A1 Receptor mediated myocardial infarct size reduction by endogenous adenosine is exerted primarily during ischaemia

Abstract

While adenosine exerts its predominant modulation of infarct size during reperfusion, the cardioprotection mediated by A1 receptor mechanisms is modest and exerted principally during the ischaemic time period.

The Effect of Antagonism of Adenosine A1 Receptor Against Ischemia and Reperfusion Injury of the Liver

“…In our study, bradycardia was observed just after reperfusion in group CT, while KW3902 prevented bradycardia. Actually, previous report described that KW3902 has an effect against R-PIA-induced bradycardia (42). It is an effect of KW3902 against negative inotropic effect of A 1 receptors.…”

Acute adenosinergic cardioprotection in ischemic-reperfused hearts

“…For example, protection with A 1 AR agonists is not always observed (197,225,312) and, as already noted, only a limited number of studies demonstrate exacerbation of ischemic injury with A 1 AR antagonism. Lasley and colleagues (162) have forwarded an intriguing hypothesis to explain some of the inconsistencies in A 1 AR-mediated responses.…”

“…Numerous subsequent investigations support A 1 AR agonist-mediated protection (75,80,136,181,182,207,210,267). Expression of A 1 ARs also confers ischemic tolerance in different models (64,197), and a relatively small number of studies document impaired tolerance with A 1 AR antagonists (225,312), supporting protection via endogenous adenosine. Signaling via the A 1 AR has been shown to provide protection not only in animal tissues but in the human myocardium (36,240).…”

“…Extracellular adenosine increases up to an order of magnitude within minutes of ischemia, and whereas it is problematic to estimate relevant interstitial adenosine concentrations, a variety of measures suggest they are more than sufficient to substantially activate cardiovascular receptors (104,109,115,285,286). This is pharmacologically validated by the effects of adenosine receptor antagonists in different models (225,245,259,311,312), keeping in mind the potential for adenosine formation to overcome effects of applied antagonism via "opening" the regulatory feedback loop between stimulus (deenergization) and signal (adenosine formation and protection) (111,123). Collectively, studies with both agonists and antagonists support substantial yet submaximal receptor activation by endogenously generated adenosine during ischemiareperfusion (see Adenosine Receptor-Mediated Cardioprotection: Which Subtypes Are Involved?).…”

“…The purine nucleoside adenosine was attributed with cardioregulatory functions almost 75 years ago (64), and since then has emerged as a crucially important control substance in essentially every tissue of the body. In the heart adenosine not only plays a role in regulating growth and differentiation, angiogenesis, coronary blood flow, cardiac conduction and heart rate, substrate metabolism, and sensitivity to adrenergic stimulation (23, 67,68,73,74,260,271,283), but may play a role as an endogenous determinant of ischemic tolerance (189,225,245,259,311,312,318). From a therapeutic viewpoint, adenosine-based therapies protect against ischemic injury in a variety of animal models (72,177,208,265,288) and in human cardiac tissue (34,36,37,240,296).…”