RT Journal Article
SR Electronic
T1 Orally Available Levosimendan Dose-Related Positive Inotropic and Lusitropic Effect in Conscious Chronically Instrumented Normal and Heart Failure Dogs
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 236
OP 247
DO 10.1124/jpet.107.134940
VO 325
IS 1
A1 Satoshi Masutani
A1 Heng-Jie Cheng
A1 Minja Hyttilä-Hopponen
A1 Jouko Levijoki
A1 Aira Heikkilä
A1 Arja Vuorela
A1 William C. Little
A1 Che-Ping Cheng
YR 2008
UL http://jpet.aspetjournals.org/content/325/1/236.abstract
AB 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. The American Society for Pharmacology and Experimental Therapeutics