Abstract
Levosimendan enhances cardiac contractility primarily via Ca2+ sensitization, and it induces vasodilation through the activation of ATP-sensitive potassium channels and large conductance Ca2+-activated K+ channels. However, the concentration-dependent hemodynamic effects of levosimendan and its metabolites (R)-N-(4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)acetamide (OR-1896) and (R)-6-(4-aminophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (OR-1855) have not been well defined. Thus, levosimendan (0.03, 0.10, 0.30, and 1.0 μmol/kg/30 min; n = 6) was infused as four escalating 30-min i.v. doses targeting therapeutic to supratherapeutic concentrations of levosimendan (Cmax, ∼62.6 ng/ml); metabolites were infused at one-half log-unit lower doses and responses compared to dobutamine (β1-agonist) and milrinone (phosphodiesterase 3 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 of the compounds, with the exception of OR-1855, elicited dose-dependent increases in dP/dt with a rank potency, based on ED50 values, 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 supratherapeutic concentrations (whereas the effects of OR-1855 in the rat are thought to be predominantly 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, which does not elicit K+ channel activation, suggesting a more balanced effect on the cardiac-contractile state and K+ channel-mediated changes in vascular resistance.
Footnotes
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.107.132530.
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ABBREVIATIONS: PDE3, phosphodiesterase 3; KATP, ATP-sensitive potassium channel; BKCa, large conductance Ca2+-activated K+ channels; OR-1896, (R)-N-(4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)acetamide; OR-1855, (R)-6-(4-aminophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one; MAP, mean arterial pressure; HR, heart rate; PCO, peripheral cardiac output; ANOVA, analysis of variance.
- The American Society for Pharmacology and Experimental Therapeutics
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