The widely accepted theories for the decreased function in the
stunned myocardium relate to Ca2+ desensitization and
free radical-mediated tissue damage 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 has been shown to improve the Ca2+ response of the myofilaments. The effects of
levosimendan on the left ventricular function and the in vivo
protein phosphorylation were examined in both the non-ischemic and the
stunned myocardium.
Myocardial stunning was induced in Langendorff-perfused guinea pig hearts by suspending the circulation for 8 min, followed by a 20-min reperfusion period. Perfusion of post-ischemic guinea pig hearts with
levosimendan (0.03-0.48 microM, 6 min) was associated with dose- and time-dependent increases in both dP/dtmax (contractility) and dP/dtmin (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 point (time-response curve) or concentration (dose-response curve). Perfusion of the guinea pig hearts with a high (0.3 microM)
levosimendan concentration did not reveal any qualitative or quantitative difference in the
phosphodiesterase inhibitory potential of the compound (elevation of tissue
cyclic AMP levels and characteristics of
protein phosphorylation) between the non-ischemic and the post-ischemic myocardium. However, when
isoproterenol was administered to induce maximal in vivo phosphorylation of cardiac
phosphoproteins, an attenuation of the 32P-incorporation into
troponin I was noted in the post-ischemic hearts. The decrease in
isoproterenol-induced 32P-incorporation into
troponin I was associated with similar alterations in the tissue level of this
protein. We conclude that the Ca2+ sensitizer
levosimendan exerts dose- and time-dependent positive inotropic and lusitropic effects on the post-ischemic myocardium, lending support to the hypothesis tha Ca2+ desensitization of the myofibrils is involved in
myocardial stunning.