Abstract 12977: Neladenoson, a Partial Adenosine A1-receptor Agonist, Improves Mitochondrial Function in Left Ventricular Cardiomyocytes Isolated From Dogs With Chronic Heart Failure
Background: Mitochondria (MITO) of failing cardiomyocytes (CMs) manifest structural and functional abnormalities characterized by hyperplasia, reduced organelle size and reduced respiration. These abnormalities lead to reduced rate of ATP synthesis and excess production of reactive oxygen species. We previously showed that chronic therapy with a partial adenosine A1-receptor agonist (pA1RA) improves LV function and normalizes tissue levels of MITO uncoupling proteins 2 and 3 in dogs with heart failure (HF).
Hypothesis: Neladenoson, a new pA1RA, improves MITO function in freshly isolated CMs from dogs with chronic HF.
Methods: CMs were isolated from LV of 7 microembolization-induced HF dogs (LV ejection fraction <30%) and from 6 normal (NL) dogs using a collagenase-based enzymatic process that yielded ~70% rod-shaped CMs that excluded trypan blue. Equal aliquotes of CMs were incubated in 0 (vehicle), 3, 10, and 30 nM concentration of Neladenoson for one hour at 37°C. MITO ADP-stimulated state-3 respiration, maximum rate of ATP synthesis and complex-IV activity (COX-IV) were measured at end of incubation. Respiration was measured with a Strathkelvin respirometer and COX-IV activity was measured polarographically and both expressed as nAtom Oxygen/min/mg protein. Rate of ATP synthesis was measured using the bioluminescent ApoSENSOR assay and quantified in RFU/μg protein.
Results: Data are shown in the table. Increasing concentration of Neladenoson had no effect on measures of MITO function in CMs from NL dogs. In CMs from HF dogs, depressed levels of MITO respiration, ATP synthesis and COX-IV increased significantly and in a dose-dependent manner after exposure to Neladenoson.
Conclusions: Neladenoson has beneficial effects on MITO function in CMs from HF dogs. Furthermore, the improvement in MITO function after treatment with Neladenoson can occur early after initiation of therapy (within one hour) and is dose-dependent up to concentrations of 30 nM.
Author Disclosures: H.N. Sabbah: None. R.C. Gupta: None. V. Singh-Gupta: None. K. Zhang: None. J. Xu: None. B. Albrecht-Küpper: Employment; Modest; Bayer Pharmaceuticals. Employment; Significant; Bayer Pharmaceuticals.
- © 2016 by American Heart Association, Inc.