The Intervention Of Tanshinone On Electrophysiological Abnormality In Hypertrophy Myocardium

Cardiac hypertrophy could raise the incidence of sudden death and malignant arrhythmia, which be considered to be correlative with electrophysiological remodeling caused by hypertrophy. The electrophysiological remodeling in left ventricle usually display prolongation of action potential duration (APD) which improve the high ununiformity of repolarization so that there occur more reentry and the incidence of early after depolarization and delayed after depolarization. The change of many ion channels and the balance of inward currents and outward currents such as transient outward current( Ito) or L-type calcium current( Ica,l) are involved in. In addition to cells, there is electrophysiological heterogeneity among different layer myocardium which is due to the APD in epicardial cadiocyte less than that in endocardial cadiocyte because of more Ito in epicardial cadiocyte. The disturbance of refractory period caused by electrophysiological heterogeneity become the foundation on which reentry arrhythmia bases. Moreover, the heterogeneity is more obvious in hypertrophical myocardium. It has been considered that the main molecular basis for ventricular hypertrophy is the activation of calcineurin. And calcineurin inhibitor could prevent myocardium from hypertrophy induced by pressure overload and decrease the prolongation of APD in myocardial cells. The effect of calcineurin on cardiac hypertrophy is thought to mediate by L-type calcium channel which not only modifies the Ca²⁺ ion concentraction(as second messenger) to influence the activation of signal passageway causing hypertrophy, but also make APD change. Calcineurin inhibitor also could interrupt the Ito channel related with Kv4.2 to shorten APD. Trials have showed that prolongation of APD, Ito decrease, Ca2+ inflow, activation of calcineurin are associated with cell growth. And calcium ion antagonist-verapamil could inhibit the process. Recently we studied the effect of tanshinone on myocardial hypertrophy, and found that tanshinone could significantly reverse the myocardial hypertrophy in spontaneous hypertensive rats and myocardial cells hypertrophy caused by AngII and decreased the left ventricle /weight index and the transverse diameter of ventricular cells. Other studies showed that tanshinone possessed the effect of Ca²⁺ antagonist and could inhibit calcium ion inflow. Now that tanshinone could modify the myocardial cells hypertrophy and has the capability of Ca²⁺ antagonist, as the result, this trial aim at the influence of tanshinone on the electrophysiological abnormality in hypertrophical myocardium. [Purpose] To study if tanshinone has antagonistic effect on electrophysiological remodeling when it reverses myocardial hypertrophy. In addition, it can found the basis for the future studies which will observe if tanshinone intervene myocardial hypertrophy through some passageways causing hypertrophy or through some ion channels such as L-type calcium ion channel.[Method] Through patch clamp and intra-cellular calcium survey technique, it would be observed and compared that the effect of tanshinone and captopril on the action potential duration, L-type calcium current (Ica,l), intra-cellular calcium ion concentration and Ito current density in cellular membrane of hypertrophic myocardium induced by the surgery of " one kidney one clamp" in this trial in order to illuminate the possible electrophysiological fundament on which tanshinone prevented the occurrence of arrhythmia caused by cardiac hypertrophy. [Result] Compared with normal cells, hypertrophic cadiocyte have more membrane capacitance, longer APD, higher Ica,l amplitude and more intra-cellular calcium ion concentration, but have lower Ito current amplitude and density. Tanshinone could obviously shorten the prolongation of APD ( P<0.001), decrease membrane capacitance and Ica,l peak amplitude( P<0.001) and reduce intra-cellular calcium ion concentration, but not affect Ica,l current density in hypertrophic myocardial cells. Tanshinone also significantly made Ito current density and peak amplitude increase, which was completely different from hypertrophy group( P<0.05). The effect of tanshinone on electrophysiological remodeling in hypertrophic myocardium is similar with captopril.[Conclusion] With reversing myocardial hypertrophy, tanshinone have the antagonistic action on electrophysiological remodeling and it can reduce L-type calcium ion channels and recover the activity of Ito ion channels to shorten the first phase and platform period in repolarization and decrease the prolongation of APD in hypertrophic cadiocyte. It indirectly demonstrates why tanshinone could decrease the incidence of malignant arrhythmia induced by myocardial hypertrophy.