Milrinone Inhibits Hypoxia Or Hydrogen Dioxide-induced Persistent Sodium Current In Ventricular Myocytes

Much evidence indicates that increased persistent sodium current (INa.P) is associated with cellular calcium overload and INa.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 INa.P under pathological conditions remains unknown. Accordingly, we investigated the effect of milrinone on increased INa.P induced by hypoxia or hydrogen dioxide in guinea pig ventricular myocytes. Milrinone (0.01 mM or 0.1 mM) or cAMP (0.1 mM) decreased INa.P respectively in control condition. However, application of 1μM H-89, a selective cAMP-dependant protein kinase inhibitor, prevented the effect of 0.1 mM milrinone in control condition. Milrinone (0.1 mM) reduced the increased INa.P induced by hypoxia. Furthermore, 0.01 mM or 0.1 mM milrinone reduced the enhanced INa.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 (APD₉₀). Bath application of 0.3 mM hydrogen dioxide markedly prolonged APD₉₀, while 2μM tetrodotoxin (TTX) reversed the prolonged APD₉₀. In the other two groups, 0.01 mM or 0.1 mM milrinone shortened the prolonged APD₉₀ induced by 0.3 mM hydrogen peroxide, ultimately 2μM TTX causing a further decurtation of APD₉₀. These findings demonstrate that milrinone inhibited INa.P under normal condition, hypoxia or hydrogen dioxide-induced INa.P, and the APD₉₀ prolonged by hydrogen dioxide-induced INa.P in ventricular myocytes, which is associated with the mechanism of milrinone increasing intracellular cAMP.