The Janus Face of Adenosine: Antiarrhythmic and Proarrhythmic Actions

Title:The Janus Face of Adenosine: Antiarrhythmic and Proarrhythmic Actions

Volume: 21 Issue: 8

Author(s): A. Jozsef Szentmiklosi, Zoltan Galajda, Agnesn Cseppento, Rudolf Gesztelyi, Zsolt Susan, Bence Hegyi and Peter P. Nanasi

Affiliation:

Keywords: Adenosinergic drugs, antiarrhythmic action, proarrhythmic effect, adenosine A₁ receptor activators, partial A₁ adenosine receptor agonists, adenosine regulators, allosteric receptor modulators, drug development.

Abstract: Adenosine is a ubiquitous, endogenous purine involved in a variety of physiological and pathophysiological regulatory mechanisms. Adenosine has been proposed as an endogenous antiarrhythmic substance to prevent hypoxia/ischemia-induced arrhythmias. Adenosine (and its precursor, ATP) has been used in the therapy of various cardiac arrhythmias over the past six decades. Its primary indication is treatment of paroxysmal supraventricular tachycardia, but it can be effective in other forms of supraventricular and ventricular arrhythmias, like sinus node reentry based tachycardia, triggered atrial tachycardia, atrioventricular nodal reentry tachycardia, or ventricular tachycardia based on a cAMP-mediated triggered activity. The main advantage is the rapid onset and the short half life (1- 10 sec). Adenosine exerts its antiarrhythmic actions by activation of A₁ adenosine receptors located in the sinoatrial and atrioventricular nodes, as well as in activated ventricular myocardium. However, adenosine can also elicit A_2A, A_2B and A₃ adenosine receptor-mediated global side reactions (flushing, dyspnea, chest discomfort), but it may display also proarrhythmic actions mediated by primarily A₁ adenosine receptors (e.g. bradyarrhythmia or atrial fibrillation). To avoid the non-specific global adverse reactions, A₁ adenosine receptor- selective full agonists (tecadenoson, selodenoson, trabodenoson) have been developed, which agents are currently under clinical trial. During long-term administration with orthosteric agonists, adenosine receptors can be internalized and desensitized. To avoid desensitization, proarrhythmic actions, or global adverse reactions, partial A1 adenosine receptor agonists, like CVT-2759, were developed. In addition, the pharmacologically “silent” site- and event specific adenosinergic drugs, such as adenosine regulating agents and allosteric modulators, might provide attractive opportunity to increase the effectiveness of beneficial actions of adenosine and avoid the adverse reactions.

Cite this article as:

Szentmiklosi Jozsef A., Galajda Zoltan, Cseppento Agnesn, Gesztelyi Rudolf, Susan Zsolt, Hegyi Bence and Nanasi P. Peter, The Janus Face of Adenosine: Antiarrhythmic and Proarrhythmic Actions, Current Pharmaceutical Design 2015; 21 (8) . https://dx.doi.org/10.2174/1381612820666141029100346