Comparative effects of levosimendan, OR-1896, OR-1855, dobutamine, and milrinone on vascular resistance, indexes of cardiac function, and O sub(2) consumption in dogs

• Published in: American Journal of Physiology: Cell Physiology Vol. 294; no. 1; pp. H238 - H248
• Main Authors: Ban, Patricia N, Preusser, Lee C, Campbell, Thomas J, Marsh, Kennan C, Polakowski, James S, Reinhart, Glenn A, Cox, Bryan F, Fryer, Ryan M
• Format: Journal Article
• Language: English
• Published: 01.01.2008
• ISSN: 0363-6143; 1522-1563

Levosimendan enhances cardiac contractility via Ca super(2+) sensitization and induces vasodilation through the activation of ATP-dependent K super(+) and large-conductance Ca super(2+)-dependent K super(+) channels. However, the hemodynamic effects of levosimendan, as well as its metabolites, OR-1896 and OR-1855, relative to plasma concentrations achieved, are not well defined. Thus levosimendan, OR-1896, OR-1855, or vehicle was infused at 0.01, 0.03, 0.1, and 0.3 mu mol.kg super(-1).30 min super(-1), targeting therapeutic to supratherapeutic concentrations of total levosimendan (62.6 ng/ml). Results were compared with those of the beta sub(1)-agonist dobutamine and the phosphodiesterase 3 inhibitor milrinone. Peak concentrations of levosimendan, OR-1896, and OR-1855 were 455 plus or minus 21, 126 plus or minus 6, and 136 plus or minus 6 ng/ml, respectively. Levosimendan and OR-1896 produced dose-dependent reductions in mean arterial pressure (-31 plus or minus 2 and -42 plus or minus 3 mmHg, respectively) and systemic resistance without affecting pulse pressure, effects paralleled by increases in heart rate; OR-1855 produced no effect at any dose tested. Dobutamine, but not milrinone, increased mean arterial pressure and pulse pressure (17 plus or minus 2 and 23 plus or minus 2 mmHg, respectively). Regarding potency to elicit reductions in time to peak pressure and time to systolic pressure recovery: OR-1896 > levosimendan > milrinone > dobutamine. Levosimendan and OR-1896 elicited dose-dependent increases in change in pressure over time (118 plus or minus 10 and 133 plus or minus 13%, respectively), concomitant with reductions in left ventricular end-diastolic pressure and ejection time. However, neither levosimendan nor OR-1896 produced increases in myocardial oxygen consumption at inotropic and vasodilatory concentrations, whereas dobutamine increased myocardial oxygen consumption (79% above baseline). Effects of the levosimendan and OR-1896 were limited to the systemic circulation; neither compound produced changes in pulmonary pressure, whereas dobutamine produced profound increases (74 plus or minus 13%). Thus levosimendan and OR-1896 are hemodynamically active in the anesthetized dog at concentrations observed clinically and elicit cardiovascular effects consistent with activation of both K super(+) channels and Ca super(2+) sensitization, whereas OR-1855 is inactive on endpoints measured in this study.