A quantitative comparison of functional and anti-ischaemic effects of the phosphodiesterase-inhibitors, amrinone, milrinone and levosimendan in rabbit isolated hearts

Br J Pharmacol. 1994 Jul;112(3):757-62. doi: 10.1111/j.1476-5381.1994.tb13143.x.

Abstract

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.

Publication types

  • Comparative Study

MeSH terms

  • Amrinone / pharmacology
  • Animals
  • Cardiotonic Agents / pharmacology*
  • Coronary Circulation / drug effects
  • Electric Stimulation
  • Heart / drug effects*
  • Heart Rate / drug effects
  • Hydrazones / pharmacology
  • In Vitro Techniques
  • Male
  • Milrinone
  • Myocardial Ischemia / metabolism
  • Myocardial Ischemia / physiopathology*
  • Myocardium / metabolism
  • NAD / metabolism
  • Phosphodiesterase Inhibitors / pharmacology*
  • Pyridazines / pharmacology
  • Pyridones / pharmacology
  • Rabbits
  • Simendan
  • Vasodilation / drug effects
  • Ventricular Pressure / drug effects

Substances

  • Cardiotonic Agents
  • Hydrazones
  • Phosphodiesterase Inhibitors
  • Pyridazines
  • Pyridones
  • NAD
  • Simendan
  • Milrinone
  • Amrinone