Institute of Physiology, Centre for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria.
Eur J Pharmacol. 2010 Feb 25;628(1-3):116-27. doi: 10.1016/j.ejphar.2009.11.013. Epub 2009 Nov 17.
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.
我们通过检测假设来验证，即三磷酸腺苷敏感性钾通道（KATP）通过反馈控制增加的心脏率时的平均功率输出，从而限制心脏的能量需求。我们分析了成年大鼠和豚鼠左心室乳头肌不断上升的能量需求与由 KATP 通道介导的下调的机电效应之间的相互关系。通过使用 KATP 开放剂匹那地尔，逐步增加刺激频率，并记录机械参数和动作电位。通过力-长度面积或力-时间积分计算得出功率输出。同时，通过黄素蛋白荧光测量来评估制剂中的氧可用性。通过 HPLC 确定 ADP/ATP 比值。我们发现，在大鼠（r²=0.993）和豚鼠肌肉（r²=0.997）中，等张功率输出与匹那地尔对等张缩短的影响之间存在高度线性关系。这些影响仅在缩短频率关系的下降支中观察到。此外，还揭示了总力-时间积分衍生功率与匹那地尔对动作电位时程（APD50）的影响之间高度线性相关（r²=0.92）。在较高频率下，匹那地尔存在时，功率输出变得恒定且与频率无关。相比之下，KATP 阻断剂格列本脲在较高功率水平下会短暂增加 APD50 的延长和力的短暂增加。匹那地尔在高频刺激期间防止核心缺氧和 ADP/ATP 比值的变化。我们得出结论，匹那地尔引发的心脏 KATP 通道在高能量需求期间对功率输出进行同源控制。这种效应与通过适应心脏功能来限制能量供应，从而减少心肌内部缺氧区域的发展有关。
