Abstract
The effect of an allosteric modulator of the adenosine A1 receptors was investigated using an ischaemia-reperfusion protocol in murine isolated hearts. Isolated hearts were perfused with Kreb-Henseleit solution gassed with carbogen gas (95% O2 and 5% CO2) in Langendorff mode and electrically paced at 480 bpm. Following 20 min equilibration and 20 min global normothermic ischaemia, the allosteric modulator VCP333 (1 μM) or the adenosine A1 receptor partial agonist VCP102 (10 μM) were infused after 5 min of reperfusion for 15 min. Upon termination of the drug treatment, reperfusion continued for a further 40 min. At the end of 60 min reperfusion, treatment with VCP333 or VCP102 improved the recovery of the left ventricular developed pressure when compared to control group responses (p < 0.05). Neither compound affected end diastolic pressure, coronary flow rates or dP/dtmax values when compared to control tissues during reperfusion (p > 0.05). The infusion of VCP102 or VCP333 during reperfusion reduced cardiac troponin I efflux to 6.7% and 25% respectively of control heart efflux (p < 0.05). This data indicates that the allosteric modulator of the adenosine A1 receptor (VCP333) has similar characteristics to the adenosine receptor partial agonist VCP102 as it improves cardiac function and reduces myocardial cell death following an ischaemic episode.
Highlights
Adenosine receptors belong to one of the largest families of cell surface proteins, the G-protein coupled receptors [1]
In hearts treated with VCP333 (1 μM), the left ventricular developed pressure (LVDP) in hearts at the end of min reperfusion recovered to ~58% of pre-ischaemic values compared to that of the control group (p < 0.05)
In hearts infused with VCP102, LVDP recovered to 74% of pre-ischaemic function following 20 min reperfusion and maintained this level of function until the end of 60 min reperfusion
Summary
Adenosine receptors belong to one of the largest families of cell surface proteins, the G-protein coupled receptors [1]. The four adenosine receptor subtypes (A1, A2A, A2B, A3) are found in the heart and are reported to regulate cardiac function [2,3], modulate coronary blood flow [4] and are cardioprotective [5]. All adenosine receptor subtypes play an important role in protection of the heart from ischaemia-reperfusion induced cell damage [8]. Extensive research involving transgenic mice have shown that overexpression of the adenosine A1 receptor is associated with a decrease in ischaemic damage to the heart [6]. It was reported that the increased expression of cardiac adenosine A1 receptors in the transgenic mouse models generated an ischaemic tolerant phenotype characterised by reduced contractile dysfunction, de-energisation, necrosis and infarction [9]
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