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Comprehensive Hemodynamic Assessment of Levosimendan and its Two Metabolites (OR‐1896 and OR‐1855) in the Anesthetized Dog
Author(s) -
Banfor Patricia N,
Preusser Lee C,
Cox Bryan F,
Reinhart Glenn A,
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-a
Subject(s) - levosimendan , preload , medicine , contractility , hemodynamics , vascular resistance , pharmacology , vasodilation , concomitant , cmax , cardiology , pharmacokinetics , heart failure
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 dog. Thus, LEVO, OR‐1896, OR‐1855 (0.01, 0.03, 0.1, 0.3 μmol/kg/30min; n=6) or VEH were infused as 4 escalating i.v. doses targeting therapeutic to supratherapeutic concentrations of total LEVO (C max ~60 ng/mL). Peak concentrations of LEVO, OR‐1896, and OR‐1855 at the end of the 0.3 μmol/kg infusion were 455±21, 126±6, and 136±6 ng/mL. LEVO and OR‐1896 produced dose‐dependent reductions in MAP (effect at end of high dose = −31±2 and −42±3 mmHg, respectively) and SVR, an effect paralleled by increases in HR; OR‐1855 produced no effect on MAP or HR at any dose tested. LEVO produced increases in dP/dt at 0.03, 0.1, and 0.3 μmol/kg (to 40±6, 103±9, and 118±10% above baseline at the end of each dose) and OR‐1896 at all doses tested (to 62±7, 116±9, 132±15, and 133±13%) concomitant with reductions in LVEDP. Effects of the compounds were limited to the systemic circulation; no compound produced any relevant effect on pulmonary pressure/vascular resistance. Thus, both LEVO and OR‐1896 are hemodynamically active in the dog at concentrations observed clinically whereas OR‐1855 is inactive on endpoints measured in this study. Moreover, both LEVO and OR‐1896 produce reductions in MAP and SVR concomitant with increases in left ventricular contractility and HR, effects consistent with activation of K ATP /BK Ca and Ca 2+ sensitization, respectively.