ORIGINAL ARTICLE Comparision of the Inotropic Effects of Levosimendan, Rolipram, and Dobutamine on Human Atrial Trabeculae Coskun Usta,* Paolo Emilio Puddu,† Ugo Papalia,† Vincenzo De Santis,‡ Domenico Vitale,‡ Luigi Tritapepe,‡ Giuseppe Mazzesi,† Fabio Miraldi,† and Sadi S. Ozdem* Abstract: The aim of this study was to compare the positive inotropic effects of 3 different agents with 3 different mechanisms of actions—levosimendan, rolipram, and dobutamine—on human atrial trabecular muscles. Samples of right atrial appendage (1 cm 2 , 500– 1000 mg) were removed and immersed in preoxygenated and modi- fied Tyrode solution. In oxygenated Tyrode solution, preparations were used to investigate the concentration-effect relationship of levosimendan, dobutamine, and rolipram on percentage developed tension (DT), from 10 29 to 10 24 M, each concentration for 15 minutes. All 3 agents produced concentration-dependent increments in DT. We found that levosimendan was the most efficacious positive inotropic agent on isolated human atrial trabeculae. Both the sensitivity (pD 2 ) and maximum response (E max ) of human atrial trabeculae to levosimendan (6.711 6 0.26 and 23.2 6 2.2 mN, respectively) were significantly greater than those of dobutamine (6.663 6 0.19 and 17.6 6 2.8 mN) and rolipram (6.497 6 0.18 and 15.0 6 1.0 mN). pD 2 and E max values for dobutamine were significantly higher than those for rolipram. It was suggested that because of its potential to enhance cardiac performance without predisposition to calcium-induced ar- rhythmias, levosimendan might be more useful as a positive inotropic agent in clinical practice. Key Words: levosimendan, rolipram, dobutamine, atrial muscle (J Cardiovasc Pharmacol TM 2004;44:622–625) H eart failure is one of the most important cardiovascular syndromes. Its pathology is characterized by the pro- found loss of myocardial contractility, which progressively leads to an inability of the heart to pump sufficient blood. The function of the heart can be improved by increasing the cardiac muscle contraction (positive inotropy). 1 Enhancing the myo- cardial contractile force is an important mechanism by which cardiac output can be increased in the management of de- compensated heart failure. Current pharmacological treatment options for decompensated heart failure include diuretics, vasodilators, and inotropic agents. Inotropic drugs can help to stabilize the patient and provide symptomatic and hemody- namic benefit in short term. However, there is evidence that prolonged use of both b-adrenergic agonists and phosphodi- esterase (PDE) inhibitors may have adverse effects on mor- tality in longer term. 2–5 Although these agents confer short- term benefits, they have a number of potentially deleterious effects that limit their long-term usefulness. For example, chronic administration of b-adrenergic agonists frequently leads to tachyphylaxis in the form of hemodynamic tol- erance, a possible consequence of progressive receptor down- regulation. 6 To date, the positive inotropes and the more recently introduced calcium sensitizers constitute the only drug classes with a direct effect on stroke volume. 7 Calcium sensitization of contractile proteins has become a new promising approach to increase contractile force in the failing heart. An advantage of this mechanism is that it does not increase intracellular calcium, so arrhythmias caused by spontaneous release of calcium from overloaded intracellular calcium stores may be avoided. 8 An important disadvantage of calcium sensitization may, however, be related to prolonged relaxation. 9,10 The novel potent calcium sensitizer levosimendan, (R)-([4-(1,4,5,6- tetrahydro-4-methyl-6-oxo-3-pyridazinyl)-phenyl] hydrazono) propane dinitrile, does not increase the affinity of troponin C (cTnC) for calcium but stabilizes the calcium-induced con- formation of this protein. 11–13 In other words, the binding of levosimendan itself to cTnC occurs in a calcium-dependent manner, and therefore the calcium sensitization does not prolong relaxation. 14,15 Besides increasing the strength of car- diac contractions, levosimendan induces coronary and periph- eral vasodilatation through the opening of ATP-dependent K + channels. 16–18 For the positive inotropic action of levo- simendan, a Ca 2+ -sensitizing mechanism has been postulated through an interaction between levosimendan and the Ca 2+ - saturated form of the cardiac cTnC molecule. 19,20 PDEs are known to be differentially distributed in a variety of subcellular compartments. In cardiac ventricular cells, cytosolic and particulate PDE (attached microsomal fractions enriched in either sarcolemmal or sarcoplasmic re- ticulum membranes) have been studied extensively. 21–23 Although PDE 3 is one of the major cAMP-hydrolyzing activities in the heart, 6 other PDE isoforms have also been identified in this organ. 24–28 In isolated ventricular myocytes, PDEs 1–4 have been shown to regulate L-type Ca 2+ chan- nels. 29 PDE 4 isoform is also present and functional in both healthy and failing human ventricular myocytes. The activity Received for publication July 6, 2004; accepted August 31, 2004. From the *Department of Pharmacology, Akdeniz University, Medical Faculty, Antalya, Turkey; †Department of Cardio-Thoracic and Vascular Sciences ‘‘Attilio Reale,’’ University ‘‘La Sapienza,’’ Rome, Italy; and ‡Department of Anesthesiological Sciences, Critical Medicine and Pain Therapy, University ‘‘La Sapienza,’’ Rome, Italy. Reprints: Coskun Usta, Department of Pharmacology, Akdeniz University, Medical Faculty, Antalya, Turkey (e-mail: fccos@msn.com). Copyright Ó 2004 by Lippincott Williams & Wilkins 622 J Cardiovasc Pharmacol ä  Volume 44, Number 5, November 2004