Adenosine A₁ and A₃ receptors: Distinct cardioprotection

Abstract

Adenosine is released in large amounts during myocardial ischemia and exerts potent cardioprotective effects in the heart. Although these observations on adenosine have been known for a long time, how adenosine acts to achieve its antiischemic effect remains incompletely understood. Recent advances in the chemistry and pharmacology of adenosine receptor ligands have provided important and novel information on the function of adenosine receptor subtypes in the cardiovascular system. The development of model systems for the cardiac actions of adenosine has yielded important insights into its mechanism of action and have begun to elucidate the sequence of signaling events from receptor activation to the actual exertion of its cardioprotective effect. The goal of the current article is to review recent advances on the cellular and molecular mechanisms that mediate the cardiac actions of adenosine and to show the cardioprotective effect of novel adenosine ligands. Drug Dev. Res. 52:366–378, 2001. © 2001 Wiley‐Liss, Inc.

Chronic Therapy With a Partial Adenosine A1-Receptor Agonist Improves Left Ventricular Function and Remodeling in Dogs With Advanced Heart Failure

“…Adenosine and adenosine analogs have been long recognized as in-vivo “cardioprotective” agents and mediators of anti-ischemic preconditioning (20). These cardioprotective effects are believed to result from activation of downstream effectors such as protein kinase C (PKC), K ATP channel and some isoforms of mitogen activated protein kinase (MAPK) (20) and partly by inhibition of adenylate cyclase activation and reduction of cAMP levels.…”

“…Adenosine and adenosine analogs have been long recognized as in-vivo “cardioprotective” agents and mediators of anti-ischemic preconditioning (20). These cardioprotective effects are believed to result from activation of downstream effectors such as protein kinase C (PKC), K ATP channel and some isoforms of mitogen activated protein kinase (MAPK) (20) and partly by inhibition of adenylate cyclase activation and reduction of cAMP levels. Given that regional myocardial ischemia and/or hypoxia frequently exist in the failing heart, it is likely that the benefits seen in the present study with CAP reflect reduced cellular injury resulting from the antiischemic cardioprotective effects of adenosine A1R activation.…”

1,2,4-Triazolo[1,5-a]quinoxaline as a Versatile Tool for the Design of Selective Human A3 Adenosine Receptor Antagonists: Synthesis, Biological Evaluation, and Molecular Modeling Studies of 2-(Hetero)aryl- and 2-Carboxy-Substitued Derivatives

“…In fact, adenosine plays an important role in many diseases of the central nervous system (CNS), as well as in peripheral organs and tissues. , Thus, the use of AR antagonists as potential therapeutic agents has been proposed. , In particular, while A 1 AR antagonists have been developed as antihypertensives, potassium-saving diuretics, and cognitive enhancers ,− for geriatric therapy and for the treatment of CNS disorders such as Alzheimer's disease, A 3 AR antagonists are sought as potential antiinflammatory agents, but they are also useful in the treatment of cancer , and glaucoma . Other applications of both A 1 and A 3 AR antagonists, such as prevention and treatment of cerebral and cardiac ischemic injuries, have been proposed. ,− Accordingly, taking into account the potential of A 3 adenosine receptor antagonists in the development of prospective therapeutic agents, , in the past few years many attempts in our laboratory have been made to explore structural requirements of different classes of tricyclic heteroaromatic compounds that could be important for the binding at each receptor subtype. − …”

“…17 Other applications of both A 1 and A 3 AR antagonists, such as prevention and treatment of cerebral and cardiac ischemic injuries, have been proposed. 14,[18][19][20] Accordingly, taking into account the potential of A 3 adenosine receptor antagonists in the development of prospective therapeutic agents, 10,11 in the past few years many attempts in our laboratory have been made to explore structural requirements of different classes of tricyclic heteroaromatic compounds that could be important for the binding at each receptor subtype. [21][22][23][24][25][26][27][28][29][30][31] In recent papers, we reported the synthesis and binding activities at bovine A 1 (bA 1 ) and A 2A (bA 2A ) and human cloned A 1 (hA 1 ), A 2A (hA 2A ), and A 3 (hA 3 ) ARs of some 4-amino-2-aryl-1,2,4-triazolo[1,5-a]quinoxaline derivatives 31 bearing different substituents on the 4-amino group (Chart 1, Series A).…”

Relating Surfactant Properties to Activity and Solubilization of the Human Adenosine A3 Receptor

“…The pharmacological profile of A 3 most closely resembles that of the adenosine A 1 receptor (A 1 ), and both are thought to mediate cardioprotection, although tissue distributions have identified isoforms in the brain, lungs, liver, and testes as well (14). Studies of cardiac myocyte models suggest that A 3 couples to phospholipase D whereas A 1 couples to phospholipase C, both of which in turn stimulate diacylglycerol accumulation and phosphokinase C response to mediate the protective effects of adenosine (15). Interestingly, the duration of A 3 response upon activation is much longer than that of A 1 , suggesting that they may work synergistically to greater effect.…”