Adenosine A1/A2a receptor agonist AMP-579 induces acute and delayed preconditioning against in vivo myocardial stunning.

Abstract

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.

• Authors: Gentian Kristo, Yukihiro Yoshimura, Byron J Keith, Randy M Stevens, Salik A Jahania, Robert M Mentzer Jr, Robert D Lasley
• Journal: American journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 287 Issue 6 Pg. H2746-53 (Dec 2004) ISSN: 0363-6135 [Print] United States
• PMID: 15271662 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• 4-(7-((2-3-chloro-2-thienyl)-1-methyl-propylamino)-3H-imidazo(4,5-b)pyridyl-3-yl)cyclopentane carboxamide
• Adenosine A1 Receptor Agonists
• Adenosine A2 Receptor Agonists
• Imidazoles
• Pyridines
• Receptor, Adenosine A1
• Receptor, Adenosine A2A

Topics

• Acute Disease
• Adenosine A1 Receptor Agonists
• Adenosine A2 Receptor Agonists
• Animals
• Coronary Circulation (drug effects)
• Disease Models, Animal
• Female
• Imidazoles (pharmacology)
• Ischemic Preconditioning, Myocardial
• Male
• Myocardial Stunning (drug therapy)
• Perfusion
• Pyridines (pharmacology)
• Receptor, Adenosine A1 (metabolism)
• Receptor, Adenosine A2A (metabolism)
• Sus scrofa