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Vol. 286, Issue 2, 611-618, August 1998
Department of Cardiovascular Discovery (NW4), Rhône-Poulenc
Rorer, Collegeville, Pennsylvania
This study examined the cardioprotective effects and pharmacology
of the novel adenosine A1/A2 receptor
agonist
([1S-[1a,2b,3b,4a(S*)]]-4-[7-[[2-(3-chloro-2-thienyl)-1-methylpropyl]amino]-3H-imidazo[4,5-b] pyridyl-3-yl] cyclopentane carboxamide) (AMP 579), in a model of
myocardial infarction. Experiments were performed in
pentobarbital-anesthetized pigs in which myocardial infarction was
induced by a 40-min occlusion of the left anterior descending coronary
artery, followed by 3 hr of reperfusion. This procedure resulted in
approximately 20% of the left ventricle being made ischemic in all
test groups. In untreated animals, an infarct size equal to 56 ± 5% of the ischemic area was observed. Preconditioning, with two cycles
of 5 min of ischemia followed by 10-min reperfusion, resulted in a 70%
reduction in infarct size (17 ± 5%) relative to risk area. Administration of AMP 579 30 min before ischemia (3 µg/kg i.v. followed by 0.3 µg/kg/min i.v. through 1 hr of reperfusion) did not
change blood pressure, HR or coronary blood flow but resulted in marked
cardioprotection: a 98% reduction in infarct size (1 ± 1%)
relative to risk area. Moreover, whereas approximately 90% of control
pigs suffered ventricular fibrillation during ischemia, no fibrillation
was observed in animals treated with AMP 579. Further experiments
determined the effects of AMP 579 when administered 30 min
after the onset of myocardial ischemia, 10 min before
reperfusion. Two doses were studied: a low hemodynamically silent dose
(3 µg/kg + 0.3 µg/kg/min through 1 hr of reperfusion) and a
10-fold higher dose that did cause reductions in blood pressure and HR.
Both doses of AMP 579 produced a comparable cardioprotective effect, reducing infarct size to approximately 50% of that observed in control
animals. The cardioprotective effect of AMP 579 was a consequence of
adenosine receptor stimulation, because it was completely inhibited by
pretreatment with the specific adenosine receptor antagonist CGS 15943 (1 mg/kg i.v.). However, the selective A1 receptor agonist
GR 79236 (3 µg/kg + 0.3 µg/kg/min i.v.) did not reduce infarct
size, which suggests that under these experimental conditions,
stimulation of adenosine A2 receptors is important for the
cardioprotective effect of AMP 579. The adenosine-regulating agent
acadesine (5 mg/kg + 0.5 mg/kg/min i.v.) also failed to reduce
infarct size. In conclusion, the novel adenosine
A1/A2 receptor agonist AMP 579 produces marked
cardioprotection whether administered before myocardial ischemia or
reperfusion. Cardioprotection is not dependent on changes in afterload
or myocardial oxygen demand and is a consequence of adenosine receptor
stimulation. The pharmacological profile of AMP 579 in this model is
consistent with its potential utility in the treatment of acute
myocardial infarction.
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