Received for publication October 11, 2007.
Revised December 28, 2007.
Accepted for publication December 28, 2007.

Evoked Changes in Cardiovascular Function in Rats by Infusion of Levosimendan, OR-1896, OR-1855, Dobutamine, and Milrinone: Comparative Effects on Peripheral Resistance, Cardiac Output, dP/dt, Pulse Rate, and Blood Pressure

Abstract

Levosimendan enhances cardiac contractility primarily via Ca²⁺-sensitization and induces vasodilation through the activation of K_ATP/BK_Ca. However, the concentration-dependent hemodynamic effects of levosimendan and its metabolites, OR-1896 and OR-1855 have not been well defined. Thus, levosimendan (0.03, 0.10, 0.30, 1.0 µmol/kg/30min; n=6) was infused as 4 escalating 30-min i.v. doses targeting therapeutic to supratherapeutic concentrations of levosimendan (C_max~62.6 ng/mL); metabolites were infused at log-unit lower doses and responses compared to dobutamine (₁-agonist) and milrinone (PDE3-inhibitor). Peak concentrations of levosimendan, OR-1896, and OR-1855 at the end of the high-dose were 323±14, 83±2, and 6±2 ng/mL, respectively (OR-1855 rapidly metabolized to OR-1896, peak=82±3 ng/mL). Levosimendan and OR-1896 produced dose-dependent reductions in blood pressure and peripheral resistance with a rank-potency, based on ED₁₅ values, of OR-1896(0.03 µmol/kg)>OR-1855>levosimendan>milrinone(0.24 µmol/kg); an ED₁₅ for dobutamine could not be defined. Only dobutamine produced increases in pulse pressure (30±5%) and rate-pressure product (34±4%). All compounds, with the exception of OR-1855, elicited dose-dependent increases in dP/dt with a rank-potency, based on ED₅₀, of dobutamine(0.03 µmol/kg)>levosimendan>OR-1896>milrinone(0.09 µmol/kg) although only levosimendan produced sustained increases in cardiac output (9±4%). Thus, levosimendan and OR-1896 are hemodynamically active at sub- to surpatherapeutic concentrations (whereas the effects of OR-1855 in the rat are thought to be predominately mediated by conversion to OR-1896) and produce direct inotropic effects and also direct relaxation of the peripheral vasculature which clearly differentiates them from dobutamine, that does not elicit K⁺ channel activation, suggesting a more balanced effect on cardiac contractile state and K⁺ channel mediated changes in vascular resistance.

Key words: Levosimendan, OR-1855, OR-1896, cardiovascular function, dobutamine, milrinone