Direct and Off-Target Effects of ATP-Sensitive Potassium Channels Opener Diazoxide

Abstract

Diazoxide (DZ) is a well-known cardioprotective drug capable of mimicking ischemic preconditioning. Being primarily a pharmacological opener of mitochondrial ATP-sensitive potassium channels (mK ATP channels), DZ is known to produce multiple side effects because of its interactions with different cellular targets (such as plasma membrane K ATP channels, F 0 F 1 ATP synthase, succinate dehydrogenase and others), capable of confounding an understanding of direct bioenergetic effects of mK ATP channels opening in mitochondria. In this review direct and offtarget effects of DZ were discussed. The emphasis was made on molecular basis of DZ interaction with K ATP channels and different K ATP channels isoforms sensitivity to this drug. The present knowledge on DZ interaction with mK ATP channels is outlined as well as DZ interactions with other molecular targets affecting mitochondrial functions and bioenergetics. Conclusion was reached that high sensitivity of mK ATP channel to DZ allows for avoiding offtarget effects of this drug in studies on isolated mitochondria, which makes it a useful tool in an appraisal of diverse functional effects of mK ATP channel opening.

Ex Vivo Lung Perfusion with K(ATP) Channel Modulators Antagonize Ischemia Reperfusion Injury

“…One additional confounding factor may have been the fact that DZ and 5-HD were reported to have other cellular effects than the modulation of the K(ATP) channels in rat and pig kidney cell lines [ 35 ] or in the pig heart [ 36 ]. DZ is also known to produce multiple side effects because of its interactions with different cellular targets such as the plasma membrane and/or sarcolemmal-specific forms of K(ATP) channels, F0F1 ATP synthase and succinate dehydrogenase [ 37 ]. As reported in heart and liver mitochondria [ 38 , 39 ], 5-HD has also displayed off-target effects other than mitochondrial K(ATP) modulation and showed a lack of activity in inhibiting oxygen-consuming mitochondria derived from the skeletal muscle [ 39 , 40 , 41 ].…”

The two pore potassium channel THIK‐1 regulates NLRP3 inflammasome activation

“…Although our data using TPA suggested K2P channels played a role in NLRP3 activation, K + channel modulators are known to inhibit cellular signaling pathways independently of K + channels (Akopova, 2017;Humphries & Dart, 2015). We therefore utilized genetic approaches to further determine which specific K + channel regulates NLRP3 activation.…”