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- Title
P662 Pleiotropic heart rate-independent cardioprotection by ivabradine: reduction of reactive oxygen species formation and improved viability in cardiomyocytes.
- Authors
Kleinbongard, P; Gedik, N; Heusch, G
- Abstract
Background: In pigs, ivabradine reduced infarct size even when given only at reperfusion and in the absence of heart rate reduction (atrial pacing). The mechanism of such non-heart rate-related cardioprotection is unknown.Methods: Pentobarbital-anesthetized C57Bl/6J mice received ivabradine (1.7 mg/kg i.v. ± left atrial pacing) or placebo and were subjected to occlusion (30 min) and reperfusion (120 min) of the left anterior coronary artery (n=5, each). Area at risk was measured with phthalo blue and infarct size was measured with triphenyl tetrazolium chloride staining. In separate experiments, ventricular cardiomyocytes were enzymatically isolated from mouse hearts (n=9). Simulated ischemia was induced (hypoxia, pH 6.5, 310 mOsm/l, without glucose, 60 min) and followed by reperfusion (normoxia, pH 7.4, 250 mOsm/l, 10mmol/l glucose, 5 min) ±3 μmol/l ivabradine given 10 min before and during reperfusion. Viability (trypan blue exclusion) was quantified in >200 cells/per preparation. Reactive oxygen species (ROS) formation was detected fluorometrically (540/580nm, Amplex Red) in the extracellular space at baseline and after simulated ischemia/reperfusion (n=9 hearts). Mitochondria were isolated from mouse hearts (n=5) by differential centrifugation and incubated ±3 μmol/l ivabradine in glutamate/malate and ADP-containing buffer at 37°C; mitochondrial ROS formation was detected fluorometrically (540/580nm, Amplex Red).Results: Ivabradine reduced infarct size from 39±5 % to 17±4% of the area at risk (p=0.01), this benefit remained with pacing (20±5%). Viability was comparable at baseline (control, 74±2%; ivabradine, 73±3%) and remained relatively stable with 60 min normoxia (53±3 vs. 62±2%). Viability was reduced with simulated ischemia/reperfusion (10±2%), but better preserved with ivabradine (28±4%, p<0.001). Cellular ROS formation was comparable at baseline, but reduced with ivabradine after ischemia (19±3 vs. 12±3 μmol H2O2/100 μg protein, p<0.001) and reperfusion (33±7 vs. 21±3 μmol H2O2/100 μg protein, p=0.02), respectively. Mitochondrial ROS formation was also reduced by ivabradine (0.31±0.8 vs. 0.17±0.7 μmol H2O2/100 μg protein, p=0.03).Conclusion: Ivabradine reduces infarct size with or without heart rate reduction and improves ventricular cardiomyocyte viability, possibly by reduction of ROS formation.
- Publication
Cardiovascular Research, 2014, Vol 103, Issue suppl_1, pS121
- ISSN
0008-6363
- Publication type
Academic Journal
- DOI
10.1093/cvr/cvu098.87