The cardiotonic effects of levosimendan in guinea pig hearts are modulated by beta-adrenergic stimulation.
The effects of the Ca2+-sensitiser levosimendan alone or in combination with beta-adrenergic stimulation on the contractile function were studied in various guinea pig cardiac preparations. Echocardiography in narcotised animals indicated that a maximal dose of levosimendan (50 microg x kg(-1)) increased the left ventricular posterior wall movement velocity during systoles and diastoles by 25 +/- 3% (mean +/- S.E.M.) and 17 +/- 2%, respectively. In Langendorff hearts, a saturating concentration of levosimendan (0.3 micromol x l(-1) for 5 min) increased +dP/dt(max) and dP/dt(max) by 28 +/- 3% and 14 +/- 2%, respectively. Further, the Ca2+-sensitising potential of levosimendan in Triton-skinned cardiomyocytes (EC50: 5 +/- 3 nmol x l(-1)) was illustrated by a maximal increase in the isometric force production by 51 +/- 5% (at pCa 6.2). However, following stimulation by isoproterenol, when the level of troponin I phosphorylation was elevated, no significant additional increase in the contractile parameters could be demonstrated upon levosimendan administration. Moreover, the levosimendan-induced increase in force production in isolated skinned myocytes could be prevented by incubation with the catalytic subunit of protein kinase A (100 U x ml(-1) for 40 min). These data indicate that thin filament-targeted Ca2+-sensitisation by levosimendan is modulated by phosphorylation of the contractile filaments, an effect that should be considered during combination therapy with levosimendan.
Bódi
A
A
Institute of Cardiology, University of Debrecen, Medical and Health Science Centre, Medical School, Hungary.
Szilágyi
S
S
Edes
I
I
Papp
Z
Z
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology; D002478:Cells, Cultured; D046508:Culture Techniques; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000000981:diagnostic imaging / Q000187:drug effects; D006835:Hydrazones / Q000494:pharmacology*; D007537:Isometric Contraction / Q000187:drug effects / Q000502:physiology; D007545:Isoproterenol / Q000494:pharmacology*; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000502:physiology*; D011724:Pyridazines / Q000494:pharmacology*; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D000077464:Simendan; D014463:Ultrasonography; D016276:Ventricular Function
D000318:Adrenergic beta-Agonists; D002316:Cardiotonic Agents; D006835:Hydrazones; D011724:Pyridazines; D011943:Receptors, Adrenergic, beta; D000077464:Simendan; D017868:Cyclic AMP-Dependent Protein Kinases; D007545:Isoproterenol; D002118:Calcium