Abstract
Levosimendan (LS), a Ca2+ 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.
Footnotes
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This work was supported, in part, by the National Institutes of Health (Grants AA12335 and HL074318; to C.-P.C.), the American Heart Association (Grant 0530079N; to H.-J.C.), and Orion Pharma, Orion Corporation.
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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.107.134940.
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ABBREVIATIONS: HF, heart failure; LS, levosimendan; LV, left ventricular; LVP, LV pressure; LAP, left atrial pressure; VCO, vena cavae occlusion; bpm, beats per minute; PES, end-systolic P; VES, end-systolic V; EES, slope of linear PES-VES relation; SW, stroke work; VED, end-diastolic V; MSW, slope of stroke work-VED relation; WSES, mean end-systolic circumference stress; EA, arterial elastance; SV, stroke volume; PVA, pressure-volume area; ANOVA, analysis of variance; HR, heart rate; TSVR, total systemic vascular resistance; DOB, dobutamine; PED, end-diastolic P; OR-1855, (R)-6-(4-amino-phenyl)-5-methyl-4,5-dihydro-2H-pyridazin-3-one; EMD 57033, (+)-5-[1-(3,4-dimethoxybenzoyl)-1,2,3,4-tetrahydro-6-quinolyl-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazino-2-one; EMD 53998, 5-[1-(3,4-dimethoxybenzoyl)-1,2,3,4-tetrahydro-6-quinolyl]-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; ORG 30029, N-hydroxy-5,6,-dimethoxy-benzo-[b]thiophene-2-carboximide hydrochloride; CGP 48506, (+)-entantiomer of the racemic mixture 1,5-benzodiazocine derivative 5-methyl-6-phenyl-1,3,5,6-tetrahydro-3,6-methano-1,5-benzodiazocine-2,4-dione.
- Received December 3, 2007.
- Accepted January 2, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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