Display Settings:

Format

Send to:

Choose Destination
See comment in PubMed Commons below
J Pharmacol Exp Ther. 2008 Jan;324(1):234-43. Epub 2007 Sep 28.

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.

Author information

  • 1Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.

Abstract

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 microg/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.

PMID:
17906066
[PubMed - indexed for MEDLINE]
PMCID:
PMC2435594
Free PMC Article

Images from this publication.See all images (12)Free text

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
Figure 9
Figure 10
Figure 11
Figure 12
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Icon for HighWire Icon for PubMed Central
    Loading ...
    Write to the Help Desk