An adenosine A1 receptor agonist, R(-)-N-(2-phenylisopropyl)-adenosine (PIA), but not adenosine itself, acts as a therapeutic preconditioning-mimetic agent in rabbits.
OBJECTIVE
A preconditioning mimetic agent could be useful therapy for cardiac ischaemic events; stimulation of adenosine receptors has been proposed as a preconditioning mediator. The ability of adenosine-receptor activation to mimic ischaemic preconditioning was tested in an in vivo rabbit model.


METHODS
Adenosine (15 mg, a maximally tolerated dose, n = 10) was infused over six minutes via a coronary artery and compared with saline (n = 12) in anaesthetised rabbits. Five minutes after infusion, a coronary artery was occluded for 40 minutes followed by three hours of reperfusion. In a second study, preischaemic intravenous treatment with adenosine (25 mg.kg-1, n = 9), or an A1-adenosine agonist, R(-)-N-(2-phenylisopropyl)-adenosine (PIA, 900 micrograms.kg-1, n = 12), were compared with saline (n = 12), when given before 40 minutes of coronary artery ligation and three hours of reperfusion in anaesthetised rabbits.


RESULTS
Intracoronary adenosine reduced mean arterial pressure during infusion (48(3) v 80(4) mm Hg, control, p < 0.001); however, infusion regional myocardial blood flow was significantly higher in adenosine treated hearts (5.00(0.90) v 2.30(0.26) ml.min-1 x g-1, p < 0.02) in the region later to become ischaemic. During occlusion ischaemic blood flow was similar in both groups as was the size of the ischaemic risk region, expressed as a % of the left ventricle (42(3)% adenosine and 37(3)% control, NS). Intracoronary adenosine treatment failed to reduce infarct size (52(5)% of the risk zone v 57(7)% in controls, NS). In the second protocol, heart rate immediately after treatment was reduced by both intravenous denosine (26%) and PIA (22%) v control, indicating atrial A1 receptor activation. Treatment with PIA resulted in a significant reduction in ultimate infarct size compared with saline (38(5)% of risk region v 57(5)%, p < 0.05). Adenosine, however, failed to reduce infarct size (50(8)%, NS v saline). There were no differences between area at risk or myocardial blood flow among groups.


CONCLUSIONS
The adenosine agonist PIA but not adenosine itself might be a useful adjunctive therapy.
Hale
S L
SL
Heart Institute of the Hospital of the Good Samaritan, Los Angeles, CA 90017.
Bellows
S D
SD
Hammerman
H
H
Kloner
R A
RA
D000241:Adenosine / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003326:Coronary Circulation / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D009203:Myocardial Infarction / Q000473:pathology / Q000517:prevention & control*; D017202:Myocardial Ischemia / Q000378:metabolism* / Q000473:pathology; D009206:Myocardium / Q000473:pathology; D010660:Phenylisopropyladenosine / Q000494:pharmacology*; D011817:Rabbits; D018047:Receptors, Purinergic P1
D018047:Receptors, Purinergic P1; D010660:Phenylisopropyladenosine; D000241:Adenosine