ATP-sensitive potassium channel is essential to maintain basal coronary vascular tone in vivo.
Glibenclamide, a known selective inhibitor of ATP-sensitive potassium channels, was infused into the coronary vasculature of anesthetized dogs and of isolated perfused rabbit hearts to assess the role of this channel in the maintenance of basal coronary resistance. Infusion of glibenclamide at a concentration of 55-80 microM in the dogs resulted in a twofold steady-state increase in coronary resistance with resultant tissue ischemia. Infusion of 1 microM glibenclamide in the isolated hearts resulted in a 67% increase in coronary resistance with resultant tissue ischemia. The ischemic changes were reversible upon removal of the drug. These findings indicate that the ATP-sensitive K+ channel plays a significant role in the maintenance of basal coronary resistance in vivo. Higher concentrations of glibenclamide (80-100 microM) in the in vivo dog heart consistently gave rise to an oscillating pattern of coronary flow. These oscillations were either eliminated or decreased in amplitude and frequency by the infusion of 8-phenyltheophylline, a specific competitive inhibitor of adenosine receptors. 31P-nuclear magnetic resonance spectroscopy performed at the peaks and troughs of these oscillations revealed oscillation of the phosphorylation potential at the same frequency. Thus adenosine release caused by tissue ischemia appears to play a major role in creating the oscillating pattern of coronary blood flow, that occurs during the inhibition of ATP-sensitive K+ channels by glibenclamide.
Samaha
F F
FF
Laboratory of Cardiac Energetics, National Heart, Lung, and Blood Institute, Bethesda, Maryland 20892.
Heineman
F W
FW
Ince
C
C
Fleming
J
J
Balaban
R S
RS
D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000818:Animals; D003331:Coronary Vessels / Q000502:physiology*; D004734:Energy Metabolism; D005905:Glyburide / Q000494:pharmacology; D006321:Heart / Q000187:drug effects; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008929:Mitochondria, Heart / Q000378:metabolism; D010084:Oxidation-Reduction; D010477:Perfusion; D010710:Phosphates / Q000378:metabolism; D010766:Phosphorylation; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*; D011817:Rabbits; D013057:Spectrum Analysis; D013806:Theophylline / Q000031:analogs & derivatives / Q000494:pharmacology; D014655:Vascular Resistance / Q000187:drug effects; D014666:Vasomotor System / Q000502:physiology*
D010710:Phosphates; D015221:Potassium Channels; D000255:Adenosine Triphosphate; D013806:Theophylline; C028322:8-phenyltheophylline; D005905:Glyburide