Milrinone inhibits hypoxia or hydrogen dioxide-induced persistent sodium current in ventricular myocytes.

Abstract 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 0.1 mM) or cAMP (0.1 mM) decreased I Na.P respectively in control condition, application of 1 μM 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 I Na.P induced by hypoxia. Furthermore, 0.01 mM or 0.1 mM 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 μM 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 μM 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.