ORM-3819 promotes cardiac contractility through Ca2+ sensitization in combination with selective PDE III inhibition, a novel approach to inotropy

Abstract

This study is the first pharmacological characterization of the novel chemical entity, ORM-3819 (L-6-{4-[N'-(4-Hydroxi-3-methoxy-2-nitro-benzylidene)-hydrazino]-phenyl}-5-methyl-4,5-dihydro-2H-pyridazin-3-one), focusing primarily on its cardiotonic effects. ORM-3819 binding to cardiac troponin C (cTnC) was confirmed by nuclear magnetic resonance spectroscopy, and a selective inhibition of the phosphodiesterase III (PDE III) isozyme (IC50=3.88±0.3 nM) was revealed during in vitro enzyme assays. The Ca(2+)-sensitizing effect of ORM-3819 was demonstrated in vitro in permeabilized myocyte-sized preparations from left ventricles (LV) of guinea pig hearts (ΔpCa50=0.12±0.01; EC50=2.88±0.14 µM). ORM-3819 increased the maximal rate of LV pressure development (+dP/dtmax) (EC50=8.9±1.7 nM) and LV systolic pressure (EC50=7.63±1.74 nM) in Langendorff-perfused guinea pig hearts. Intravenous administration of ORM-3819 increased LV+dP/dtmax (EC50=0.13±0.05 µM/kg) and improved the rate of LV pressure decrease (-dP/dtmax); (EC50=0.03±0.02 µM/kg) in healthy guinea pigs. In an in vivo dog model of myocardial stunning, ORM-3819 restored the depressed LV+dP/dtmax and improved % segmental shortening (%SS) in the ischemic area (to 18.8±3), which was reduced after the ischaemia-reperfusion insult (from 24.1±2.1 to 11.0±2.4). Our data demonstrate ORM-3819 as a potent positive inotropic agent exerting its cardiotonic effect by a cTnC-dependent Ca(2+)-sensitizing mechanism in combination with the selective inhibition of the PDE III isozyme. This dual mechanism of action results in the concentration-dependent augmentation of the contractile performance under control conditions and in the postischemic failing myocardium.

Short-Term Therapies for Treatment of Acute and Advanced Heart Failure—Why so Few Drugs Available in Clinical Use, Why Even Fewer in the Pipeline?

“…As regards drug discovery and translational science in the field of acute cardiac care, the translational committee of the ESC-HFA issued some scientific bases [78] designed to pave the way towards the development of new agents but the preclinical field remains scarcely populated, with just some notable exceptions such as the calcium sensitizer/PDE inhibitor ORM-3819 [79,80].…”

The Novel Inodilator ORM-3819 Relaxes Isolated Porcine Coronary Arteries: Role of Voltage-Gated Potassium Channel Activation

“…The phosphodiesterase inhibitor and inodilator milrinone were indeed shown to interfere with the BKCa channels. 49 In a previous article, 22 we tested the PDE inhibitory effect of ORM-3819 on purified PDEIII and PDEIV isozymes and found that ORM-3819 is a very selective inhibitor of PDEIII, with a selectivity versus PDEIV of more than 12,000-fold. In comparison, such selectivity was 8000 for levosimendan 50 but only 14 for milrinone (see Table 2 on page 11 in de Cheffoy de Courcelles et al 51 ).…”

“…41 4-AP-sensitive potassium channels have been proposed to play a role in the vasomotor tone of coronary arteries under pathological conditions. 42 Both ORM-3819 and levosimendan have been shown to elicit beneficial hemodynamic effects in canine pathological cardiac models 22,43 and, in the case of levosimendan, in human severe heart failure. [44][45][46] The activation of voltage-gated potassium channels is significantly involved in the vasodilatory mechanism induced by ORM-3819.…”

“…The dose range of ORM-3819 in the current experiments was selected on the basis of the previous experience with the in vitro and ex vivo effects of the drug. 22…”

“…[17][18][19][20][21] We have recently studied the effect of a new inodilator, ORM-3819, which acts through 2 mechanisms: (1) calcium sensitization and (2) highly specific phosphodiesterase III inhibition. 22 The positive inotropic effect of this novel chemical entity was recently demonstrated both in vitro and in vivo, 22 but the potential effect of this compound on vascular tone and the mechanism underpinning that effect remain unrevealed.…”