Milrinone inhibits hypoxia or hydrogen dioxide-induced persistent sodium current in ventricular myocytes.
Much evidence indicates that increased persistent sodium current (I(Na.P)) is associated with cellular calcium overload and I(Na.P) is considered to be a potential target for therapeutic intervention in ischaemia and heart failure. By inhibiting type III phosphodiesterase, milrinone increases intracellular cyclic adenosine monophosphate (cAMP), with a positive inotropic effect. However, the effect of milrinone on increased I(Na.P) under pathological conditions remains unknown. Accordingly, we investigated the effect of milrinone on increased I(Na.P) induced by hypoxia or hydrogen dioxide in guinea pig ventricular myocytes. While milrinone (0.01 mM or 0.1mM) or cAMP (0.1 mM) decreased I(Na.P) respectively in control condition, application of 1 microM H-89, a selective cAMP-dependant protein kinase inhibitor, prevented the effect of 0.1mM milrinone in control condition. Milrinone (0.1 mM) reduced the increased I(Na.P) induced by hypoxia. Furthermore, 0.01 mM or 0.1mM milrinone reduced the enhanced I(Na.P) induced by 0.3 mM hydrogen peroxide. In addition, 0.01 mM or 0.1 mM milrinone shortened action potential duration at 90% repolarization (APD(90)). Bath application of 0.3 mM hydrogen dioxide markedly prolonged APD(90), while 2 microM tetrodotoxin (TTX) reversed the prolonged APD(90). In the other two groups, 0.01 mM or 0.1 mM milrinone shortened the prolonged APD(90) induced by 0.3 mM hydrogen peroxide, ultimately 2 microM TTX causing a further decurtation of APD(90). These findings demonstrate that milrinone inhibited I(Na.P) under normal condition, hypoxia or hydrogen dioxide-induced I(Na.P), and the APD(90) prolonged by hydrogen dioxide-induced I(Na.P) in ventricular myocytes, which is associated with the mechanism of milrinone increasing intracellular cAMP.
Zheng
Jie
J
Cardio-Electrophysiological Research Laboratory, Medical College, Wuhan University of Science and Technology, Wuhan, Hubei, China.
Ma
Jihua
J
Zhang
Peihua
P
Hu
Liangkun
L
Fan
Xinrong
X
Tang
Qiong
Q
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D015687:Cell Hypoxia / Q000187:drug effects; D004553:Electric Conductivity; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000166:cytology*; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D020105:Milrinone / Q000494:pharmacology*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D012964:Sodium / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology
D004791:Enzyme Inhibitors; D007546:Isoquinolines; D013449:Sulfonamides; D012964:Sodium; D006861:Hydrogen Peroxide; D020105:Milrinone; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide