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Metabolic inhibition reduces cardiac L-type Ca2+ channel current due to acidification caused by ATP hydrolysis.
- Source :
-
PloS one [PLoS One] 2017 Aug 31; Vol. 12 (8), pp. e0184246. Date of Electronic Publication: 2017 Aug 31 (Print Publication: 2017). - Publication Year :
- 2017
-
Abstract
- Metabolic stress evoked by myocardial ischemia leads to impairment of cardiac excitation and contractility. We studied the mechanisms by which metabolic inhibition affects the activity of L-type Ca2+ channels (LTCCs) in frog ventricular myocytes. Metabolic inhibition induced by the protonophore FCCP (as well as by 2,4- dinitrophenol, sodium azide or antimycin A) resulted in a dose-dependent reduction of LTCC current (ICa,L) which was more pronounced during β-adrenergic stimulation with isoprenaline. ICa,L was still reduced by metabolic inhibition even in the presence of 3 mM intracellular ATP, or when the cell was dialysed with cAMP or ATP-γ-S to induce irreversible thiophosphorylation of LTCCs, indicating that reduction in ICa,L is not due to ATP depletion and/or reduced phosphorylation of the channels. However, the effect of metabolic inhibition on ICa,L was strongly attenuated when the mitochondrial F1F0-ATP-synthase was blocked by oligomycin or when the cells were dialysed with the non-hydrolysable ATP analogue AMP-PCP. Moreover, increasing the intracellular pH buffering capacity or intracellular dialysis of the myocytes with an alkaline solution strongly attenuated the inhibitory effect of FCCP on ICa,L. Thus, our data demonstrate that metabolic inhibition leads to excessive ATP hydrolysis by the mitochondrial F1F0-ATP-synthase operating in the reverse mode and this results in intracellular acidosis causing the suppression of ICa,L. Limiting ATP break-down by F1F0-ATP-synthase and the consecutive development of intracellular acidosis might thus represent a potential therapeutic approach for maintaining a normal cardiac function during ischemia.
- Subjects :
- Adenosine Triphosphate metabolism
Animals
Calcium Channels, L-Type genetics
Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone administration & dosage
Heart Ventricles metabolism
Heart Ventricles physiopathology
Isoproterenol administration & dosage
Mitochondria enzymology
Muscle Cells drug effects
Muscle Cells metabolism
Myocardial Contraction drug effects
Myocardial Ischemia genetics
Myocardial Ischemia physiopathology
Myocytes, Cardiac drug effects
Myocytes, Cardiac metabolism
Myocytes, Cardiac pathology
Rana esculenta
Stress, Physiological drug effects
Stress, Physiological genetics
Calcium Channels, L-Type metabolism
Mitochondrial Proton-Translocating ATPases metabolism
Myocardial Contraction genetics
Myocardial Ischemia metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 12
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 28859158
- Full Text :
- https://doi.org/10.1371/journal.pone.0184246