title: Zatebradine, a specific bradycardic agent, alters the hemodynamic and left ventricular mechanical actions of levosimendan, a new myofilament calcium sensitizer, in conscious dogs.
abstract: The cardiovascular and left ventricular (LV) functional effects of levosimendan were examined (LSM; 0.5, 1.0, 2.0 and 4.0 micrograms.kg-1.min-1) in conscious, chronically instrumented dogs (n = 8) in the presence and absence of heart rate control with zatebradine (ZAT) or ZAT alone (0.25, 0.5 and 1.0 mg.kg-1). LSM increased heart rate (HR) cardiac output (CO), diastolic coronary blood flow velocity (DCBFV) and pressure-work index (PWI; calculated myocardial oxygen consumption) and decreased mean arterial, LV systolic and end-diastolic pressures, systemic vascular resistance and diastolic coronary vascular resistance (DCVR). ZAT alone decreased HR and PWI and increased stroke volume. LSM-induced increases in HR and PWI were attenuated by ZAT. Increases in DCBFV and decreases in DCVR occurred without changes in PWI in the presence of ZAT. LSM increased preload recruitable stroke work slope (Mw, 68 +/- 6 to 159 +/- 13 mm Hg) and +dP/dt. These positive inotropic effects were partially attenuated by ZAT. LSM alone decreased the time constant of isovolumic relaxation (tau, 36 +/- 2 to 29 +/- 2 ms). LSM-induced decreases in tau were blunted by ZAT, indicating that changes in tau were partially dependent on heart rate. LSM increased the maximal rate of segment lengthening to a similar degree in ZAT-treated versus -untreated dogs. ZAT alone had minimal effects on LV function. Control of LSM-induced tachycardia with ZAT decreases myocardial oxygen consumption but also partially attenuates the positive inotropic and lusitropic effects of LSM.
authors.affiliation: Department of Pharmacology, Medical College of Wisconsin, Milwaukee, USA.
authors.forename: P S
authors.initials: PS
authors.lastname: Pagel
authors.forename: C P
authors.initials: CP
authors.lastname: Harkin
authors.forename: D A
authors.initials: DA
authors.lastname: Hettrick
authors.forename: D C
authors.initials: DC
authors.lastname: Warltier
mesh_terms: D008841:Actin Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism / Q000502:physiology; D002316:Cardiotonic Agents / Q000494:pharmacology*; D003243:Consciousness; D003326:Coronary Circulation / Q000187:drug effects; D003971:Diastole / Q000187:drug effects; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D006321:Heart / Q000187:drug effects / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D006835:Hydrazones / Q000494:pharmacology*; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology; D011724:Pyridazines / Q000494:pharmacology*; D000077464:Simendan; D016277:Ventricular Function, Left / Q000187:drug effects*
chemical_list: D001552:Benzazepines; D002316:Cardiotonic Agents; D006835:Hydrazones; D011724:Pyridazines; D000077464:Simendan; D002118:Calcium; C043636:zatebradine