The A3 Adenosine Receptor Agonist CP-532,903 [N6-(2,5-Dichlorobenzyl)-3′-aminoadenosine-5′-N-methylcarboxamide] Protects against Myocardial Ischemia/Reperfusion Injury via the Sarcolemmal ATP-Sensitive Potassium Channel

The A3 Adenosine Receptor Agonist CP-532,903 [N6-(2,5-Dichlorobenzyl)-3′-aminoadenosine-5′-N-methylcarboxamide] Protects against Myocardial Ischemia/Reperfusion Injury via the Sarcolemmal ATP-Sensitive Potassium Channel

We examined the cardioprotective profile of the new A 3 adenosine receptor (AR) agonist CP-532,903 [ N 6 -(2,5-dichlorobenzyl)-3′-aminoadenosine-5′- N -methylcarboxamide] in an in vivo mouse model of infarction and an isolated heart model of global ischemia/reperfusion injury. In radioligand bin...

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Bibliographic Details
Published in:The Journal of pharmacology and experimental therapeutics 2008-01, Vol.324 (1), p.234-243
Main Authors: Wan, Tina C, Ge, Zhi-Dong, Tampo, Akihito, Mio, Yasushi, Bienengraeber, Martin W, Tracey, W Ross, Gross, Garrett J, Kwok, Wai-Meng, Auchampach, John A
Format: Article
Language:eng
Subjects:
Adenosine A3 Receptor Agonists
Animals
Blood Pressure - drug effects
Cardiotonic Agents - pharmacology
Cell Line
Cyclic AMP - metabolism
Furans - pharmacology
Heart - drug effects
Heart - physiology
Histamine - blood
Humans
In Vitro Techniques
KATP Channels - physiology
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Mitochondria, Heart - physiology
Myocardial Infarction - drug therapy
Myocardial Infarction - physiopathology
Myocardial Reperfusion Injury - physiopathology
Myocardial Reperfusion Injury - prevention & control
Purines - pharmacology
Radioligand Assay
Receptor, Adenosine A1 - metabolism
Receptor, Adenosine A3 - deficiency
Receptor, Adenosine A3 - physiology
Sarcolemma - physiology
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Summary:We examined the cardioprotective profile of the new A 3 adenosine receptor (AR) agonist CP-532,903 [ N 6 -(2,5-dichlorobenzyl)-3′-aminoadenosine-5′- N -methylcarboxamide] in an in vivo mouse model of infarction and an isolated heart model of global ischemia/reperfusion injury. In radioligand binding and cAMP accumulation assays using human embryonic kidney 293 cells expressing recombinant mouse ARs, CP-532,903 was found to bind with high affinity to mouse A 3 ARs ( K i = 9.0 ± 2.5 nM) and with high selectivity versus mouse A 1 AR (100-fold) and A 2A ARs (1000-fold). In in vivo ischemia/reperfusion experiments, pretreating mice with 30 or 100 μg/kg CP-532,903 reduced infarct size from 59.2 ± 2.1% of the risk region in vehicle-treated mice to 42.5 ± 2.3 and 39.0 ± 2.9%, respectively. Likewise, treating isolated mouse hearts with CP-532,903 (10, 30, or 100 nM) concentration dependently improved recovery of contractile function after 20 min of global ischemia and 45 min of reperfusion, including developed pressure and maximal rate of contraction/relaxation. In both models of ischemia/reperfusion injury, CP-532,903 provided no benefit in studies using mice with genetic disruption of the A 3 AR gene, A 3 knockout (KO) mice. In isolated heart studies, protection provided by CP-532,903 and ischemic preconditioning induced by three brief ischemia/reperfusion cycles were lost in Kir6.2 KO mice lacking expression of the pore-forming subunit of the sarcolemmal ATP-sensitive potassium (K ATP ) channel. Whole-cell patch-clamp recordings provided evidence that the A 3 AR is functionally coupled to the sarcolemmal K ATP channel in murine cardiomyocytes. We conclude that CP-532,903 is a highly selective agonist of the mouse A 3 AR that protects against ischemia/reperfusion injury by activating sarcolemmal K ATP channels.
ISSN:0022-3565
1521-0103