A3 adenosine receptor-mediated protection of the ischemic heart

The A(3) adenosine receptor (A(3)AR) is attributed with multiple beneficial actions in ischemic-reperfused myocardium, including modulation of oncotic and apoptotic cell death and enhancement of contractile function. Additionally, the A(3)AR may attenuate vascular dysfunction and improve long-term outcome from myocardial insult (modulating hypertrophy and angiogenesis). Available evidence indicates that this receptor sub-type is minimally activated by endogenous adenosine during ischemia (A(3)AR antagonists exerting no effects on ischemic outcome), and is thus amenable to activation with exogenous agonists. Protected phenotypes arise with both pre- and post-ischemic treatment with A(3)AR agonists, and transient A(3)AR agonism also triggers early and delayed preconditioned states. The molecular basis for the varied protective actions of the A(3)AR remains poorly del tried, and may well vary between species (e.g. rodent vs. human) and protective responses (e.g. acute vs. delayed protection). Nonetheless, A(3)ARs may be more promising as therapeutic anti-ischemic targets compared with other adenosine receptor subtypes, since A(3)AR agonists elicit fewer and less significant side-effects. This review addresses current knowledge and controversy regarding the protective actions (and associated signaling) of A(3)ARs in ischemic - reperfused heart. (c) 2005 Elsevier Inc. All rights reserved.