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-imida zo[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 microg/kg i.v. followed by 0.3 microg/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 microg/kg + 0.3 microg/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 microg/kg + 0.3 microg/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.