| Autor: |
Zhu XJ; Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China., Wang YW; Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China., Zhang WH; Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China., Gao L; Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China., Xiao YJ; Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China., Gao QW; Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China., Wang RR; Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China., Chen L; 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. longchen@njucm.edu.cn. |
| Abstrakt: |
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 2+ 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 2+ 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 2+ transients mediated by facilitating sarcoplasmic reticulum Ca 2+ -ATPase-2a (SERCA2a) (P < 0.05). (4) PF-04449613 (5 μmol/L) decreased the SR Ca 2+ 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. |
