Nitric oxide inhibits cardiac energy production via inhibition of mitochondrial creatine kinase.
Nitric oxide biosynthesis in cardiac muscle leads to a decreased oxygen consumption and lower ATP synthesis. It is suggested that this effect of nitric oxide is mainly due to the inhibition of the mitochondrial respiratory chain enzyme, cytochrome c oxidase. However, this work demonstrates that nitric oxide is able to inhibit soluble mitochondrial creatine kinase (CK), mitochondrial CK bound in purified mitochondria, CK in situ in skinned fibres as well as the functional activity of mitochondrial CK in situ in skinned fibres. Since mitochondrial isoenzyme is functionally coupled to oxidative phosphorylation, its inhibition also leads to decreased sensitivity of mitochondrial respiration to ADP and thus decreases ATP synthesis and oxygen consumption under physiological ADP concentrations.
Laboratoire de Cardiologie Cellulaire et Moléculaire INSERM U-446, Université de Paris-Sud, Faculté de Pharmacie, Châtenay-Malabry, France. allen@ut.ee
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Kaasik
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Minajeva
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De Sousa
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Ventura-Clapier
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Veksler
D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D003401:Creatine / Q000378:metabolism; D003402:Creatine Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects*; D005978:Glutathione / Q000031:analogs & derivatives / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D007527:Isoenzymes; D008929:Mitochondria, Heart / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D009569:Nitric Oxide / Q000494:pharmacology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009603:Nitroso Compounds / Q000494:pharmacology; D010085:Oxidative Phosphorylation / Q000187:drug effects; D010100:Oxygen / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D026422:S-Nitrosoglutathione; D012503:Saponins / Q000494:pharmacology; D012995:Solubility
D007527:Isoenzymes; D020030:Nitric Oxide Donors; D009603:Nitroso Compounds; D012503:Saponins; D009569:Nitric Oxide; D026422:S-Nitrosoglutathione; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D003402:Creatine Kinase; D005978:Glutathione; D003401:Creatine; D010100:Oxygen