Adenosine A1/A2a receptor agonist AMP-579 induces acute and delayed preconditioning against in vivo myocardial stunning.
The purpose of this study was to determine whether the adenosine A1/A2a receptor agonist AMP-579 induces acute and delayed preconditioning against in vivo myocardial stunning. Regional stunning was produced by 15 min of coronary artery occlusion and 3 h of reperfusion (RP) in anesthetized open-chest pigs. In acute protection studies, animals were pretreated with saline, low-dose AMP-579 (15 microg/kg iv bolus 10 min before ischemia), or high-dose AMP-579 (50 microg/kg iv at 14 microg/kg bolus + 1.2 microg.kg(-1).min(-1) for 30 min before coronary occlusion). The delayed preconditioning effects of AMP-579 were evaluated 24 h after administration of saline vehicle or high-dose AMP-579 (50 microg/kg iv). Load-insensitive contractility was assessed by measuring regional preload recruitable stroke work (PRSW) and PRSW area. Acute preconditioning with AMP-579 dose dependently improved regional PRSW: 129 +/- 5 and 100 +/- 2% in high- and low-dose AMP-579 groups, respectively, and 78 +/- 5% in the control group at 3 h of RP. Administration of the adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (0.7 mg/kg) blocked the acute protective effect of high-dose AMP-579, indicating that these effects are mediated through A1 receptor activation. Delayed preconditioning with AMP-579 significantly increased recovery of PRSW area: 64 +/- 5 vs. 33 +/- 5% in control at 3 h of RP. In isolated perfused rat heart studies, kinetics of the onset and washout of AMP-579 A1 and A2a receptor-mediated effects were distinct compared with those of other adenosine receptor agonists. The unique nature of the adenosine agonist AMP-579 may play a role in its ability to induce delayed preconditioning against in vivo myocardial stunning.
Dept. of Surgery, Univ. of Kentucky College of Medicine, 800 Rose St., Lexington, KY 40536-0298, USA.
Gentian
G
Kristo
Yukihiro
Y
Yoshimura
Byron J
BJ
Keith
Randy M
RM
Stevens
Salik A
SA
Jahania
Robert M
RM
Mentzer
Robert D
RD
Lasley
D000208:Acute Disease; D058907:Adenosine A1 Receptor Agonists; D058908:Adenosine A2 Receptor Agonists; D000818:Animals; D003326:Coronary Circulation / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D007093:Imidazoles / Q000494:pharmacology*; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D017682:Myocardial Stunning / Q000188:drug therapy*; D010477:Perfusion; D011725:Pyridines / Q000494:pharmacology*; D043682:Receptor, Adenosine A1 / Q000378:metabolism; D043705:Receptor, Adenosine A2A / Q000378:metabolism; D034421:Sus scrofa
C113971:4-(7-((2-3-chloro-2-thienyl)-1-methyl-propylamino)-3H-imidazo(4,5-b)pyridyl-3-yl)cyclopentane carboxamide; D058907:Adenosine A1 Receptor Agonists; D058908:Adenosine A2 Receptor Agonists; D007093:Imidazoles; D011725:Pyridines; D043682:Receptor, Adenosine A1; D043705:Receptor, Adenosine A2A