Coronary function and adenosine receptor-mediated responses in ischemic-reperfused mouse heart.
OBJECTIVE
To assess the impact of ischemia-reperfusion (I/R) on coronary function, and the role of endogenous adenosine in modifying post-ischemic vascular function in asanguinous hearts.


METHODS
Vascular function was studied in Langendorff perfused mouse hearts subjected to 20-25-min ischemia and 30-min reperfusion.


RESULTS
Ischemia altered the dependence of flow on work-rate observed in normoxic hearts, and inhibited reflow by mechanisms additional to diastolic compression. Coronary responses were selectively reduced: 2-chloroadenosine and ADP dilated with pEC(50)s of 8.4+/-0.1 and 7.4+/-0.1 in non-ischemic hearts versus 7.7+/-0.1 and 7.1+/-0.1 after 20-min ischemia (P<0.05). Sensitivity was further reduced after 25-min ischemia. Responses to nitroprusside were unaltered. NO-synthase antagonism (50 microM nitro-L-arginine methylester) reduced sensitivities to 2-chloroadenosine and ADP up to 10-fold, and eliminated inhibitory effects of I/R. K(ATP) blockade with 5 microM glibenclamide impaired sensitivity pre- and post-ischemia, not eliminating the inhibitory effects of I/R. A(1) adenosine receptor antagonism with 100 nM 8-cyclopentyl-1,3-dipropylxanthine worsened effects of ischemia on sensitivity. A(2A) adenosine receptor antagonism with 100 nM 8-(3-chlorostyryl)caffeine reduced post-ischemic flow by 50%, yet paradoxically enhanced post-ischemic contractile recovery.


CONCLUSIONS
Ischemia modifies vascular control and impairs NO- versus K(ATP)-dependent coronary dilation in an asanguinous model. Endogenous adenosine protects against vascular dysfunction via A(1) receptors, and determines coronary reflow via A(2A) receptors. However, intrinsic A(2A) activation apparently worsens contractile dysfunction.
Flood
Amanda J
AJ
Heart Foundation Research Centre, School of Health Science, Griffith University Gold Coast Campus, Southport, Qld 4217, Australia.
Willems
Laura
L
Headrick
John P
JP
D015762:2-Chloroadenosine / Q000494:pharmacology; D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D002110:Caffeine / Q000031:analogs & derivatives* / Q000494:pharmacology; D003326:Coronary Circulation; D006321:Heart / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D009200:Myocardial Contraction; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology*; D009599:Nitroprusside / Q000494:pharmacology; D010477:Perfusion; D010627:Phenethylamines / Q000494:pharmacology; D058915:Purinergic P1 Receptor Antagonists; D014665:Vasodilator Agents / Q000494:pharmacology; D014970:Xanthines / Q000494:pharmacology
D010627:Phenethylamines; D058915:Purinergic P1 Receptor Antagonists; D014665:Vasodilator Agents; D014970:Xanthines; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D015762:2-Chloroadenosine; C081320:8-(3-chlorostyryl)caffeine; D009599:Nitroprusside; D002110:Caffeine; D000244:Adenosine Diphosphate; C051360:1,3-dipropyl-8-cyclopentylxanthine; D000241:Adenosine