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

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Abstract
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°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. Cumulative concentration‐response curves in spontaneously beating hearts in the presence of isoprenaline (10−1 m), showed a higher inotropic and coronary vasodilator potency for levosimendan (EC50: 7 × 10−7 m) compared to milrinone (EC50: 7.7 × 10−6 m) or amrinone (EC50: 2 × 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). In regionally ischaemic hearts, milrinone (10−5 m) or levosimendan (5 × 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). 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.