Inhibition of phosphodiesterase-3 by levosimendan is sufficient to account for its inotropic effect in failing human heart

Br J Pharmacol. 2014 Dec;171(23):5169-81. doi: 10.1111/bph.12647.

Abstract

Background and purpose: Levosimendan is known as a calcium sensitizer, although it is also known to inhibit PDE3. We aimed to isolate each component and estimate their contribution to the increased cardiac contractility induced by levosimendan.

Experimental approach: Contractile force was measured in electrically stimulated ventricular strips from explanted failing human hearts and left ventricular strips from normal male Wistar rats. PDE activity was measured in a two-step PDE activity assay on failing human ventricle.

Key results: Levosimendan exerted a positive inotropic effect (PIE) reaching maximum at 10(-5) M in ventricular strips from failing human hearts. In the presence of the selective PDE3 inhibitor cilostamide, the PIE of levosimendan was abolished. During treatment with a PDE4 inhibitor and a supra-threshold concentration of isoprenaline, levosimendan generated an amplified inotropic response. This effect was reversed by β-adrenoceptor blockade and undetectable in strips pretreated with cilostamide. Levosimendan (10(-6) M) increased the potency of β-adrenoceptor agonists by 0.5 log units in failing human myocardium, but not in the presence of cilostamide. Every inotropic response to levosimendan was associated with a lusitropic response. Levosimendan did not affect the concentration-response curve to calcium in rat ventricular strips, in contrast to the effects of a known calcium sensitizer, EMD57033 [5-(1-(3,4-dimethoxybenzoyl)-1,2,3,4-tetrahydroquinolin-6-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one]. PDE activity assays confirmed that levosimendan inhibited PDE3 as effectively as cilostamide.

Conclusions and implications: Our results indicate that the PDE3-inhibitory property of levosimendan was enough to account for its inotropic effect, leaving a minor, if any, effect to a calcium-sensitizing component.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic beta-Agonists / pharmacology
  • Animals
  • Calcium / physiology
  • Cardiotonic Agents / pharmacology*
  • Heart / physiopathology
  • Heart Failure / physiopathology*
  • Humans
  • Hydrazones / pharmacology*
  • In Vitro Techniques
  • Isoproterenol / pharmacology
  • Male
  • Milrinone / pharmacology
  • Myocardial Contraction / drug effects
  • Phosphodiesterase 3 Inhibitors / pharmacology*
  • Phosphodiesterase 4 Inhibitors / pharmacology
  • Pyridazines / pharmacology*
  • Quinolines / pharmacology
  • Quinolones / pharmacology
  • Rats, Wistar
  • Rolipram / pharmacology
  • Simendan
  • Thiadiazines / pharmacology

Substances

  • Adrenergic beta-Agonists
  • Cardiotonic Agents
  • Hydrazones
  • Phosphodiesterase 3 Inhibitors
  • Phosphodiesterase 4 Inhibitors
  • Pyridazines
  • Quinolines
  • Quinolones
  • Thiadiazines
  • EMD 53998
  • Simendan
  • cilostamide
  • Milrinone
  • Rolipram
  • Isoproterenol
  • Calcium