Comparative effects of levosimendan, OR-1896, OR-1855, dobutamine, and milrinone on vascular resistance, indexes of cardiac function, and O2 consumption in dogs.
Levosimendan enhances cardiac contractility via Ca(2+) sensitization and induces vasodilation through the activation of ATP-dependent K(+) and large-conductance Ca(2+)-dependent K(+) 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 mumol.kg(-1).30 min(-1), targeting therapeutic to supratherapeutic concentrations of total levosimendan (62.6 ng/ml). Results were compared with those of the beta(1)-agonist dobutamine and the phosphodiesterase 3 inhibitor milrinone. Peak concentrations of levosimendan, OR-1896, and OR-1855 were 455 +/- 21, 126 +/- 6, and 136 +/- 6 ng/ml, respectively. Levosimendan and OR-1896 produced dose-dependent reductions in mean arterial pressure (-31 +/- 2 and -42 +/- 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 +/- 2 and 23 +/- 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 +/- 10 and 133 +/- 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 +/- 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(+) channels and Ca(2+) sensitization, whereas OR-1855 is inactive on endpoints measured in this study.
Banfor
Patricia N
PN
Department of Integrative Pharmacology R46R, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Rd., Abbott Park, IL 60064-6119, USA.
Preusser
Lee C
LC
Campbell
Thomas J
TJ
Marsh
Kennan C
KC
Polakowski
James S
JS
Reinhart
Glenn A
GA
Cox
Bryan F
BF
Fryer
Ryan M
RM
D000081:Acetamides / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002302:Cardiac Output / Q000187:drug effects; D002316:Cardiotonic Agents / Q000097:blood / Q000494:pharmacology*; D002319:Cardiovascular System / Q000187:drug effects* / Q000378:metabolism; D004280:Dobutamine / Q000494:pharmacology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects; D006835:Hydrazones / Q000097:blood / Q000494:pharmacology*; D008297:Male; D020105:Milrinone / Q000494:pharmacology*; D009200:Myocardial Contraction / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects*; D011188:Potassium / Q000378:metabolism; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism; D011652:Pulmonary Circulation / Q000187:drug effects; D011724:Pyridazines / Q000097:blood / Q000494:pharmacology*; D000077464:Simendan; D013997:Time Factors; D014655:Vascular Resistance / Q000187:drug effects*; D014665:Vasodilator Agents / Q000097:blood / Q000494:pharmacology*; D016277:Ventricular Function, Left / Q000187:drug effects
D000081:Acetamides; D002316:Cardiotonic Agents; D006835:Hydrazones; C414222:N-(4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)acetamide; D015221:Potassium Channels; D011724:Pyridazines; D014665:Vasodilator Agents; D000077464:Simendan; D004280:Dobutamine; D020105:Milrinone; D011188:Potassium; D002118:Calcium