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Cooperative cardioprotection through adenosine A1 and A2A receptor agonism in ischemia-reperfused isolated mouse heart.

Abstract
Recent reports have shown that adenosine A1 receptor-mediated cardioprotection requires concomitant A2 receptor activation, but no study thus far has shown that this phenomenon occurs using A1 agonists at reperfusion. Thus, we compared adenosine A2A receptor knockout (A2AKO) and wild-type mouse hearts (n = 9-11) subjected to global ischemia (30 minutes) and reperfusion (60 minutes) in the presence and absence of the A1 agonist N-cyclopentlyadenosine (CPA). We also determined the effects of selective antagonists at A2A and A2B receptors on CPA-induced protection. In wild-type hearts, CPA (100 nM) significantly (P < 0.05) improved contractility (52.7 ± 6.2% versus 23.9 ± 4.9% of preischemia), left ventricular developed pressure, end diastolic pressure; reduced infarct size (7.9 ± 1.7% versus 23.9 ± 6.6% area at risk); decreased lactate dehydrogenase efflux; and increased ERK1/2 phosphorylation at 60 minutes of reperfusion. Adenosine A2A (ZM241385, 50 nM) and A2B (MRS1754, 100 nM) receptor antagonists abolished CPA-mediated cardioprotection in wild-type groups as did the A1 receptor antagonist DPCPX (P < 0.05). In A2AKO hearts, CPA did not improve functional parameters and protective signaling with the exception of end diastolic pressure. In this model, using a clinically relevant mode of pharmacologic intervention, pERK 1/2-dependent A1-mediated cardioprotection requires a cooperative activation of A2 receptors, presumably through endogenous adenosine.
AuthorsVijay B Urmaliya, Colin W Pouton, Catherine Ledent, Jennifer L Short, Paul J White
JournalJournal of cardiovascular pharmacology (J Cardiovasc Pharmacol) Vol. 56 Issue 4 Pg. 379-88 (Oct 2010) ISSN: 1533-4023 [Electronic] United States
PMID20930592 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Acetamides
  • Adenosine A1 Receptor Agonists
  • Adenosine A1 Receptor Antagonists
  • Adenosine A2 Receptor Agonists
  • Adenosine A2 Receptor Antagonists
  • Cardiotonic Agents
  • N-(4-cyanophenyl)-2-(4-(2,3,6,7-tetrahydro-2,6-dioxo-1,3-dipropyl-1H-purin-8-yl)-phenoxy)acetamide
  • Purines
  • Receptor, Adenosine A2A
  • Triazines
  • Triazoles
  • Xanthines
  • ZM 241385
  • N(6)-cyclopentyladenosine
  • 1,3-dipropyl-8-cyclopentylxanthine
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Adenosine
Topics
  • Acetamides (pharmacology)
  • Adenosine (analogs & derivatives, pharmacology)
  • Adenosine A1 Receptor Agonists (pharmacology)
  • Adenosine A1 Receptor Antagonists (pharmacology)
  • Adenosine A2 Receptor Agonists (pharmacology)
  • Adenosine A2 Receptor Antagonists (pharmacology)
  • Animals
  • Blood Pressure (drug effects)
  • Cardiotonic Agents (pharmacology)
  • Drug Synergism
  • In Vitro Techniques
  • Male
  • Mice
  • Mice, Knockout
  • Mitogen-Activated Protein Kinase 1 (metabolism)
  • Mitogen-Activated Protein Kinase 3 (metabolism)
  • Myocardial Contraction (drug effects)
  • Myocardial Reperfusion Injury (metabolism, pathology, prevention & control)
  • Phosphorylation
  • Purines (pharmacology)
  • Receptor, Adenosine A2A (genetics)
  • Triazines (pharmacology)
  • Triazoles (pharmacology)
  • Xanthines (pharmacology)

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