QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.107.132530v1 325/1/331    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Segreti, J. A. Articles by Fryer, R. M. PubMed PubMed Citation Articles by Segreti, J. A. Articles by Fryer, R. M. Pubmed/NCBI databases Compound via MeSH Substance via MeSH

CARDIOVASCULAR

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

Integrative Pharmacology, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois

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 (C_max, 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.