Pinacidil-primed ATP-sensitive potassium channels mediate feedback control of mechanical power output in isolated myocardium of rats and guinea pigs.
We tested the hypothesis, that ATP-sensitive potassium (K(ATP)) channels limit cardiac energy demand by a feedback control of mean power output at increased cardiac rates. We analysed the interrelationships between rising energy demand of adult rat and guinea pig left ventricular papillary muscle and down-regulatory electromechanical effects mediated by K(ATP) channels. Using the K(ATP)-opener pinacidil the stimulation frequency was increased stepwise and the mechanical parameters and action potentials were recorded. Power output was derived from force-length area or force-time integral calculations, respectively. Simultaneously oxygen availability in the preparations was estimated by flavoprotein fluorescence measurements. ADP/ATP ratios were determined by HPLC. We found highly linear relationships between isotonic power output and the effects of pinacidil on isotonic shortening in both rat (r(2)=0.993) and guinea pig muscles (r(2)=0.997). These effects were solely observed for the descending limb of shortening-frequency relationships. In addition, a highly linear correlation between total force-time integral-derived power and pinacidil effects on action potential duration (APD(50), r(2)=0.92) was revealed. Power output became constant and frequency-independent in the presence of pinacidil at higher frequencies. In contrast, the K(ATP)-blocker glibenclamide produced a lengthening of APD(50) and increased force transiently at higher power levels. Pinacidil prevented core hypoxia and a change in ADP/ATP ratio during high frequency stimulation. We conclude, that pinacidil-primed cardiac K(ATP) channels homeostatically control power output during periods of high energy demand. This effect is associated with a reduced development of hypoxic areas inside the heart muscle by adapting cardiac function to a limited energy supply.
Schmid
Diethart
D
Institute of Physiology, Centre for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria.
Staudacher
Dawid L
DL
Plass
Christian A
CA
Loew
Hans G
HG
Fritz
Eva
E
Steurer
Guenter
G
Chiba
Peter
P
Moeslinger
Thomas
T
D000200:Action Potentials / Q000187:drug effects; D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001696:Biomechanical Phenomena; D002118:Calcium / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects*; D025461:Feedback, Physiological / Q000187:drug effects*; D005420:Flavoproteins / Q000378:metabolism; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D054086:KATP Channels / Q000378:metabolism*; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D010210:Papillary Muscles / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D020110:Pinacidil / Q000494:pharmacology*; D051381:Rats
D005420:Flavoproteins; D054086:KATP Channels; D000244:Adenosine Diphosphate; D020110:Pinacidil; D000255:Adenosine Triphosphate; D002118:Calcium