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 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.
Kristof
E
E
Department of Heart and Lung Diseases, University Medical School, Debrecen, Hungary.
Szigeti
G
G
Papp
Z
Z
Bodi
A
A
Ball
N A
NA
Walsh
R A
RA
Edes
I
I
D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D000242:Cyclic AMP / Q000032:analysis; D006168:Guinea Pigs; D006835:Hydrazones / Q000494:pharmacology*; D008297:Male; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000503:physiopathology; D017682:Myocardial Stunning / Q000188:drug therapy; D009206:Myocardium / Q000378:metabolism; D010766:Phosphorylation; D011506:Proteins / Q000378:metabolism*; D011724:Pyridazines / Q000494:pharmacology*; D000077464:Simendan; D016277:Ventricular Function, Left / Q000187:drug effects*
D002316:Cardiotonic Agents; D006835:Hydrazones; D011506:Proteins; D011724:Pyridazines; D000077464:Simendan; D000242:Cyclic AMP