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Hemodynamic Effects of Levosimendan and its Two Metabolites (OR‐1896 and OR‐1855) in Anesthetized Rats: Comparison to Dobutamine and Milrinone
Author(s) -
Segreti Jason A,
Cox Bryan F,
Polakowski James S,
Fryer Ryan M
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.a798
Subject(s) - milrinone , dobutamine , levosimendan , medicine , concomitant , hemodynamics , contractility , vascular resistance , vasodilation , anesthesia , pharmacology , inotrope
Levosimendan (LEVO) enhances cardiac contractility via Ca 2+ sensitization and induces vasodilation through the activation of K ATP /BK Ca in humans. However, the hemodynamic effects of LEVO as well as its metabolites, OR‐1896 and OR‐1855, in relation to plasma concentrations achieved have not been well defined in rats. Thus, LEVO (0.03, 0.10, 0.30, and 1.0 μmol/kg/30min; n=6) or VEH was infused as 4 escalating 30min i.v. doses targeting therapeutic to supratherapeutic concentrations of total LEVO (C max ~60 ng/mL); OR‐1896 and OR‐1855 were infused at ½ log unit lower doses. Responses were compared with dobutamine (β1 agonist) and milrinone (PDE3 inhibitor). Peak plasma concentrations of LEVO, OR‐1896, and OR‐1855 at the end of the high dose were 323±14, 84±2, and 6±2 ng/mL, respectively (OR‐1855 was rapidly metabolized to OR‐1896, peak concentration = 82±3 ng/mL). LEVO and OR‐1896 produced dose‐dependent reductions in MAP (to −30±4 and −30±7 mmHg below baseline, respectively, at end of high dose) and peripheral vascular resistance (PVR; to −40±6 and −23±6%) concomitant with increases in dP/dt 50 (to 71±8 and 60±12%) and HR (68±8 and 67±3 bpm). Reductions in MAP produced by dobutamine (−15±4 mmHg) were limited by large increases in HR (to 181±6 beats/min above baseline) and dP/dt 50 (109±8%). Maximal reductions in MAP produced by milrinone (−35±6 mmHg) were similar to that of LEVO, an effect occurring concomitant with increases in HR (43±11 beats/min) and dP/dt 50 (51±9%). Thus, both LEVO and OR‐1896 produce reductions in MAP and PVR concomitant with increases in left ventricular contractility and HR. However, when analyzed as ΔdP/dt vs. ΔPVR dobutamine appears more potent than either LEVO or OR‐1896 to induce increases in dP/dt vs. vasodilation.