title: Levosimendan enhances left ventricular systolic and diastolic function in conscious dogs with pacing-induced cardiomyopathy.
abstract: We examined the left ventricular (LV) mechanical actions of levosimendan (LSM) before and after the development of pacing-induced cardiomyopathy in conscious dogs chronically instrumented for measurement of aortic and LV pressure, +dP/dt, subendocardial segment length, and cardiac output (CO). The slope (Mw) of the regional preload recruitable stroke work relation was used to assess myocardial contractility. Diastolic function was evaluated with a time constant of isovolumic relaxation (tau), the maximal rate of segment-lengthening velocity (dL/dt), and a regional chamber-stiffness constant (Kp). On different experimental days, dogs were assigned to receive LSM (12- or 24-microgram/kg loading dose and 0.2 or 0.4 microgram/kg/min infusion) before rapid ventricular pacing was initiated. Dogs were then paced at 240 beats/min for 22 +/- 2 days, and the low and high doses of LSM were repeated on separate days. LSM increased Mw and +dP/dt in dogs before the initiation of pacing, consistent with enhanced myocardial contractility. LSM also improved indices of LV diastolic function (decreases in tau and Kp and increases in dL/dt) in dogs before pacing. Rapid ventricular pacing over a 3-week period increased LV end-diastolic pressure and produced systolic (decreases in Mw and +dP/dt) and diastolic (increases in tau and Kp and decreases in dL/dt) dysfunction. LSM significantly (p < 0.05) increased Mw (54 +/- 3 to 98 +/- 6 mm Hg) +dP/dt and dL/dt (57 +/- 13 to 72 +/- 13 mm/s) and decreased tau (66 +/- 4 to 52 +/- 3 ms) and Kp (1.14 +/- 0.14 to 0.71 +/- 0.03 mm-1) in the presence of LV dysfunction. In contrast to the findings in normal dogs, however, LSM did not alter heart rate and calculated indices of myocardial oxygen consumption in dogs after pacing. The findings indicate that LSM produces favorable alterations in hemodynamics and positive inotropic and lusitropic effects in conscious dogs with left ventricular dysfunction.
authors.affiliation: Department of Anesthesiology, Medical College of Wisconsin, Milwaukee 53226, USA.
authors.forename: P S
authors.initials: PS
authors.lastname: Pagel
authors.forename: M F
authors.initials: MF
authors.lastname: McGough
authors.forename: D A
authors.initials: DA
authors.lastname: Hettrick
authors.forename: D
authors.initials: D
authors.lastname: Lowe
authors.forename: J P
authors.initials: JP
authors.lastname: Tessmer
authors.forename: I N
authors.initials: IN
authors.lastname: Jamali
authors.forename: D C
authors.initials: DC
authors.lastname: Warltier
mesh_terms: D000818:Animals; D002304:Cardiac Pacing, Artificial; D002311:Cardiomyopathy, Dilated / Q000503:physiopathology*; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D003971:Diastole / Q000187:drug effects / Q000502:physiology; D004285:Dogs; D006439:Hemodynamics / Q000187:drug effects; D006835:Hydrazones / Q000008:administration & dosage / Q000494:pharmacology*; D007700:Kinetics; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects; D011724:Pyridazines / Q000008:administration & dosage / Q000494:pharmacology*; D000077464:Simendan; D013599:Systole / Q000187:drug effects / Q000502:physiology; D016277:Ventricular Function, Left / Q000187:drug effects*
chemical_list: D002316:Cardiotonic Agents; D006835:Hydrazones; D011724:Pyridazines; D000077464:Simendan