The effects of levosimendan on the left ventricular function and protein phosphorylation in post-ischemic guinea pig hearts

The widely accepted theories for the decreased function in the stunned myoc ardium relate to Ca2+ desensitization and free radical-mediated tissue dama ge of the myofilaments. The aim of the present study was to examine whether the depressed contractile function and Ca2+ responsiveness of the stunned myocardium may be restored by a new Ca2+ sensitizer (levosimendan), which h as been shown to improve the Ca2+ response of the myofilaments. The effects of levosimendan on the left ventricular function and the in vivo protein p hosphorylation were examined in both the non-ischemic and the stunned myoca rdium. Myocardial stunning was induced in Langendorff-perfused guinea pig h earts by suspending the circulation for 8 min, followed by a 20-min reperfu sion period. Perfusion of post-ischemic guinea pig hearts with levosimendan (0.03-0.48 mu M, 6 min) was associated with dose- and time-dependent incre ases in both dP/dt(max) (contractility) and dP/dt(min) (speed of relaxation ). When the effectiveness of levosimendan was compared in non-ischemic and post-ischemic hearts, no significant differences were noted in the relative stimulatory effects on contractility and relaxation, at any given time poi nt (time-response curve) or concentration (dose-response curve). Perfusion of the guinea pig hearts with a high (0.3 mu M) levosimendan concentration did not reveal any qualitative or quantitative difference in the phosphodie sterase inhibitory potential of the compound (elevation of tissue cyclic AM P levels and characteristics of protein phosphorylation) between the non-is chemic and the post-ischemic myocardium. However, when isoproterenol was ad ministered to induce maximal in vivo phosphorylation of cardiac phosphoprot eins, an attenuation of the P-32-incorporation into troponin I was noted in the post-ischemic hearts. The decrease in isoproterenol-induced P-32-incor poration into troponin I was associated with similar alterations in the tis sue level of this protein. We conclude that the Ca2+ sensitizer levosimenda n exerts dose- and time-dependent positive inotropic and lusitropic effects on the postischemic myocardium, lending support to the hypothesis tha Ca2 desensitization of the myofibrils is involved in myocardial stunning.