OR-1896 increases force of contraction in the isolated human atrium

Naunyn Schmiedebergs Arch Pharmacol. 2023 Dec;396(12):3823-3833. doi: 10.1007/s00210-023-02592-5. Epub 2023 Jun 24.

Abstract

OR-1896 ((R)-N-(4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)acetamide) is the main active metabolite of levosimendan. However, nobody has reported a positive inotropic effect of OR-1896 in isolated human cardiac preparations. The mechanism of action of OR-1896 remains controversial. Hence, we wanted to know whether OR-1896 exerts a positive inotropic effect in humans and what might be the underlying mechanism. Therefore, we measured the contractile effects of OR-1896 (0.01-10 µM cumulatively applied) in isolated electrically stimulated (1 Hz) human right atrial preparations (HAP) obtained during cardiac surgery. OR-1896, given alone, exerted time- and concentration-dependent positive inotropic effects; 1-µM OR-1896 increased force by 72 ± 14.7% (p < 0.05, n = 6) and shortened the time of relaxation by 10.6 ± 3.6% (p < 0.05, n = 11) in HAP started at 0.1 µM, plateaued at 1-µM OR-1896, and was antagonized by 1-µM propranolol. The maximum positive inotropic effect of OR-1896 in human right atrial preparations was less than that of 10-µM isoprenaline. EMD 57033 (10 µM), a calcium sensitizer, enhanced the force of contraction further in the additional presence of 1-µM OR-1896 by 109 ± 19% (p < 0.05, n = 4). Cilostamide (10 µM), an inhibitor of phosphodiesterase III given before OR-1896 (1 µM), blocked the positive inotropic effect of OR-1896 in HAP. Our data suggest that OR-1896 is, indeed, a positive inotropic agent in the human heart. OR-1896 acts as a PDE III inhibitor. OR-1896 is unlikely to act as a calcium sensitizer in the human heart.

Keywords: Human atrium; Mouse atrium; OR1896; Phospholamban.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Atrial Fibrillation*
  • Calcium / metabolism
  • Cardiotonic Agents* / pharmacology
  • Heart Atria / metabolism
  • Humans
  • Myocardial Contraction
  • Phosphodiesterase Inhibitors / pharmacology

Substances

  • N-(4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)acetamide
  • Cardiotonic Agents
  • Calcium
  • Phosphodiesterase Inhibitors