Journal
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Volume 324, Issue 1, Pages 234-243Publisher
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/jpet.107.127480
Keywords
-
Categories
Funding
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL060051, F32HL073643, R01HL077707] Funding Source: NIH RePORTER
- NHLBI NIH HHS [F32 HL073643, R01 HL077707-03, R01 HL060051, R01 HL60051, R01 HL07707, T32 HL73643, R01 HL077707, R01 HL060051-09] Funding Source: Medline
Ask authors/readers for more resources
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 mu g/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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available