Effects of A(3) adenosine receptor activation and gene knock-out in ischemic-reperfused mouse heart.
OBJECTIVE
To characterize effects of A(3) adenosine receptor (A(3)AR) activation and gene knock-out on responses to ischemia-reperfusion in mouse heart.


METHODS
Perfused hearts from wild-type and A(3)AR gene knock-out (A(3)AR KO) mice were subjected to 20 min ischemia and 30 min reperfusion. Functional responses were assessed and changes in energy metabolism and cytosolic pH monitored via 31P-NMR spectroscopy.


RESULTS
Selective A(3)AR agonism with 100 nM 2-chloro-N(6)-(3-iodobenzyl)-adenosine-5'-N-methyluronamide (chloro-IB-MECA) enhanced post-ischemic contractile recovery without altering contracture development in wild-type hearts, an effect unrelated to non-selective activation of A(1) or A(2) adenosine receptors. Chloro-IB-MECA also improved recovery in hearts overexpressing A(1)ARs. Paradoxically, post-ischemic recovery was enhanced by A(3)AR KO. Developed pressure, +dP/dt, and -dP/dt all recovered to higher levels in A(3)AR KO (70-80% of pre-ischemia) vs. wild-type hearts (45-50% of pre-ischemia) (P<0.05). Enhanced recovery was unrelated to recoveries of ATP, phosphocreatine (PCr), inorganic phosphate (P(i)), energy state ([ATP]/[ADP] x [P(i)], DeltaG(ATP)) or cytosolic pH.


CONCLUSIONS
Selective A(3)AR activation is cardioprotective in wild-type hearts and hearts overexpressing A(1)ARs, yet A(3)AR gene deletion generates an ischemia-tolerant phenotype without altering energy metabolism or pH. This may be due to compensatory changes or undefined genotypic differences in A(3)AR KO vs. wild-type hearts.
Harrison
Glenn J
GJ
Heart Foundation Research Centre, Griffith University Gold Coast Campus, Southport, QLD, Australia.
Cerniway
Rachael J
RJ
Peart
Jason
J
Berr
Stuart S
SS
Ashton
Kevin
K
Regan
Sara
S
Paul Matherne
G
G
Headrick
John P
JP
D000241:Adenosine / Q000031:analogs & derivatives* / Q000032:analysis / Q000494:pharmacology; D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D003401:Creatine / Q000032:analysis; D006339:Heart Rate / Q000187:drug effects; D006863:Hydrogen-Ion Concentration; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000187:drug effects; D015428:Myocardial Reperfusion Injury / Q000378:metabolism*; D009206:Myocardium / Q000737:chemistry / Q000378:metabolism*; D010477:Perfusion; D010627:Phenethylamines / Q000494:pharmacology; D010875:Pipecolic Acids / Q000494:pharmacology; D058915:Purinergic P1 Receptor Antagonists; D011799:Quinazolines / Q000494:pharmacology; D043684:Receptor, Adenosine A3; D018047:Receptors, Purinergic P1 / Q000235:genetics / Q000378:metabolism*; D014230:Triazoles / Q000494:pharmacology; D014970:Xanthines / Q000494:pharmacology
C110041:9-chloro-2-(2-furyl)-5-phenylacetylamino(1,2,4)triazolo(1,5-c)quinazoline; D000596:Amino Acids; D010627:Phenethylamines; D010875:Pipecolic Acids; D058915:Purinergic P1 Receptor Antagonists; D011799:Quinazolines; D043684:Receptor, Adenosine A3; D018047:Receptors, Purinergic P1; D014230:Triazoles; D014970:Xanthines; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; C076144:cyclopentenosine; C051360:1,3-dipropyl-8-cyclopentylxanthine; D000241:Adenosine; D003401:Creatine