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Positive inotropic effect of phosphodiesterase type 9 inhibitor PF-04449613 in rats and its underlying mechanism

ZHU Xiao-Jia¹, WANG Yu-Wei¹, ZHANG Wen-Hui¹, GAO Li¹, XIAO Yu-Jie¹, GAO Qian-Wen¹, WANG Rong-Rong¹, CHEN Long^1,2,*

¹Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China；²Institute of Chinese Medicine of Taizhou China Medical City, Taizhou 225300, China

Abstract

This study aimed to explore the positive inotropic effect of phosphodiesterase type 9 (PDE9) inhibitor PF-04449613 in rats and 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) Ca²⁺ 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 Ca²⁺ 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 Ca²⁺ transients mediated by facilitating sarcoplasmic reticulum Ca²⁺-ATPase-2a (SERCA2a) (P < 0.05). (4) PF-04449613 (5 μmol/L) decreased the SR Ca2+ 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.

Key words: phosphodiesterase type 9; ventricular pressure-volume loop; Ca2+ transient; SERCA2a

Received: 2020-05-31　　Accepted: 2021-01-25

Corresponding author: 陈龙　　E-mail: longchen@njucm.edu.cn

DOI: 10.13294/j.aps.2021.0010

Citing This Article：

ZHU Xiao-Jia, WANG Yu-Wei, ZHANG Wen-Hui, GAO Li, XIAO Yu-Jie, GAO Qian-Wen, WANG Rong-Rong, CHEN Long. Positive inotropic effect of phosphodiesterase type 9 inhibitor PF-04449613 in rats and its underlying mechanism. Acta Physiol Sin 2021; 73 (2): 275-285 (in Chinese with English abstract).