A quantitative comparison of functional and anti-ischaemic effects of the phosphodiesterase-inhibitors, amrinone, milrinone and levosimendan in rabbit isolated hearts.
1. The functional and anti-ischaemic effects of the phosphodiesterase (PDE)-inhibitors, amrinone, milrinone and levosimendan, a new agent combining PDE-inhibitory with calcium-sensitizing properties, were investigated in rabbit isolated hearts (Langendorff, constant pressure: 70 cmH2O, Tyrode solution, Ca2+ 1.8 mmol l-1, 37 degrees C). Anti-ischaemic effects were studied in electrically-driven hearts (200 beats min-1). Acute regional ischaemia was induced by ligature of a branch of the circumflex coronary artery and quantified from epicardial NADH-fluorescence photography. 2. Cumulative concentration-response curves in spontaneously beating hearts in the presence of isoprenaline (10(-10) M), showed a higher inotropic and coronary vasodilator potency for levosimendan (EC50: 7 x 10(-7) M) compared to milrinone (EC50: 7.7 x 10(-6) M) or amrinone (EC50: 2 x 10(-5) M). Although the maximal coronary dilator activity was similar for the three agents, the maximal inotropic and chronotropic effects were lower for levosimendan than for amrinone or milrinone (P < 0.05). 3. In regionally ischaemic hearts, milrinone (10(-5) M) or levosimendan (5 x 10(-6) M) similarly enhanced the left ventricular pressure (+15-20%) (P < 0.05) and the global coronary flow (+40-50%) (P < 0.05). The epicardial NADH-fluorescence area was significantly diminished by milrinone or levosimendan (-20-30%) (P < 0.05) and there was no significant difference between the anti-ischaemic effects of either agent (P > 0.05). 4. It is concluded that amrinone and milrinone possess similar functional profiles in rabbit isolated hearts and a higher inotropic and chronotropic efficacy than levosimendan. At functionally equieffective concentrations, milrinone and levosimendan show similar anti-ischaemic effects, related to an improvement of myocardial perfusion. The calcium-sensitizing properties seem not to be relevant for cardioprotection by levosimendan at the concentration used.
Rump
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AF
Institut für Pharmakologie, Universität Köln, Germany.
Acar
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D
Klaus
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D000676:Amrinone / Q000494:pharmacology; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D003326:Coronary Circulation / Q000187:drug effects; D004558:Electric Stimulation; D006321:Heart / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D006835:Hydrazones / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D020105:Milrinone; D017202:Myocardial Ischemia / Q000378:metabolism / Q000503:physiopathology*; D009206:Myocardium / Q000378:metabolism; D009243:NAD / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011724:Pyridazines / Q000494:pharmacology; D011728:Pyridones / Q000494:pharmacology; D011817:Rabbits; D000077464:Simendan; D014664:Vasodilation / Q000187:drug effects; D017725:Ventricular Pressure / Q000187:drug effects
D002316:Cardiotonic Agents; D006835:Hydrazones; D010726:Phosphodiesterase Inhibitors; D011724:Pyridazines; D011728:Pyridones; D009243:NAD; D000077464:Simendan; D020105:Milrinone; D000676:Amrinone