Ischaemic preconditioning and a mitochondrial KATP channel opener both produce cardioprotection accompanied by F1F0-ATPase inhibition in early ischaemia.
Ischaemic preconditioning gives powerful protection against prolonged ischaemia affecting several intracellular regulatory and messenger pathways, although their mutual importance is far from established. Protective, preconditioning-like effects have been reported for K(ATP) channel openers, and most of the evidence points to the mitochondrial K(ATP) channels. We show here that the K(ATP) channel opener diazoxide, which acts selectively on the mitochondrial channel, causes potentiation of ischaemic inhibition of mitochondrial ATP synthase (F(1)F(0)-ATPase) along with cardioprotection. These effects are comparable with that of ischaemic preconditioning. The administration of diazoxide did not affect the cellular energy state as monitored with (31)P NMR. The actions of both diazoxide and ischaemic preconditioning were prevented by 5-hydroxydecanoate, a specific inhibitor of the mitochondrial K(ATP) channel. Thus mitochondrial K(ATP) channel opening and ischaemic preconditioning must share common mechanisms of action involving mitochondrial F(1)F(0)-ATPase, although involvement of the energy state in protection could not be proved.
Ala-Rämi
Antti
A
Department of Medical Biochemistry and Molecular Biology, University of Oulu, P.O. Box 5000, 90014 Oulu, Finland.
Ylitalo
Kari V
KV
Hassinen
Ilmo E
IE
D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology*; D003326:Coronary Circulation / Q000187:drug effects; D003600:Cytosol / Q000378:metabolism; D003652:Decanoic Acids / Q000494:pharmacology; D003981:Diazoxide / Q000494:pharmacology*; D005420:Flavoproteins / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D006880:Hydroxy Acids / Q000494:pharmacology; D066298:In Vitro Techniques; D015640:Ion Channel Gating / Q000187:drug effects; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism*; D010084:Oxidation-Reduction; D010101:Oxygen Consumption / Q000187:drug effects; D015221:Potassium Channels / Q000502:physiology*; D006180:Proton-Translocating ATPases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014665:Vasodilator Agents / Q000494:pharmacology
D000889:Anti-Arrhythmia Agents; D002316:Cardiotonic Agents; D003652:Decanoic Acids; D005420:Flavoproteins; D006880:Hydroxy Acids; D015221:Potassium Channels; D014665:Vasodilator Agents; D000244:Adenosine Diphosphate; C052853:5-hydroxydecanoic acid; D000255:Adenosine Triphosphate; D006180:Proton-Translocating ATPases; D003981:Diazoxide