Orally Available Levosimendan Dose-Related Positive Inotropic and Lusitropic Effect in Conscious Chronically Instrumented Normal and Heart Failure Dogs

Levosimendan (LS), a Ca 2+ sensitizer, is presently limited to i.v. administration. The dose-related pharmacodynamic effects of newly developed oral LS remain undetermined. We assessed the dose-response relationship of oral LS in nine normal and seven pacing-induced heart failure (HF), conscious, ch...

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Published in:The Journal of pharmacology and experimental therapeutics 2008-04, Vol.325 (1), p.236-247
Main Authors: Masutani, Satoshi, Cheng, Heng-Jie, Hyttilä-Hopponen, Minja, Levijoki, Jouko, Heikkilä, Aira, Vuorela, Arja, Little, William C, Cheng, Che-Ping
Format: Article
Language:English
Subjects:
Administration, Oral
Animals
Cardiotonic Agents - pharmacology
Diastole - drug effects
Dogs
Dose-Response Relationship, Drug
Heart Failure - drug therapy
Hemodynamics - drug effects
Hydrazones - administration & dosage
Hydrazones - pharmacokinetics
Hydrazones - pharmacology
Myocardial Contraction - drug effects
Pyridazines - administration & dosage
Pyridazines - pharmacokinetics
Pyridazines - pharmacology
Vasodilation - drug effects
Ventricular Function, Left - drug effects
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Summary:Levosimendan (LS), a Ca 2+ sensitizer, is presently limited to i.v. administration. The dose-related pharmacodynamic effects of newly developed oral LS remain undetermined. We assessed the dose-response relationship of oral LS in nine normal and seven pacing-induced heart failure (HF), conscious, chronically instrumented mongrel dogs. Animals received a placebo capsule on day 1, and then LS was administered at single oral doses of 0.025 (day 2), 0.05 (day 4), and 0.1 (day 8) mg/kg. We serially measured plasma LS concentrations, hemodynamic, and left ventricular (LV) systolic and diastolic functional responses periodically until 12 h after oral LS. In both normal and HF, after three incremental dosages of oral LS, the peak plasma LS concentrations (34.6, 66.8, and 123.2 ng/ml in normal and 38.3, 71.5, and 137.4 ng/ml in HF) were achieved within 2 h in proportion to the dose, parallel to an increased LV contractility (normal, from 5.7 mm Hg/ml placebo to 8.2, 10.5, and 12.6 mm Hg/ml; HF, from 3.7 mm Hg/ml placebo to 5.7, 7.1, and 8.7 mm Hg/ml), and decreased time constant of LV relaxation (τ) (normal, from 28.8 ms of placebo to 25.6, 24.7, and 23.5 mm Hg/ml; HF, from 44.7 ms of placebo to 38.9, 36.4, and 34.6 ms). Compared with placebo, total systemic vascular resistance and mean left atrial pressure were significantly reduced after LS. In HF, oral LS caused a dose-dependent increase of LV-arterial coupling and mechanical efficiency. Heart rate increased only after 0.1 mg/kg LS in normal dogs. In conclusion, oral LS produces vasodilatation and dose-dependent augmentation in LV contractility and relaxation both in normal and HF.
ISSN:0022-3565
1521-0103
DOI:10.1124/jpet.107.134940