Multiplicity of effectors of the cardioprotective agent, diazoxide

Abstract

Diazoxide has been identified over the past 50 years to have a number of physiological effects, including lowering the blood pressure and rectifying hypoglycemia. Today it is used clinically to treat these conditions. More recently, another important mode of action emerged: diazoxide has powerful protective properties against cardiac ischemia. The heart has intrinsic protective mechanisms against ischemia injury; one of which is ischemic preconditioning. Diazoxide mimics ischemic preconditioning. The purpose of this treatise is to review the literature in an attempt to identify the many effectors of diazoxide and discuss how they may contribute diazoxide’s cardioprotective properties. Particular emphasis is placed on the concentration ranges in which diazoxide affects its different targets and how this compares with the concentrations commonly used to study cardioprotection. It is concluded that diazoxide may have several potential effectors that may potentially contribute to cardioprotection, including KATP channels in the pancreas, smooth muscle, endothelium, neurons and the mitochondrial inner membrane. Diazoxide may also affect other ion channels and ATPases and may directly regulate mitochondrial energetics. It is possible that the success of diazoxide lies in this promiscuity and that the compound acts to rebalance multiple physiological processes during cardiac ischemia.

Cardioprotective effect of zileuton: a 5-lipoxygenase inhibitor against myocardial ischemia/reperfusion injury

“…The activation of protein kinase C-delta may also lead to the activation of mitochondrial ATP dependent potassium channels (mitoKATP), which has been reported to decrease myocardial I/R injury. [26,27] In the present study, throughout a similar signalling pathway, zileuton may also have activated mitoKATP and the tissue protective effect of it may have depended on this activation.…”

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

“…Diazoxide (DZ) is an effective cardioprotective drug capable of mimicking ischemic preconditioning via the opening of mitochondrial ATP-sensitive potassium channels (mK ATP channels) [1][2][3]. K ATP channels are ubiquitously expressed in plasma membrane (sK ATP channels) and mitochondria (mK ATP channels), and different isoforms of these channels differ in their sensitivity to DZ [4].…”

“…K ATP channels are ubiquitously expressed in plasma membrane (sK ATP channels) and mitochondria (mK ATP channels), and different isoforms of these channels differ in their sensitivity to DZ [4]. Being preferably mK ATP channels opener, DZ is capable of interactions with sK ATP channels isoforms sensitive to this drug within circulation, CNS, endocrine, and other systems of a living organism [2,5,6].…”

“…This implies that DZ administration should result in the modulation of mitochondrial functions, ensuing from mK ATP channel opening and affect mitochondrial bioenergetics as it was shown in the heart, brain, liver, and pancreatic beta-cells [8][9][10]. But while the opening of mK ATP channel is generally thought to be cytoprotective, appraisal of bioenergetic and functional effects of mK ATP channel opening in mitochondria using DZ as pharmacological tool, is complicated by several side effects of this drug [2,11]. Bioenergetic effects of DZ (modulation of the oxygen consumption, mitochondrial uncoupling, ATP synthesis and ROS production) have been widely described in the literature.…”

“…Being a highly hydrophobic compound, DZ easily binds to and penetrates cellular membranes [12]. This ability implies several cellular targets of DZ, and thus far several side effects of DZ on mitochondrial functions have been reported, such as protonophoric properties at high micromolar concentrations [13,14]; inhibition of succinate dehydrogenase (SDH) and succinatedriven respiration [15][16][17]; inhibition of F 0 F 1 ATP synthase [18,19]; flavoprotein oxidation and the interference with ROS detection using the fluorescent probe Dichlorofluorescein (DCF) [16,20]; at last, direct activation of protein kinases (C and B) and other signaling pathways [2,21,22].…”