Arcaro Alessia, Lembo Giuseppe, Tocchetti Carlo G
IRCCS Neuromed, Pozzilli, IS, Italy.
Curr Heart Fail Rep. 2014 Sep;11(3):227-35. doi: 10.1007/s11897-014-0210-z.
The loss of contractile function is a hallmark of heart failure. Although increasing intracellular Ca(2+) is a possible strategy for improving contraction, current inotropic agents that achieve this by raising intracellular cAMP levels, such as β-agonists and phosphodiesterase inhibitors, are generally deleterious when administered as long-term therapy due to arrhythmia and myocardial damage. Nitroxyl donors have been shown to improve cardiac function in normal and failing dogs, and in isolated cardiomyocytes they increase fractional shortening and Ca(2+) transients, independently from cAMP/PKA or cGMP/PKG signaling. Instead, nitroxyl targets cysteines in the EC-coupling machinery and myofilament proteins, reversibly modifying them to enhance Ca(2+) handling and myofilament Ca(2+) sensitivity. Phase I-IIa trials with CXL-1020, a novel pure HNO donor, reported declines in left and right heart filling pressures and systemic vascular resistance, and increased cardiac output and stroke volume index. These findings support the concept of nitroxyl donors as attractive agents for the treatment of acute decompensated heart failure.
收缩功能丧失是心力衰竭的一个标志。虽然增加细胞内Ca(2+)是改善收缩功能的一种可能策略，但目前通过提高细胞内cAMP水平来实现这一目的的正性肌力药物，如β-激动剂和磷酸二酯酶抑制剂，作为长期治疗使用时，由于心律失常和心肌损伤，通常是有害的。已证明硝酰供体可改善正常和衰竭犬的心脏功能，在离体心肌细胞中，它们可增加缩短分数和Ca(2+)瞬变，独立于cAMP/PKA或cGMP/PKG信号通路。相反，硝酰作用于兴奋-收缩偶联机制和肌丝蛋白中的半胱氨酸，可逆地修饰它们以增强Ca(2+)处理能力和肌丝对Ca(2+)的敏感性。使用新型纯HNO供体CXL-1020进行的I-IIa期试验报告称，左、右心充盈压和全身血管阻力下降，心输出量和每搏量指数增加。这些发现支持了硝酰供体作为治疗急性失代偿性心力衰竭的有吸引力药物的概念。
