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Cardioselective sulfonylthiourea HMR 1098 blocks mitochondrial uncoupling induced by a KATP channel opener, P-1075, in beating rat hearts.
- Source :
-
Biochimica et biophysica acta [Biochim Biophys Acta] 2003 Jul 14; Vol. 1638 (2), pp. 121-8. - Publication Year :
- 2003
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Abstract
- We investigated effects of blockade of cardiac ATP-sensitive potassium channels (KATP) with a novel cardioselective sulfonylthiourea, HMR 1098, on metabolic uncoupling caused by a potent KATP opener, P-1075, in Langendorff-perfused rat hearts. We used (1) 87Rb-NMR to detect activation-deactivation of sarcolemmal KATP, (2) 31P-NMR to monitor high-energy phosphates, (3) oxygen uptake measurements to monitor cellular respiration, and (4) myocardial optical absorbance measurements at 603 nm to follow changes in cytochrome c oxidase redox state. Activation of sarcolemmal KATP by P-1075 (5 microM) and a mitochondrial uncoupler 2,4-dinitrophenol (DNP) (50 microM) stimulated Rb+ efflux from the hearts by 130% and 60%, respectively. HMR 1098 (5 and 30 microM) blocked activation of sarcolemmal KATP in situ. HMR 1098 also prevented cardiac arrest and mitochondrial uncoupling induced by P-1075, such as (a) depletion of phosphocreatine and ATP by 40%, (b) two-fold decrease in venous oxygen, and (c) reduction of cytochrome c oxidase (demonstrated by an increase in 603 nm optical absorbance). The metabolic effects of P-1075 can be readily explained by activation of putative mitochondrial KATP. We concluded that blockade of mitochondrial uncoupling by HMR 1098 included an inhibiting effect of HMR 1098 on sarcolemmal and mitochondrial KATP in beating rat hearts.
- Subjects :
- 2,4-Dinitrophenol pharmacology
Adenosine Triphosphate metabolism
Animals
Electron Transport Complex IV drug effects
Electron Transport Complex IV metabolism
Kinetics
Male
Membrane Proteins metabolism
Mitochondria, Heart drug effects
Oxidative Phosphorylation drug effects
Oxygen Consumption drug effects
Phosphates metabolism
Phosphocreatine metabolism
Potassium Channels
Rats
Rats, Sprague-Dawley
Sarcolemma drug effects
Sarcolemma metabolism
Sulfonylurea Compounds pharmacology
Thiourea pharmacology
Uncoupling Agents pharmacology
Benzamides pharmacology
Guanidines pharmacology
Membrane Proteins pharmacology
Mitochondria, Heart metabolism
Potassium Channel Blockers pharmacology
Pyridines pharmacology
Thiourea analogs & derivatives
Subjects
Details
- Language :
- English
- ISSN :
- 0006-3002
- Volume :
- 1638
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Biochimica et biophysica acta
- Publication Type :
- Academic Journal
- Accession number :
- 12853117
- Full Text :
- https://doi.org/10.1016/s0925-4439(03)00078-4