Circulation, Vol 89, 1229-1236, Copyright © 1994 by American Heart Association
Z Yao and GJ Gross
BACKGROUND: Adenosine has been proposed to be an important mediator of
ischemic preconditioning. Intracoronary administration of adenosine has
recently been shown to mimic the effects of preconditioning in isolated
rabbit hearts. However, it is not known whether this agent can duplicate
the effects of preconditioning in vivo or in other species. Thus, the first
objective of the present study was to determine whether adenosine can limit
myocardial necrosis to the same extent as preconditioning in anesthetized
dogs. A second objective was to determine whether the duration of the
adenosine-induced cardioprotection persisted as long as that of ischemic
preconditioning. Finally, a third aim was to determine whether adenosine
mediates its cardioprotection via the KATP channel, which has been shown to
be an important mediator of preconditioning in several animal species,
including dogs. METHODS AND RESULTS: Barbital-anesthetized open-chest dogs
were subjected to 60 minutes of left anterior descending coronary artery
(LAD) occlusion followed by 4 hours of reperfusion. Preconditioning was
elicited by 10 minutes of LAD occlusion followed by 10 or 60 minutes of
reperfusion before the 60-minute occlusion period. Adenosine (400
micrograms/min) or an equivalent volume of saline was infused into the LAD
for 10 minutes, followed by a 10- or 60-minute drug-free period before the
60-minute ischemic insult. Glibenclamide (0.3 mg/kg i.v.), a selective KATP
channel blocker, was given 15 minutes before adenosine administration, and
another selective KATP channel blocker, 5-hydroxydecanoate (5-HD, 3 mg/min
IC) was infused concomitantly with adenosine into the LAD for 10 minutes.
Transmural myocardial blood flow was measured at 5 minutes of occlusion,
and infarct size was determined by triphenyltetrazolium staining and
expressed as a percent of the area at risk (AAR). There were no significant
differences in hemodynamics, collateral blood flow, or AAR between groups.
Preconditioning with either 10 or 60 minutes of reperfusion produced a
marked reduction (P < .05) in infarct size (6.7 +/- 2.5% and 8.7 +/-
2.6%, respectively, versus 26.9 +/- 4.3% in controls). Administration of
adenosine with a 10-minute drug-free period before 60 minutes of occlusion
resulted in a marked decrease in infarct size similar to that seen with
preconditioning (9.6 +/- 1.7% versus 26.9 +/- 4.3% in controls); however,
the protection disappeared when a 60-minute drug-free period was allowed
after adenosine administration (23.0 +/- 2.4% versus 26.9 +/- 4.3% in
controls). In addition, treatment with either glibenclamide or 5-HD
completely abolished the protective effects of adenosine (26.4 +/- 6.8 and
25.0 +/- 4.4%, respectively, versus 26.9 +/- 4.3% in controls).
CONCLUSIONS: These results clearly reveal that (1) a 10-minute
intracoronary infusion of adenosine exhibits the same efficacy as ischemic
preconditioning in reducing myocardial necrosis in dogs; (2) similar to
preconditioning, adenosine mediates its cardioprotection via a cardiac KATP
channel-linked mechanism; and (3) adenosine-induced cardioprotection is
transient (disappearing within 60 minutes), whereas ischemic
preconditioning persists for at least 60 minutes. These data support the
hypothesis that endogenous adenosine released during ischemia is an
important mediator of ischemic preconditioning; however, important
differences exist between the time course of effects of exogenously
administered adenosine and preconditioning, which suggests that other
factors may also be involved.
ARTICLES
A comparison of adenosine-induced cardioprotection and ischemic preconditioning in dogs. Efficacy, time course, and role of KATP channels
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee 53226.
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