title: Comparison of three different A1 adenosine receptor antagonists on infarct size and multiple cycle ischemic preconditioning in anesthetized dogs.
abstract: A(1) adenosine receptor (AR) antagonists are effective diuretic agents that may be useful for treating fluid retention disorders including congestive heart failure. However, antagonism of A(1)ARs is potentially a concern when using these agents in patients with ischemic heart disease. To address this concern, the present study was designed to compare the actions of the A(1)AR antagonists CPX (1,3-dipropyl-8-cyclopentylxanthine), BG 9719 (1,3-dipropyl-8-[2-(5,6-epoxynorbornyl)]xanthine), and BG 9928 (1,3-dipropyl-8-[1-(4-propionate)-bicyclo-[2,2,2]octyl]xanthine) on acute myocardial ischemia/reperfusion injury and ischemic preconditioning (IPC) in an in vivo dog model of infarction. Barbital-anesthetized dogs were subjected to 60 min of left anterior descending coronary artery occlusion followed by 3 h of reperfusion, after which infarct size was assessed by staining with triphenyltetrazolium chloride. IPC was elicited by four 5-min occlusion/5-min reperfusion cycles produced 10 min before the 60-min occlusion. Multiple-cycle IPC produced a robust reduction ( approximately 65%) in infarct size; this effect of IPC on infarct size was not abrogated in dogs pretreated with any of the three AR antagonists. Surprisingly, in the absence of IPC, pretreatment with CPX or BG 9928 before occlusion or immediately before reperfusion resulted in significant reductions ( approximately 40-50%) in myocardial infarct size. However, treatment with an equivalent dose of BG 9719 had no similar effect. We conclude that the A(1)AR antagonists BG 9719, BG 9928, and CPX do not exacerbate cardiac injury and do not interfere with IPC induced by multiple ischemia/reperfusion cycles. We discuss the possibility that the cardioprotective actions of CPX and BG 9928 may be related to antagonism of A(2B)ARs.
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226, USA. jauchamp@mcw.edu
authors.forename: John A
authors.initials: JA
authors.lastname: Auchampach
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Jin
authors.forename: Jeannine
authors.initials: J
authors.lastname: Moore
authors.forename: Tina C
authors.initials: TC
authors.lastname: Wan
authors.forename: Laura M
authors.initials: LM
authors.lastname: Kreckler
authors.forename: Zhi-Dong
authors.initials: ZD
authors.lastname: Ge
authors.forename: Jayashree
authors.initials: J
authors.lastname: Narayanan
authors.forename: Eric
authors.initials: E
authors.lastname: Whalley
authors.forename: William
authors.initials: W
authors.lastname: Kiesman
authors.forename: Barry
authors.initials: B
authors.lastname: Ticho
authors.forename: Glenn
authors.initials: G
authors.lastname: Smits
authors.forename: Garrett J
authors.initials: GJ
authors.lastname: Gross
mesh_terms: D058916:Adenosine A1 Receptor Antagonists; D000758:Anesthesia; D000818:Animals; D004195:Disease Models, Animal; D004285:Dogs; D019157:Ischemic Preconditioning, Myocardial; D009203:Myocardial Infarction / Q000517:prevention & control*; D017202:Myocardial Ischemia / Q000150:complications; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D011869:Radioligand Assay; D043705:Receptor, Adenosine A2A / Q000187:drug effects / Q000378:metabolism; D014970:Xanthines / Q000627:therapeutic use*
chemical_list: C097280:1,3-dipropyl-8-(2-(5,6-epoxy)norbornyl)xanthine; D058916:Adenosine A1 Receptor Antagonists; D043705:Receptor, Adenosine A2A; D014970:Xanthines; C051360:1,3-dipropyl-8-cyclopentylxanthine