The time course of cardioprotection induced by GR79236, a selective adenosine A1-receptor agonist, in myocardial ischaemia-reperfusion injury in the pig.
The cardioprotective effects of the selective adenosine A1-receptor agonist, GR79236 (N-[(1S, trans)-2-hydroxycyclopentyl]adenosine), were examined in a porcine model of myocardial ischaemia-reperfusion injury. When pigs were subjected to a 50-min coronary artery occlusion followed by 3-h reperfusion, GR79236 (10 nmol/kg, i.v.) significantly reduced infarct size whether given 10 min before the onset of ischaemia or reperfusion. This effect was independent of the bradycardia induced by GR79236, as it was also observed in animals in which heart rate was maintained by electrical pacing. However, GR79236 administered 10 min after reperfusion did not reduce infarct size. GR79236 had no effect on the incidence or outcome of ventricular dysrhythmias in this pig model of infarction. Similarly, ischaemic preconditioning (IPC, 2 x 10-min ischaemia and 10-min reperfusion) significantly reduced infarct size. The selective adenosine A1-receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; 3.3 micromol/kg, i.v.), abolished the haemodynamic and cardioprotective effects of GR79236 and the cardioprotective effects of IPC in anaesthetised pigs. In conclusion, GR79236 exerted a marked cardioprotective effect in a porcine model of myocardial ischaemia-reperfusion injury, provided that it was administered before reperfusion. This suggests that GR79236 may have clinical utility in the treatment of various aspects of ischaemic heart disease.
Systems Biology Unit, Glaxo-Wellcome Research and Development, Medicines Research Centre, Stevenage, Hertfordshire, UK.
J B
JB
Louttit
A A
AA
Hunt
M P
MP
Maxwell
G M
GM
Drew
D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000758:Anesthesia; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D003327:Coronary Disease / Q000473:pathology; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D015394:Molecular Structure; D009203:Myocardial Infarction / Q000473:pathology*; D058906:Purinergic P1 Receptor Agonists; D015427:Reperfusion Injury / Q000517:prevention & control*; D013552:Swine; D013997:Time Factors; D018754:Ventricular Dysfunction / Q000473:pathology*; D014970:Xanthines / Q000494:pharmacology
D058906:Purinergic P1 Receptor Agonists; D014970:Xanthines; C051360:1,3-dipropyl-8-cyclopentylxanthine; D000241:Adenosine; C082299:N-((1S,trans)-2-hydroxycyclopentyl)adenosine