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Cardiac responses to β-adrenoceptor stimulation is partly dependent on mitochondrial calcium uniporter activity.
- Source :
-
British journal of pharmacology [Br J Pharmacol] 2014 Sep; Vol. 171 (18), pp. 4207-21. Date of Electronic Publication: 2014 Jul 01. - Publication Year :
- 2014
-
Abstract
- Background and Purpose: Despite the importance of mitochondrial Ca(2+) to metabolic regulation and cell physiology, little is known about the mechanisms that regulate Ca(2+) entry into the mitochondria. Accordingly, we established a system to determine the role of the mitochondrial Ca(2+) uniporter in an isolated heart model, at baseline and during increased workload following β-adrenoceptor stimulation.<br />Experimental Approach: Cardiac contractility, oxygen consumption and intracellular Ca(2+) transients were measured in ex vivo perfused murine hearts. Ru360 and spermine were used to modify mitochondrial Ca(2+) uniporter activity. Changes in mitochondrial Ca(2+) content and energetic phosphate metabolite levels were determined.<br />Key Results: The addition of Ru360 , a selective inhibitor of the mitochondrial Ca(2+) uniporter, induced progressively and sustained negative inotropic effects that were dose-dependent with an EC50 of 7 μM. Treatment with spermine, a uniporter agonist, showed a positive inotropic effect that was blocked by Ru360 . Inotropic stimulation with isoprenaline elevated oxygen consumption (2.7-fold), Ca(2+) -dependent activation of pyruvate dehydrogenase (5-fold) and mitochondrial Ca(2+) content (2.5-fold). However, in Ru360 -treated hearts, this parameter was attenuated. In addition, β-adrenoceptor stimulation in the presence of Ru360 did not affect intracellular Ca(2+) handling, PKA or Ca(2+) /calmodulin-dependent PK signalling.<br />Conclusions and Implications: Inhibition of the mitochondrial Ca(2+) uniporter decreases β-adrenoceptor response, uncoupling between workload and production of energetic metabolites. Our results support the hypothesis that the coupling of workload and energy supply is partly dependent on mitochondrial Ca(2+) uniporter activity.<br /> (© 2014 The British Pharmacological Society.)
- Subjects :
- Adrenergic beta-Agonists pharmacology
Animals
Calcium-Binding Proteins metabolism
Cardiotonic Agents pharmacology
Cyclic AMP metabolism
Cyclic AMP-Dependent Protein Kinases metabolism
Glutathione metabolism
Heart drug effects
Isoproterenol pharmacology
Male
Mice
Mitochondria, Heart drug effects
Myocytes, Cardiac metabolism
Oxidative Stress drug effects
Oxygen Consumption
Rats, Wistar
Ruthenium Compounds pharmacology
Spermine pharmacology
Calcium physiology
Calcium Channels physiology
Heart physiology
Mitochondria, Heart physiology
Receptors, Adrenergic, beta physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5381
- Volume :
- 171
- Issue :
- 18
- Database :
- MEDLINE
- Journal :
- British journal of pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 24628066
- Full Text :
- https://doi.org/10.1111/bph.12684