Abstract
Adenosine, a catabolite of ATP, displays a wide variety of effects in the heart including regulation of cardiac response to myocardial ischemia and reperfusion injury. Nonetheless, the precise mechanism of adenosine-induced cardioprotection is still elusive. Isolated Sprague-Dawley rat hearts underwent 30 min global ischemia and 120 min reperfusion using a Langendorff apparatus. Both adenosine and acetylcholine treatment recovered the post-reperfusion cardiac function associated with adenosine and muscarinic receptors activation. Simultaneous administration of adenosine and acetylcholine failed to exert any additive protective effect, suggesting a shared mechanism between the two. Our data further revealed a cross-talk between the adenosine and acetylcholine receptor signaling in reperfused rat hearts. Interestingly, the selective M2 muscarinic acetylcholine receptor antagonist methoctramine significantly attenuated the cardioprotective effect of adenosine. In addition, treatment with adenosine upregulated the expression and the maximal binding capacity of muscarinic acetylcholine receptor, which were inhibited by the selective A1 adenosine receptor antagonist 8-Cyclopentyl-1,3-dipropylxanthine (DPCPX) and the nitric oxide synthase inhibitor Nω-nitro-L-arginine methyl ester (L-NAME). These data suggested a possible functional coupling between the adenosine and muscarinic receptors behind the observed cardioprotection. Furthermore, nitric oxide was found involved in triggering the response to each of the two receptor agonist. In summary, there may be a cross-talk between the adenosine and muscarinic receptors in ischemic/reperfused myocardium with nitric oxide synthase might serve as the distal converging point. In addition, adenosine contributes to the invigorating effect of adenosine on muscarinic receptor thereby prompting to regulation of cardiac function. These findings argue for a potentially novel mechanism behind the adenosine-mediated cardioprotection.
Highlights
Adenosine is an endogenous purine metabolite that may act as acute ‘‘retaliatory’’ systems mediating immediate responses to injurious stimuli and offer potential as targets for therapeutic cardioprotection
No difference was found in the pre-ischemic cardiac function among experimental groups
DPCPX and METH alone had no appreciable effect on nitric oxide production (NOx) release. These results indicated that the effects of adenosine and acetylcholine on NOx release might likely involve activation of A1 adenosine receptor (A1AR) and M2AChR, respectively
Summary
Adenosine is an endogenous purine metabolite that may act as acute ‘‘retaliatory’’ systems mediating immediate responses to injurious stimuli and offer potential as targets for therapeutic cardioprotection. Substantial evidence has accumulated that adenosine is capable of rapidly responding to myocardial ischemic stress and reperfusion insult, contributing to coronary hyperemia, improved microcirculation and reduced infarct size [1,2,3,4]. Several small-scale clinical studies have recently demonstrated that administration of adenosine during reperfusion rescues ventricular function and improves the overall clinical outcomes [5]. Adenosine elicits its cardioprotection via activation of A1AR to attenuate myocardial responsiveness to toxic effects of adrenergic overstimulation [3]. Such antiadrenergic property of adenosine plays an essential role in the regulation of autonomic nervous activity
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