LEVOSIMENDAN (OR-1259), A MYOFILAMENT CALCIUM SENSITIZER, ENHANCES MYOCARDIAL-CONTRACTILITY BUT DOES NOT ALTER ISOVOLUMIC RELAXATION IN CONSCIOUS AND ANESTHETIZED DOGS

Background: Levosimendan is a myofilament calcium sensitizer with phosphodiesterase III inhibiting properties which increases contractile state in vitro by stabilizing calcium-induced changes in troponin C. This latter effect may produce positive inotropic actions but may also cause deleterious negative lusitropic effects. This investigation examined the effects of levosimendan on systemic and coronary hemodynamics and left ventricular systolic and diastolic function in conscious and anesthetized dogs. Methods: Because autonomic nervous system activity may influence the actions of levosimendan and volatile anesthetics in vivo, experiments were conducted in the presence of pharmacologic blockade of the autonomic nervous system. A total of 24 experiments were performed in eight dogs chronically instrumented for measurement of aortic and left ventricular pressure, the peak rate of increase and decrease of left ventricular pressure, subendocardial segment length, diastolic coronary blood flow velocity, and cardiac output. The slope of the regional preload recruitable stroke work relation was used to assess myocardial contractility. Diastolic function was evaluated by the peak rate of decrease of left ventricular pressure, a time constant of isovolumic relaxation, maximum segment lengthening velocity during rapid ventricular filling, and a regional chamber stiffness constant. Systemic and coronary hemodynamics and left ventricular pressure-segment length diagrams and waveforms were recorded after 10 min equilibration at each dose of levosimendan (0.5, 1.0, 2.0, and 4.0 mu g.kg(-1).min(-1)) in the conscious state or during isoflurane or halothane anesthesia (1.0 MAC) on 3 days of experimentation. Results: In conscious dogs, levosimendan increased heart rate, cardiac output, diastolic coronary blood flow velocity, and segment shortening and decreased left ventricular end-diastolic pressure, systemic vascular resistance, and diastolic coronary vascular resistance. Levosimendan caused dose-dependent increases in the slope of the regional preload recruitable stroke work relation (65 +/- 6 during control to 139 +/- 9 mmHg during the high dose), consistent with a direct positive inotropic effect. No changes in the peak rate of decrease of left ventricular pressure or in the time constant of isovolumic relaxation were produced by with levosimendan in conscious dogs, indicating that isovolumic relaxation was unaffected. In contrast, increases in rapid ventricular filling were observed (maximum segment lengthening velocity 34 +/- 3 during control to 47 +/- 5 mm.s(-1) at the high dose). In the presence of isoflurane and halothane, levosimendan caused cardiovascular actions which were similar to those observed in the conscious state. Levosimendan increased, in a dose-related manner, the slope of the regional preload recruitable stroke work relation and in the maximum segment lengthening velocity during rapid ventricular filling in anesthetized dogs. However, there were no changes in the time constant of isovolumic relaxation or in the peak rate of decrease of left ventricular pressure. Conclusions: The results indicate that levosimendan causes systemic and coronary vasodilatation in conscious and anesthetized dogs during blockade of the autonomic nervous system. Levosimendan caused direct positive inotropic effects and improved rapid ventricular filling but did not alter indices of isovolumic relaxation, suggesting that levosimendan may selectively enhance systolic performance and diastolic filling without affecting left ventricular relaxation.