Cardioprotection with adenosine-regulating agent, GP531: effects on no-reflow, infarct size, and blood flow following ischemia/ reperfusion in the rabbit.
GP531, a potent, second-generation adenosine-regulating agent, is pharmacologically silent under basal conditions but increases localized endogenous adenosine during ischemia. GP531 improves functional recovery after myocardial ischemia, but its effects on infarct size and no-reflow have not been reported. The objective was to determine whether GP531 reduces necrosis and the anatomic no-reflow defect and to evaluate its effects on regional myocardial blood flow (RMBF). GP531 was given as a loading dose plus infusion at 2 doses (700 microg/kg and 10 microg/kg per minute or 2100 microg/kg and 30 microg/kg per minute) or vehicle, starting 12 minutes before a 30-minute coronary occlusion and throughout 3 hours reperfusion in rabbits. Risk zone was delineated by blue dye, necrosis by tetrazolium staining, RMBF by radioactive microspheres, and no-reflow defect by thioflavin S. The extent of the ischemic risk zone was similar in all groups. Low-dose GP531 reduced infarct size by 34% (0.33 +/- 0.4 of the risk zone) compared with vehicle (0.50 +/- 0.4, P < .01) and reduced the extent of the anatomic no-reflow zone by 31% compared with vehicle (0.25 +/- 0.3 of the risk zone vs 0.36 +/- 0.4 in the vehicle group, P < .05). Infarct size and zone of no-reflow in the high dose were reduced by 22% and 16%, respectively (P = NS vs the other 2 groups). GP531 did not affect hemodynamics or blood flow. Thus, GP531 was effective at the lower dose evaluated in this study, reducing the severity of ischemic/reperfusion injury, without inducing the adverse hemodynamic effects associated with adenosine administration such as bradycardia and hypotension.
The Heart Institute of Good Samaritan Hospital, Los Angeles, CA 90017, USA. sharon.hale@netscape.com
Sharon L
SL
Hale
Robert A
RA
Kloner
D000241:Adenosine / Q000494:pharmacology*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D003853:Deoxyribonucleosides / Q000494:pharmacology*; D004195:Disease Models, Animal; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D009203:Myocardial Infarction / Q000517:prevention & control*; D017202:Myocardial Ischemia; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000503:physiopathology*; D011817:Rabbits; D011897:Random Allocation
D003853:Deoxyribonucleosides; C103214:GP 531; D000620:Aminoimidazole Carboxamide; D000241:Adenosine