KMUP-1 Protects Against Serotonin -Induced Cardiac Hypertrophy via Inhibition of L-type Calcium Channels in H9c2 Cells

• Main Authors: Yan-Jie Lai, 賴彥傑
• Other Authors: Bin-Nan Wu
• Format: Others
• Language: zh-TW
• Published: 2010
• Online Access: http://ndltd.ncl.edu.tw/handle/16565317090888162724

碩士 === 高雄醫學大學 === 藥理學研究所 === 98 === Serotonin (5-hydroxytryptamine) is considered to play a role in the regulation of cardiac growth in pathological conditions. KMUP-1, a chemically synthetic xanthine-based derivative, has been demonstrated not only a K+ channels activator, but also a phosphodiesterases inhibitor. However, it has not been addressed in the inhibition of Ca2+ channels in H9c2 cardiomyocytes. There are two aims of this study. First, it is to examine whether KMUP-1 has an inhibition of L-type Ca2+ channel (LTCC) in H9c2 cardiomyocytes. Second, it is to examine whether KMUP-1 can suppress the activation of LTCC and prevent the development of serotonin-induced hypertrophy in H9c2 cardiomyocytes. Rat heart-derived H9c2 cells were treated with serotonin (10 μM) for 4 days, the cell surface area was increased 55.5% and that was prevented by KMUP-1 (1 μM) and ketanserin (0.1 μM). Conventional whole cell patch-clamp technique was used to investigate Ca2+ currents through LTCC (ICa,L) in H9c2 cells. Under voltage-clamp conditions, KMUP-1 inhibited the ICa,L in a concentration-dependent manner. Additionally, KMUP-1 inhibited the protein kinase C (PKC) activator, phorbol 12-myristate 13-acetate (PMA, 5 μM) and 8-Br-cAMP (100 μM) enhanced ICa,L. Pretreatment with the PKG inhibitor KT5823 (1 μM) attenuated KMUP-1-inhibited ICa,L. However, in normal H9c2 cells, serotonin (10 μM) induced the ICa,L, and KMUP-1 (1 μM) also can inhibit serotonin-induced ICa,L. Pretreatment with the PKC and PKA inhibitors chelerythrine (5 μM), H-89 (5 μM) attenuated serotonin-induced ICa,L. Notably, the ICa,L was increased 2.87-fold in serotonin-induced hypertrophy in H9c2 cells. This increase in ICa,L was inhibited by KMUP-1 in a concentration-dependent manner. In conclusion, KMUP-1 inhibits the ICa,L in H9c2 cells, which might in part involve the PKA, PKC and PKG pathways. Serotonin induces ICa,L activity that might in part involve the 5-HT2A receptor, PKA, PKC and PKG pathways. KMUP-1 also prevents serotonin-induced hypertrophy, which might attribute to its ICa,L inhibition. KMUP-1 inhibits serotonin-induced ICa,L activity that might in part involve the PKA, PKC and PKG pathways.