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+ sensit izer with phosphodiesterase (PDE)-inhibiting properties, on systemic a nd coronary hemodynamics and left ventricular (LV) systolic and diasto lic function in conscious dogs with intact and blocked autonomic nervo us system (ANS) reflexes, Twenty experiments were conducted in 10 dogs chronically instrumented for measurement of aortic and LV pressure, t he peak rate of increase and decrease in LV pressure (+ dP/dt(max) and - dP/dt(min)), subendocardial segment length, diastolic coronary bloo d flow (CBF) velocity, and cardiac output (CO). The slope (M(w)) of th e 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)), an d a regional chamber stiffness constant (K-p). Dogs were randomly assi gned to receive levosimendan (0.5, 1.0, 2.0, and 4.0 mu g . kg(-1) . m in(-1)) with or without ANS blockade. On separate experimental days, s ystemic and coronary hemodynamics and LV pressure-segment length diagr ams and waveforms were recorded after 10-min equilibration at each dos e in the conscious ANS-intact or ANS-blocked state. Levosimendan incre ased heart rate (HR), CO, mean and diastolic CBF velocity, and pressur e-work index (PWI, an estimate of myocardial oxygen consumption) and d ecreased LV end-diastolic pressure (EDP), systemic vascular resistance (SVR), end-systolic and end-diastolic segment length, and mean and di astolic coronary vascular resistance (CVR) in dogs with intact ANS fun ction. Levosimendan-induced increases in HR and PWI and decreases in S VR were attenuated by ANS blockade. Levosimendan caused equivalent dos e-dependent increases in M(w) in ANS-intact and ANS-blocked dogs, cons istent with a positive inotropic effect independent of ANS activity, L evosimendan 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) i n dogs with intact but not blocked ANS reflexes, suggesting that relax ation was enhanced by favorable changes in systemic hemodynamics or AN S activation and direct effects of this drug on lusitropic state. Levo simendan also increased dL/dt(max) to a greater degree in ANS-intact d ogs, indicating that improvement of rapid ventricular filling was also partially dependent on ANS tone. No changes in K-p were observed in e ither experimental group. The results indicate that levosimendan decre ases preload and afterload and has positive inotropic and lusitropic p roperties. The actions of levosimendan on diastolic function are large ly mediated by the ANS.