Intravenous AMP 579, a novel adenosine A(1)/A(2a) receptor agonist, induces a delayed protection against myocardial infarction in minipig.
The aim of the study was to probe if acute administration of [1S-[1a, 2b,3b, 4a(S*)]]-4-[7-[[2-(3-chloro-2-thienyl)-1-methylpropyl]amino]-3H-imida zo[4,5-b] pyridin-3-yl] cyclopentane carboxamide (AMP 579) could provide a delayed protection against myocardial ischemia-reperfusion injury after 24 h. Anesthetized Yucatan minipigs were given an intravenous (i.v.) loading dose (3 microg/kg) of AMP 579 in 2 min followed by a 68-min infusion (0.3 microg/kg/min) and were allowed to recover. After 24 h, the animals were subjected to an open-chest operation and the left anterior descending coronary artery was occluded for 40 min, followed by 3 h of reperfusion. Results indicated that there were no significant differences in hemodynamic parameters between vehicle- and drug-treated groups either during drug infusion or ischemia-reperfusion. Both groups had similar area at risk (24.9% for vehicle and 25.1% for AMP 579-treated). However, the infarct size was 36.5% of area at risk in vehicle group (n=8) and 12.5% in AMP 579 group (n=8), representing a 66% reduction of infarct size by AMP 579 (p=0.011). This is the first report to demonstrate that in a large animal model, a hemodynamically silent, single i.v. dose of an adenosine receptor agonist can result in a delayed protection against myocardial infarction.
Meng
H
H
Cardiovascular Drug Discovery, Mail Stop NW4, Rhône-Poulenc Rorer, Collegeville, PA 19426, USA. harry.meng@rp-rorer.com
McVey
M
M
Perrone
M
M
Clark
K L
KL
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology*; D007262:Infusions, Intravenous; D009203:Myocardial Infarction / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000150:complications / Q000503:physiopathology / Q000517:prevention & control; D020011:Protective Agents / Q000494:pharmacology; D058906:Purinergic P1 Receptor Agonists; D011725:Pyridines / Q000494:pharmacology*; D013552:Swine; D013556:Swine, Miniature; D013997:Time Factors; D014693:Ventricular Fibrillation / Q000209:etiology / Q000503:physiopathology
C113971:4-(7-((2-3-chloro-2-thienyl)-1-methyl-propylamino)-3H-imidazo(4,5-b)pyridyl-3-yl)cyclopentane carboxamide; D007093:Imidazoles; D020011:Protective Agents; D058906:Purinergic P1 Receptor Agonists; D011725:Pyridines