CHAPTER 47 – K+ Channel Openers

This chapter focuses on potassium channel openers target adenosine triphosphate-sensitive potassium (K ATP ) channels. These channels couple cellular metabolism with membrane excitability, and have been implicated in the regulation of vascular tone and cardioprotection under metabolic stress. Potassium channel openers have a unique therapeutic potential as combined cardioprotective and vasodilatory agents. Potassium channel openers include benzopyrans, thioformamides, nicotinamides, cyanoguanidines, pyrimidines, and benzothiadiazines. Specific binding sites for potassium channel openers have been identified on the SUR subunit of the K ATP channel in both vascular smooth muscle and cardiac muscle. Potassium channel openers preferentially activate K + channels in smooth muscle cells, leading to membrane hyperpolarization. Thereby, the primary pharmacodynamic effect of potassium channel openers is the relaxation of vascular smooth muscle, resulting in vasodilatation. Potassium channel openers also open K ATP channels in the myocardium, the effect of which is more pronounced during ischemia. Opening of cardiac K ATP channels shortens the action potential duration, with diminished time available for Ca 2+ influx. This can reduce the force of contraction, but also preserves energy expenditure associated with the maintenance of cellular Ca 2+ homeostasis. Potassium channel openers improve the recovery of myocardial function following metabolic insult, decrease loss of adenine nucleotides, and diminish infarct size. Such a protective effect is independent from changes in collateral blood flow, which suggests a direct cytoprotective action on the cardiomyocyte.