HF提供新的治疗方法。
Phosphodiesterase type-1 (PDE1) hydrolyzes cyclic AMP and cGMP and is constitutively expressed in the heart, though cardiac effects from its acute inhibition in vivo are largely unknown. Existing data are limited to rodents expressing mostly the cGMP-favoring PDE1A isoform. Human heart predominantly express PDE1C with balanced selectivity for cAMP and cGMP. Here, we determined acute effects of PDE1 inhibition in PDE1C-expressing mammals, dogs and rabbits, in normal and failing hearts, and explored its regulatory pathways. Conscious dogs chronically instrumented for pressure-volume relations were studied before and after tachypacing-induced heart failure (HF). A selective PDE1 inhibitor (ITI-214) was administered orally or intravenously ± dobutamine. Pressure-volume analysis in anesthetized rabbits tested the role of beta-adrenergic and adenosine receptor signaling on ITI-214 effects. Sarcomere and calcium dynamics were studied in rabbit left-ventricular myocytes. In normal and HF dogs, ITI-214 increased load-independent contractility, improved relaxation, and reduced systemic arterial resistance, raising cardiac output without altering systolic blood pressure. Heart rate increased, but less so in HF dogs. ITI-214 effects were additive to beta-adrenergic receptor (β-AR) agonism (dobutamine). Dobutamine but not ITI-214 increased plasma cAMP. ITI-214 induced similar cardiovascular effects in rabbits, whereas mice displayed only mild vasodilation and no contractility effects. In rabbit, β-AR-blockade (esmolol) prevented ITI-214-mediated chronotropy, but inotropy and vasodilation remained unchanged. By contrast, adenosine A2B-receptor blockade (MRS-1754) suppressed ITI-214 cardiovascular effects. Adding fixed-rate atrial pacing did not alter the findings. ITI-214 alone did not affect sarcomere or whole-cell calcium dynamics, whereas β-AR agonism (isoproterenol) or PDE3 inhibition (cilostamide, CIL) increased both. Unlike CIL, which further enhanced shortening and peak calcium when combined with isoproterenol, ITI-214 had no impact on these responses. Both PDE1 and PDE3 inhibitors increased shortening and accelerated calcium decay when combined with forskolin, yet only CIL increased calcium transients. PDE1 inhibition by ITI-214 in vivo confers acute inotropic, lusitropic, and arterial vasodilatory effects in PDE1C-expressing mammals with and without HF. The effects appear related to cAMP signaling that is different from that provided via beta-AR receptors or PDE3 modulation. ITI-214, which has completed Phase I trials, may provide a novel therapy for HF.