Zhu Xiao-Jia, Wang Yu-Wei, Zhang Wen-Hui, Gao Li, Xiao Yu-Jie, Gao Qian-Wen, Wang Rong-Rong, Chen Long
Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.
Institute of Chinese Medicine of Taizhou China Medical City, Taizhou 225300, China.
Sheng Li Xue Bao. 2021 Apr 25;73(2):275-285.
This study aimed to explore the positive inotropic effect of phosphodiesterase type 9 (PDE9) inhibitor PF-04449613 in ratsand its cellular and molecular mechanisms. The heart pressure-volume loop (P-V loop) analysis was used to detect the effects of PF-04449613 on rat left ventricular pressure-volume relationship, aortic pressures and peripheral vessel resistance in healthy rats. The Langendorff perfusion of isolated rat heart was used to explore the effects of PF-04449613 on heart contractility. The cardiomyocyte sarcoplasmic reticulum (SR) Ca transients induced by field stimulation and caffeine were used to analyze the mechanism underlying the effect of PF-04449613 using Fluo-4 AM as a Ca indicator. The results indicated as follows: (1) PF-04449613 (5.5 mg/kg, ip) significantly increased the stroke work, cardiac output, stroke volume, end-systolic pressure and ejection fraction (P < 0.05), and decreased the end-systolic volume, end-diastolic volume and end-diastolic pressure (P < 0.05). Meanwhile, the systolic blood pressure was increased and diastolic blood pressure and arterial elastance were decreased after PF-04449613 treatment (P < 0.05). (2) PF-04449613 (0.001, 0.01, 0.1, 1 μmol/L) significantly increased the left ventricular developed pressure (LVDP) in a concentration-dependent manner in vitro (P < 0.05). (3) PF-04449613 (5 μmol/L) significantly increased the amplitude of SR Ca transients mediated by facilitating sarcoplasmic reticulum Ca-ATPase-2a (SERCA2a) (P < 0.05). (4) PF-04449613 (5 μmol/L) decreased the SR Ca leak rate via ryanodine receptor 2 (RyR2) (P < 0.05). In conclusion, PF-04449613 exerted positive inotropic effect both in vivo and in vitro by enhancing SERCA2a activity.
本研究旨在探讨磷酸二酯酶9（PDE9）抑制剂PF - 04449613对大鼠的正性肌力作用及其细胞和分子机制。采用心脏压力 - 容积环（P - V环）分析检测PF - 04449613对健康大鼠左心室压力 - 容积关系、主动脉压力和外周血管阻力的影响。利用离体大鼠心脏的Langendorff灌注法探讨PF - 04449613对心脏收缩力的影响。以Fluo - 4 AM作为钙指示剂，通过电场刺激和咖啡因诱导心肌细胞肌浆网（SR）钙瞬变，分析PF - 04449613作用的机制。结果如下：（1）PF - 04449613（5.5 mg/kg，腹腔注射）显著增加每搏功、心输出量、每搏量、收缩末期压力和射血分数（P < 0.05），并降低收缩末期容积、舒张末期容积和舒张末期压力（P < 0.05）。同时，PF - 04449613治疗后收缩压升高，舒张压和动脉弹性降低（P < 0.05）。（2）PF - 04449613（0.001、0.01、0.1、1 μmol/L）在体外以浓度依赖性方式显著增加左心室舒张末压（LVDP）（P < 0.05）。（3）PF - 04449613（5 μmol/L）通过促进肌浆网钙 - ATP酶2a（SERCA2a）显著增加SR钙瞬变的幅度（P < 0.05）。（4）PF - 04449613（5 μmol/L）通过兰尼碱受体2（RyR2）降低SR钙泄漏率（P < 0.05）。总之，PF - 04449613通过增强SERCA2a活性在体内和体外均发挥正性肌力作用。
