Comprehensive Hemodynamic Assessment Of Levosimendan And Its Two Metabolites (Or-1896 And Or-1855) In The Anesthetized Dog

Levosimendan (LEVO) enhances cardiac contractility via Ca2+ sensitization and induces vasodilation through the activation of KATP/BKCa 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 (Cmax ~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 KATP/BKCa and Ca2+ sensitization, respectively.