Gen. Physiol. Biophys. (2003), 22, 313—327 313 The Cardiotonic Effects of Levosimendan in Guinea Pig Hearts Are Modulated by β-Adrenergic Stimulation A. Bódi, S. Szilágyi, I. Édes and Z. Papp Institute of Cardiology, University of Debrecen, Medical and Health Science Centre, Medical School, Hungary Abstract. The effects of the Ca 2+ -sensitiser levosimendan alone or in combination with β-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 μg·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 concentra- tion of levosimendan (0.3 μmol·l −1 for 5 min) increased +dP/dt max and −dP/dt max by 28 ± 3% and 14 ± 2%, respectively. Further, the Ca 2+ -sensitising potential of levosimendan in Triton-skinned cardiomyocytes (EC 50 :5 ± 3 nmol·l −1 ) was illus- trated 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·ml −1 for 40 min). These data indicate that thin filament-targeted Ca 2+ - sensitisation by levosimendan is modulated by phosphorylation of the contractile filaments, an effect that should be considered during combination therapy with levosimendan. Key words: Contractility — Heart — Cardiomyocytes — Ca 2+ -sensitisers — Levosimendan Introduction In the clinical practice, correction for the diminished contractile function of the fail- ing myocardium is a major therapeutic challenge. Conventional positive inotropic agents increase the intracellular Ca 2+ concentration ([Ca 2+ ] i ), and their applica- tion is therefore associated with adverse effects: an increased energy demand and Correspondence to: Dr. Zoltán Papp, Institute of Cardiology, University of Debre- cen, Medical and Health Science Centre, Medical School, P.O.Box 1, H–4004 Debrecen, Hungary. E-mail: pappz@jaguar.unideb.hu