Both metabolic inhibition and mitochondrial K(ATP) channel opening are myoprotective and initiate a compensatory sarcolemmal outward membrane current.
BACKGROUND
Blockade of oxidative phosphorylation may activate ATP sensitive mitochondrial potassium (mitoK(ATP)) channels. We examined whether both metabolic inhibition and mitoK(ATP) channel openers protect both the whole organ and isolated cells from ischemia.


RESULTS
Using a Langendorff preparation, one group of isolated rabbit hearts were exposed to ischemic preconditioning (IPC) via 2 episodes of flow interruption. The second group of hearts was preconditioned with 2 episodes of either the metabolic inhibitor, sodium cyanide (NaCN), or the mitoK(ATP) channel opener, diazoxide. The third group of hearts was exposed to the mitoK(ATP) channel inhibitor, 5-hydroxydecanoic acid (5-HD) prior to preconditioning with NaCN, diazoxide or IPC. Controls had no drug infused. Then, ischemia was induced in all hearts by left anterior descending coronary artery occlusion and infarct size was determined. Compared with controls (40+/-3%), infarct size was significantly reduced in hearts preconditioned with NaCN, diazoxide or IPC (18+/-3%, 26+/-3%, 21+/-2%, respectively; P<0.05 versus control). These reductions were reversed by 5-HD (36+/-3%, 33+/-2%, 37+/-2%; NaCN, diazoxide, IPC, respectively). Secondly, whole cell patch clamped isolated guinea pig ventricular myocytes were preconditioned with 2 episodes of either NaCN or diazoxide followed by Tyrodes perfusion with membrane potential set to -70 mV. Control cells were exposed to Tyrodes solution. All cells were then clamped to -20 mV and exposed to NaCN, which caused induction of an outward potassium current. Compared with controls, the average time to induction of the outward current was significantly reduced in cells preconditioned with either brief application of NaCN (11.6+/-1.8 versus 5.1+/-1.0 minutes, control versus NaCN, P<0.05) or diazoxide (5.5+/-1.4 versus 2.0+/-0.8 minutes, control versus diazoxide, P<0.05).


CONCLUSIONS
Preconditioning protects the heart through mitoK(ATP). This protection also alters a surface membrane current, which may be important in myocardial protection.
Irie
Hiroshi
H
Division of Cardiothoracic Surgery, Department of Physiology & Biophysics, Institute for Molecular Cardiology, State University of New York at Stony Brook, 11794-8191, USA.
Gao
Junyuan
J
Gaudette
Glenn R
GR
Cohen
Ira S
IS
Mathias
Richard T
RT
Saltman
Adam E
AE
Krukenkamp
Irvin B
IB
D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology / Q000627:therapeutic use; D002478:Cells, Cultured; D003326:Coronary Circulation / Q000187:drug effects; D003981:Diazoxide / Q000627:therapeutic use; D004553:Electric Conductivity; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects; D019157:Ischemic Preconditioning, Myocardial; D007700:Kinetics; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D009203:Myocardial Infarction / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology*; D009924:Organ Culture Techniques; D010085:Oxidative Phosphorylation / Q000187:drug effects; D018408:Patch-Clamp Techniques; D015221:Potassium Channels; D011817:Rabbits; D012508:Sarcolemma / Q000502:physiology*; D012966:Sodium Cyanide / Q000494:pharmacology / Q000627:therapeutic use; D017725:Ventricular Pressure
D002316:Cardiotonic Agents; D008565:Membrane Proteins; D015221:Potassium Channels; C117780:mitochondrial K(ATP) channel; D003981:Diazoxide; D012966:Sodium Cyanide