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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. [ABSTRACT FROM AUTHOR]

Diabetic heart disease contributes to the high mortality in diabetics, although effective clinical management is lacking. The protease inhibitor 5-[5-(2-nitrophenyl) furfuryliodine]-1,3-diphenyl-2-thiobarbituric acid (UCF-101) was reported to protect the hearts against ischemic injury. This study examined the role of UCF101 on streptozotocin (STZ)-induced diabetic heart defect. Vehicle or UCF101 was administrated to STZ diabetic mice, and cardiomyocyte mechanical properties were analyzed. UCF101 reduced STZ-induced hyperglycemia and alleviated STZ-induced aberration in cardiomyocyte contractile mechanics. Diabetes dramatically decreased AMPK phosphorylation at Thr172 of catalytic α-subunit, which was restored by UCF101. Neither diabetes nor UCF-101 affected the expression of HtrA2/Omi and XIAP or caspase-3 activity. The AMPK activator resveratrol mimicked the UCF-101-induced beneficial effect against diabetic cardiac dysfunction. Mechanical properties in cardiomyocytes from the AMPK kinase-dead (1(D) mice displayed markedly impaired contractile function reminiscent of diabetes. STZ injection in AMPK-KD mice failed to elicit any additional cardiomyocyte contractile defect. UCF101 significantly downregulated the AMPK-degrading enzymes PP2A and PP2C, the effect of which was mimicked by resveratrol. Taken together, these results indicate that UCF101 protects against STZ-induced cardiac dysfunction, possibly through AMPK signaling. [ABSTRACT FROM AUTHOR]