Multiplicity of effectors of the cardioprotective agent, diazoxide

Abstract

Diazoxide has been identified over the past 50years 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 to 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.

Keywords: 2,4-dinitrophenol; 5-hydroxydecanoate; 5HD; ATP-sensitive K(+) channel; Cardioprotection; DNP; Diazoxide; I/R injury; IPC; Ischemia; Ischemic preconditioning; K(ATP) channel; K(ATP) channels; Mitochondria; ROS; SDH; ischemia/reperfusion injury; ischemic preconditioning; mitochondrial membrane potential; reactive oxygen species; succinate dehydrogenase; ΔΨm.

Figure 1

The number of PubMed citations returned when searching with the keyword “diazoxide”. The data are binned over the time period 1960–2013. The inset shows the structural formula for diazoxide.

Figure 2

A cartoon summary of the main potential effectors of diazoxide, depicting some of the potential mechanisms by which they may contribute to cardioprotection. NO is nitric oxide, NE is norepinephrine and Ach is acetylcholine. For details and concentrations at which diazoxide affects these targets, please refer to the text and the Tables.