Pinacidil-primed ATP-sensitive potassium channels mediate feedback control of mechanical power output in isolated myocardium of rats and guinea pigs

Abstract

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.