SYSTEMIC AND CORONARY HEMODYNAMIC ACTIONS AND LEFT-VENTRICULAR FUNCTIONAL-EFFECTS OF LEVOSIMENDAN IN CONSCIOUS DOGS

We examined the effects of levosimendan, a new myofilament Ca2+ sensitizer with phosphodiesterase (PDE)-inhibiting properties, on systemic and coronary hemodynamics and left ventricular (LV) systolic and diastolic function in conscious dogs with intact and blocked autonomic nervous system (ANS) reflexes, Twenty experiments were conducted in 10 dogs chronically instrumented for measurement of aortic and LV pressure, the peak rate of increase and decrease in LV pressure (+ dP/dt(max) and - dP/dt(min)), subendocardial segment length, diastolic coronary blood flow (CBF) velocity, and cardiac output (CO). The slope (M(w)) of the regional preload recruitable stroke work relation was used to assess myocardial contractility. Diastolic function was evaluated by - dP/dt(min) a time constant of isovolumic relaxation (tau), maximum segment lengthening velocity during rapid ventricular filling (dL/dt(max)), and a regional chamber stiffness constant (K-p). Dogs were randomly assigned to receive levosimendan (0.5, 1.0, 2.0, and 4.0 mu g . kg(-1) . min(-1)) with or without ANS blockade. On separate experimental days, systemic and coronary hemodynamics and LV pressure-segment length diagrams and waveforms were recorded after 10-min equilibration at each dose in the conscious ANS-intact or ANS-blocked state. Levosimendan increased heart rate (HR), CO, mean and diastolic CBF velocity, and pressure-work index (PWI, an estimate of myocardial oxygen consumption) and decreased LV end-diastolic pressure (EDP), systemic vascular resistance (SVR), end-systolic and end-diastolic segment length, and mean and diastolic coronary vascular resistance (CVR) in dogs with intact ANS function. Levosimendan-induced increases in HR and PWI and decreases in SVR were attenuated by ANS blockade. Levosimendan caused equivalent dose-dependent increases in M(w) in ANS-intact and ANS-blocked dogs, consistent with a positive inotropic effect independent of ANS activity, Levosimendan decreased tau (e.g., 35 +/- 1 ms during control to 29 +/- 1 ms at the high dose) and increased the magnitude of LV -dP/dt(min) in dogs with intact but not blocked ANS reflexes, suggesting that relaxation was enhanced by favorable changes in systemic hemodynamics or ANS activation and direct effects of this drug on lusitropic state. Levosimendan also increased dL/dt(max) to a greater degree in ANS-intact dogs, indicating that improvement of rapid ventricular filling was also partially dependent on ANS tone. No changes in K-p were observed in either experimental group. The results indicate that levosimendan decreases preload and afterload and has positive inotropic and lusitropic properties. The actions of levosimendan on diastolic function are largely mediated by the ANS.