The effect of body temperature on myocardial protection conferred by ischaemic preconditioning or the selective adenosine A1 receptor agonist GR79236, in an anaesthetized rabbit model of myocardial ischaemia and reperfusion.
1 The cardioprotective effect of N-[(1S, trans)-2-hydroxycyclopentyl]adenosine (GR79236), an adenosine A1 receptor agonist, was compared with that produced by ischaemic preconditioning in an anaesthetized rabbit model of myocardial ischaemia and reperfusion. In addition, we examined the effect of different body core temperatures on GR79236- or ischaemic preconditioning-induced cardioprotection when administered prior to ischaemia, and on cardioprotection induced by GR79236 administered 10 min prior to the onset of reperfusion. 2 When rabbits were subjected to 30 min occlusion of the left coronary artery, followed by 2 h reperfusion, GR79236 (3 x 10(-8) mol kg-1 i.v. (10.5 microg kg-1 i.v.)) or ischaemic preconditioning (5 min ischaemia followed by 5 min reperfusion), administered or applied 10 min prior to the occlusion, significantly limited the development of infarction. The cardioprotective effect of ischaemic preconditioning was significantly greater than that seen after administration of GR79236. Pre-treatment with the selective adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, 3.3 x 10(-6) mol kg-1 (1 mg kg-1 i.v.)), prevented the cardioprotective effect of GR79236, but not that of ischaemic preconditioning. 3 Maintaining body core temperature at 38.5 degrees C rather than at 37.0 degrees C did not influence infarct size in control groups of rabbits, but reduced the cardioprotective effect of GR79236 when administered 10 min prior to occlusion or 10 min prior to the onset of reperfusion. The cardioprotective effect of ischaemic preconditioning was not temperature-dependent. 4 In conclusion, myocardial protection conferred by GR79236 in anaesthetized rabbits is mediated via adenosine A1 receptors. Myocardial protection can be conferred when GR79236 is administered before the onset of ischaemia or reperfusion, and is reduced when body core temperature is maintained at 38.5 degrees C rather than at 37.0 degrees C. In contrast, myocardial protection conferred by ischaemic preconditioning is not reduced by adenosine A1 receptor blockade, or by maintaining body core temperature at 38.5 degrees C rather than at 37.0 degrees C. These findings point to distinct differences in the mechanisms of induction of myocardial protection by adenosine A1 receptor agonist and ischaemic preconditioning. They also highlight the need for careful control of body core temperature when investigating the phenomenon of cardioprotection.
Sheldrick
A
A
Systems Biology Unit, Glaxo Wellcome Research and Development, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY.
Gray
K M
KM
Drew
G M
GM
Louttit
J B
JB
D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000758:Anesthesia; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001831:Body Temperature / Q000502:physiology*; D006339:Heart Rate / Q000187:drug effects; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D009203:Myocardial Infarction / Q000473:pathology / Q000517:prevention & control; D017202:Myocardial Ischemia / Q000473:pathology* / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000473:pathology / Q000517:prevention & control*; D058906:Purinergic P1 Receptor Agonists; D011817:Rabbits; 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