2,4-dinitrophenol (DNP) is a FDA-banned weight-loss agent and EPA-regulated environmental toxicant, traditionally used in research labs as an uncoupler of OXPHOS. Although not licensed for human consumption, DNP and DNP crystal form are used by bodybuilders and extreme dieters for their fat burning properties through inhibiting efficient energy (ATP) production in cells. Through uncoupling mitochondrial oxidative phosphorylation by facilitating proton transport across the mitochondrial membrane, DNP leads to rapid consumption of energy without generating ATP and consequently, to increased fat metabolism. However, the weight-loss effect comes with serious, and in some cases potentially fatal, adverse side effects, namely hyperthermia (the leading cause of fatality with acute DNP toxicity) and cardiac arrest, but also diaphoresis, tachycardia, tachypnea, skin toxicity, Fourier’s gangrene and cataracts with low dose chronic exposure. The proposed mechanism of DNP induced toxicity suggests the activation of ATP-sensitive K+ channels.

Adenosine triphosphate (ATP) is an adenine nucleotide containing three phosphate groups esterified to the sugar moiety. Adenosine triphosphate is the energy source in living cells. In physiological conditions, the average concentration varies from 3150 mM in mammalian cells to 1500–1900 mM in human blood cells. Extracellular adenosine and adenosine triphosphate (ATP) are involved in biological processes including neurotransmission, muscle contraction, cardiac function, platelet function, vasodilatation, signal transduction and secretion in a variety of cell types. A large family of membrane-bound receptors mediates cell signalling by ATP and adenosine. These purinergic receptors ultimately determine the variety of effects induced by extracellular ATP and adenosine. ATP and adenosine have strong negative chronotropic and dromotropic effects on the mammalian heart. The sensitivity of the sinus node and the atrioventricular node to ATP and adenosine manifests pronounced variability among species. For more than three decades, ATP has been used routinely in Europe in the acute therapy of paroxysmal supraventricular tachycardia. ATPace™, an injectable formulation of adenosine 5′-triphosphate (ATP), was developed by Cordex Pharma, Inc. (Cordex) as a diagnostic and therapeutic drug for the management of cardiac bradyarrhythmias. Extracellular ATP exerts multiple effects in various cell types by activating cell-surface receptors known as P2 receptors. In the heart, ATP suppresses the automaticity of cardiac pacemakers and atrioventricular (AV) nodal conduction via adenosine, the product of its degradation by ecto-enzymes, as well as by triggering a cardio-cardiac vagal reflex. ATP, given as a rapid intravenous bolus injection, has been used since the late 1940s as a highly effective and safe therapeutic agent for the acute termination of reentrant paroxysmal supraventricular tachycardia (PSVT) involving the AV node. In addition, preliminary studies have shown that ATP can also be used as a diagnostic agent for the identification of several cardiac disorders including sinus node dysfunction (sick sinus syndrome), dual AV nodal pathways, long QT syndrome, and bradycardic syncope. The US Food and Drug Administration has approved Cordex formulation for ATP as an Investigational New Drug and two pathways for its marketing approval; one therapeutic, i.e., acute termination of paroxysmal PSVT, and the other diagnostic, i.e., the identification of patients with bradycardic syncope who can benefit from pacemaker therapy. However later ATPace development for the treatment of bradycardia and paroxysmal supraventricular tachycardia was discontinued.