Original Contribution

Basic Research in Cardiology

, Volume 91, Issue 4, pp 296-307

First online:

Comparison of the effects of levosimendan, pimobendan, and milrinone on canine left ventricular-arterial coupling and mechanical efficiency

  • P. S. PagelAffiliated withMedical College of Wisconsin
  • , D. A. HettrickAffiliated withMedical College of Wisconsin
  • , D. C. WarltierAffiliated withMedical College of Wisconsin

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We examined and compared the effects of levosimendan, a new myofilament calcium sensitizer with phosphodiesterase inhibiting activity, pimobendan, and milrinone on left ventricular-arterial coupling and mechanical efficiency in 21 experiments performed in open-chest, barbiturate-anesthetized dogs instrumented for measurement of aortic and left ventricular (LV) pressure (micromanometer-tipped catheter), +dP/dt, and LV volume (conductance catheter). Myocardial contractility was assessed with the endsystolic pressure-volume relation (Ees) and preload recruitable stroke work (Msw) generated from a series of differentially loaded LV pressurevolume diagrams. LV-arterial coupling and mechanical efficiency were determined by the ratio of Ees to effective arterial elastance (Ea; the ratio of end-systolic arterial pressure to stroke volume) and the ratio of stroke work (SW) to pressure-volume area (PVA), respectively. Levosimendan (0.75, 1.5, and 3.0 μg·kg−1·min−1) significantly (p<0.05) increased heart rate, +dP/dt, and ejection fraction (EF) and decreased mean arterial pressure (MAP), pressurework index (PWI; an estimate of myocardial oxygen consumption), and LV systolic and end-diastolic pressures (LVSP and LVEDP) and volumes (EDV and ESV). Levosimendan-induced augmentation of myocardial contractility (Ees, Msw, and+dP/dt) and reductions in LV afterload (Ea) caused increases in the Ees/Ea ratio (0.61±0.10 during control to 3.3±0.7 during the high dose) consistent with enhancement of LV-arterial coupling. Levosimendan increased SW/PVA (0.48±0.05 during control to 0.84±0.04 during the high dose), indicating this drug improves the transfer of myocardial potential energy to external work. Levosimendan also increased the ratio of SW to PWI (109±18 during control to 255±50 mmHg·min·100g during the high dose), suggesting that myocardial metabolic efficiency was improved as well. Like levosimendan, pimobendan and milrinone (10, 20, and 40 and 1.0, 2.0, and 4.0 μg·kg−1·min−1, respectively) increased HR, +dP/dt, EF, Ees, and Msw and decreased MAP, LVSP, LVEDP, EDV, ESV, and Ea. In contrast to levosimendan, neither agent reduced PWI. Pimobendan and milrinone caused dose-related increases in Ees/Ea, SW/PVA, and SW/PWI. The results indicate that levosimendan, pimobendan, and milrinone augment myocardial contractility, produce venous and arteriolar vasodilation, and enhance LV-arterial coupling and mechanical efficiency in open-chest, barbiturateanesthetized dogs.

Key words

Heart: myocardial contractility mechanical efficiency end-systolic pressure-volume relation ventricular-arterial coupling pressure-volume area. Myofilaments: calcium sensitizer troponin C. Pharmacology: inotropes levosimendan, pimobendan, milrinone