Abstract
A1 adenosine receptor (AR) antagonists are effective diuretic agents that may be useful for treating fluid retention disorders including congestive heart failure. However, antagonism of A1ARs 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 A1AR 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 (∼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 (∼40–50%) in myocardial infarct size. However, treatment with an equivalent dose of BG 9719 had no similar effect. We conclude that the A1AR 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 A2BARs.
Footnotes
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This work was supported by National Institutes of Health Grants R01 HL60051, R01 HL08311, and T32 HL07792, by American Heart Association Research Fellowships 0320019Z and 0315274Z, and by a research grant from Biogen, Inc. (Cambridge, MA).
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DOI: 10.1124/jpet.103.057943.
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ABBREVIATIONS: AR, adenosine receptor; CPX, 1,3-dipropyl-8-cyclopentylxanthine; BG 9719, 1,3-dipropyl-8-[2-(5,6-epoxynorbornyl)]xanthine; BG 9928, 1,3-dipropyl-8-[1-(4-propionate)-bicyclo-[2,2,2]octyl]xanthine; IPC, ischemic preconditioning; GFR, glomerular filtration rate; G418, geneticin; [125I]ZM 241385, 4-(2-[7-amino-2-(2-furyl)[1,2,4]-triazolo[2,3-a][1,3,5]triazin-5-yl amino]ethyl)-3-[125I]iodophenol; [125I]AB-MECA, N6-(4-amino-3-[125I]iodobenzyl)adenosine-5′-N-methylcarboxamide; [3H]MRS 1754, 1,3-dipropyl-8-[4-[((4-cyano-[2,6-3H]phenyl)carbamoylmethyl)oxy-]phenyl]xanthine; NECA, adenosine-5′-N-ethylcarboxamide; LAD, left anterior descending; DPSPX, 1,3-dipropyl-8-sulfophenylxanthine; CCPA, 2-chloro-N6-cyclopentyladenosine; CGS 21680, 2-[p-(2-carboxyethyl)phenethylamino]-5′-N-ethylcarboxamidoadenosine; Precond, preconditioning.
- Received August 22, 2003.
- Accepted November 5, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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