Changes in ventricular repolarization during acidosis and low-flow ischemia.
Myocardial ischemia, primarily a metabolic insult, is also defined by altered cardiac mechanical and electrical activity. We have investigated the metabolic contributions to the electrophysiological changes during low-flow ischemia (7.5% of the control flow) using 31P NMR spectroscopy to monitor metabolic parameters, suction electrodes to study epicardial monophasic action potentials, and 86Rb as a tracer for K+-equivalent efflux during low-flow ischemia in the Langendorff-perfused ferret heart. Shortening of the action potential duration at 90% repolarization (APD90) was most marked between 1 and 5 min after induction of ischemia, at which time it shortened from 261 +/- 4 to 213 +/- 8 ms. The period of marked APD90 shortening was accompanied by a fivefold increase in the rate of 86Rb efflux, both of which were inhibited by the ATP-sensitive K+ (KATP)-channel blockers glibenclamide and 5-hydroxydecanoate (5-HD), as well as by a significant fall in intracellular pH (pHi) from 7.14 +/- 0.02 to 6.83 +/- 0.03 but no change in intracellular ATP concentration ([ATP]i). We therefore investigated whether a fall in pHi could be the metabolic change responsible for modulating cardiac KATP channel activity in the intact heart during ischemia. Both metabolic (30 mM lactate added to extracellular solution) and respiratory (PCO2 increased to 15%) acidosis caused an initial lengthening of APD90 to 112 +/- 1.5 and 113 +/- 0.9%, respectively, followed by shortening during continued acidosis to 106 +/- 1.2 and 106 +/- 1.4%, respectively. The shortening of APD90 during continued acidosis was inhibited by glibenclamide, consistent with acidosis causing activation of KATP channels at normal [ATP]i. The similar responses to metabolic (induced by adding either l- or d-lactate) and respiratory acidosis suggest that lactate has no independent metabolic effect on action potential repolarization.
Section of Cardiovascular Biology, Department of Biochemistry, University of Cambridge, Cambridge CB2 1QW, United Kingdom.
H W
HW
Bethell
J I
JI
Vandenberg
G A
GA
Smith
A A
AA
Grace
D000138:Acidosis / Q000503:physiopathology*; D000200:Action Potentials / Q000187:drug effects; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D003652:Decanoic Acids / Q000494:pharmacology; D005289:Ferrets; D005905:Glyburide / Q000494:pharmacology; D006321:Heart / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology*; D006352:Heart Ventricles; D006863:Hydrogen-Ion Concentration; D006880:Hydroxy Acids / Q000494:pharmacology; D066298:In Vitro Techniques; D007773:Lactates / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D017202:Myocardial Ischemia / Q000503:physiopathology*; D015425:Myocardial Reperfusion; D009206:Myocardium / Q000378:metabolism*; D010496:Pericardium / Q000502:physiology / Q000503:physiopathology; D011188:Potassium / Q000378:metabolism; D026902:Potassium Channel Blockers; D012414:Rubidium Radioisotopes / Q000493:pharmacokinetics
D003652:Decanoic Acids; D006880:Hydroxy Acids; D007773:Lactates; D026902:Potassium Channel Blockers; D012414:Rubidium Radioisotopes; C052853:5-hydroxydecanoic acid; D000255:Adenosine Triphosphate; D011188:Potassium; D005905:Glyburide