title: P2X7 receptor agonists pre- and postcondition the heart against ischemia-reperfusion injury by opening pannexin-1/P2X₇ channels.
abstract: Protection of the heart from ischemia-reperfusion injury can be achieved by ischemic preconditioning and ischemic postconditioning. Previous studies revealed that a complex of pannexin-1 with the P2X(7) receptor forms a channel during ischemic preconditioning and ischemic postconditioning that results in the release of endogenous cardioprotectants. ATP binds to P2X(7) receptors, inducing the formation of a channel in association with pannexin-1. We hypothesized that this channel would provide a pathway for the release of these same cardioprotectants. Preconditioning-isolated perfused rat hearts with 0.4 μM ATP preceding 40 min of ischemia minimized infarct size upon subsequent reperfusion (5% of risk area) and resulted in >80% recovery of left ventricular developed pressure. Postconditioning with ATP after ischemia during reperfusion was also protective (6% infarct and 72% recovery of left ventricular developed pressure). Antagonists of both pannexin-1 (carbenoxolone and mefloquine) and P2X(7) receptors (brilliant blue G and A438079) blocked ATP pre- and postconditioning, indicating that ATP protection was elicited via the opening of a pannexin-1/P2X(7) channel. An antagonist of binding of the endogenous cardioprotectant sphingosine 1-phosphate to its G protein-coupled receptor diminished protection by ATP, which is also consistent with an ATP-dependent release of cardioprotectants. Suramin, an antagonist of binding of ATP (and ADP) to P2Y receptors, was without effect on ATP protection. Benzoyl benzoyl-ATP, a more specific P2X(7) agonist, was also a potent pre- and postconditioning agent and sensitive to blockade by pannexin-1/P2X(7) channel antagonists. The data point out for the first time the potential of P2X(7) agonists as cardioprotectants.
authors.affiliation: Liver Study Unit, Department of Veterans Affairs Medical Center, San Francisco, California 94121, USA. donald.vessey@va.gov
authors.forename: Donald A
authors.initials: DA
authors.lastname: Vessey
authors.forename: Luyi
authors.initials: L
authors.lastname: Li
authors.forename: Michael
authors.initials: M
authors.lastname: Kelley
mesh_terms: D000255:Adenosine Triphosphate / Q000008:administration & dosage / Q000031:analogs & derivatives; D000704:Analysis of Variance; D000818:Animals; D002316:Cardiotonic Agents / Q000008:administration & dosage*; D017630:Connexins / Q000819:agonists* / Q000378:metabolism; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D008246:Lysophospholipids / Q000378:metabolism; D008297:Male; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000819:agonists* / Q000378:metabolism; D010477:Perfusion; D058911:Purinergic P2X Receptor Agonists / Q000008:administration & dosage*; D058920:Purinergic P2X Receptor Antagonists / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D049349:Receptors, Lysosphingolipid / Q000378:metabolism; D058486:Receptors, Purinergic P2X7 / Q000187:drug effects* / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism; D013997:Time Factors; D016277:Ventricular Function, Left / Q000187:drug effects; D017725:Ventricular Pressure / Q000187:drug effects
chemical_list: D002316:Cardiotonic Agents; D017630:Connexins; D008246:Lysophospholipids; D009419:Nerve Tissue Proteins; D058911:Purinergic P2X Receptor Agonists; D058920:Purinergic P2X Receptor Antagonists; D049349:Receptors, Lysosphingolipid; D058486:Receptors, Purinergic P2X7; C479936:pannexin 1, rat; C060506:sphingosine 1-phosphate; C033901:3'-O-(4-benzoyl)benzoyladenosine 5'-triphosphate; D000255:Adenosine Triphosphate; D013110:Sphingosine