CARDIAC ATP-SENSITIVE K+ CHANNELS - REGULATION BY INTRACELLULAR NUCLEOTIDES AND K+ CHANNEL-OPENING DRUGS

ATP-sensitive K+ (K-ATP) channels are present at high density in membranes of cardiac cells where they regulate cardiac function during cellular metabolic impairment. K-ATP channels have been implicated in the shortening of the action potential duration and the cellular loss of K+ that occurs during metabolic inhibition. K-ATP channels have been associated with the cardioprotective mechanism of ischemia-related preconditioning. Intracellular ATP (ATP(i)) is the main regulator of K-ATP channels. ATP(i) has two functions: 1) to close the channel (ligand function) and 2) in the presence of Mg2+, to maintain the activity of K-ATP channels (presumably through an enzymatic reaction). K-ATP channel activity is modulated by intracellular nucleoside diphosphates that antagonize the ATP(i)-induced inhibition of channel opening or induce K-ATP channels to open. How nucleotides will affect K-ATP channels depends on the state of the channel. K+ channel-opening drugs are pharmacological agents that enhance K-ATP channel activity through different mechanisms and have great potential in the management of cardiovascular conditions. K-ATP channel activity is also modulated by neurohormones. Adenosine, through the activation of a GTP-binding protein, antagonizes the ATP(i)-induced channel closure. Understanding the molecular mechanisms that underlie K-ATP channel regulation should prove essential to further define the function of K-ATP channels and to elucidate the pharmacological regulation of this channel protein. Since the molecular structure of the K-ATP channel has now become available, it is anticipated that major progress in the K-ATP channel field will be achieved.