Adenosine Receptor-Mediated Cardioprotection—Current Limitations and Future Directions

Abstract

Since the seminal reports of adenosine receptor-mediated cardioprotection in the early 1990s, there have been a multitude of such reports in various species and preparations. Original observations of the beneficial effects of A1 receptor agonists have been followed up with numerous reports also implicating A2A, A3, and most recently A2B, receptor agonists as cardioprotective agents. Although adenosine has been approved for clinical use in the United States for the treatment of supraventricular tachycardia and coronary artery imaging, and the selective A2A agonist, regadenoson, for the latter, clinical use of adenosine receptor agonists for protecting the ischemic heart has not advanced beyond early trials. An examination of the literature indicates that existing experimental studies have several limitations in terms of clinical relevance, as well as lacking incorporation of recent new insights into adenosine receptor signaling. Such deficiencies include the lack of experimental studies in models that most closely mimic human cardiovascular disease. In addition, there have been very few studies in chronic models of myocardial ischemia, where limiting myocardial remodeling and heart failure, not reduction of infarct size, are the primary endpoints. Despite an increasing number of reports of the beneficial effects of adenosine receptor antagonists, not agonists, in chronic diseases, this idea has not been well-studied in experimental myocardial ischemia. There have also been few studies examining adenosine receptor subtype interactions as well as receptor heterodimerization. The purpose of this Perspective article is to discuss these deficiencies to highlight future directions of research in the field of adenosine receptor-mediated protection of ischemic myocardium.

Historical and Current Adenosine Receptor Agonists in Preclinical and Clinical Development

“…DeNinno et al (2003) reported that CP-608,039 35 is a highly A 3 AR selective and water-soluble agonist that was being evaluated for the prevention of perioperative myocardial ischemic injury. This follows numerous other reports showing that A 3 AR activation protects ischemic cardiomyocytes by preconditioning (Lasley, 2018).…”

“…Anti-ischemic effect of A 1 AR agonists has been demonstrated in animal studies, but clinical successes are lacking, and more relevant clinical models are needed (Borea et al, 2016; Lasley, 2018).…”

FSCPX, a Chemical Widely Used as an Irreversible A1 Adenosine Receptor Antagonist, Modifies the Effect of NBTI, a Nucleoside Transport Inhibitor, by Reducing the Interstitial Adenosine Level in the Guinea Pig Atrium

“…The A 1 adenosine receptor (A 1 receptor) is a member of the ancient and ubiquitous adenosine receptor family that exerts complex regulatory functions in almost all tissues [ 3 , 4 , 5 ]. In the heart, the A 1 receptor mediates strong negative tropic effects including negative inotropy on the ventricle and, even more, on the atrium [ 6 ], as a component of the A 1 adenosinergic cardioprotection against ischemic/hypoxic stress [ 7 , 8 , 9 ]. Accordingly, in earlier studies, we aimed to assess the guinea pig atrial A 1 receptor reserve for the direct negative inotropic effect of several A 1 adenosine receptor agonists (the term direct means that experiments were conducted on atria lacking prior stimulation of contractility).…”

Focusing on Adenosine Receptors as a Potential Targeted Therapy in Human Diseases

“…There is no "direct" evidence of the effect of A 2B AR on ventricular myocytes [178]; however, A 2B AR was shown to be required for A 1 AR-mediated cardioprotection [237]. In fact, adenosine levels during myocardial ischemia-reperfusion increase; therefore, low-affinity A 2B AR still has cardioprotective effects upon its activation [238].…”

“…The role of cardioprotection by A 3 AR is enticing, enigmatic, and elusive [294]. Further clinical studies on cardioprotection induced by adenosine receptors need to establish the role of adenosine receptor agonists and antagonists in more clinically relevant models of myocardial ischemia [238].…”