Comparison of Three Different A₁Adenosine 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 (ϳ65%) 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 (ϳ40 -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.

Effect of modulating cardiac A1adenosine receptor expression on protection with ischemic preconditioning

“…That study demonstrated that inhibition of A 1 AR during reperfusion diminished infarct size (IF) and regional myocardial dysfunction after I/R (8). Another study in anesthetized dogs (2) further supported this theory by demonstrating that pretreatment with either of two A 1 AR antagonists (DPCPX and BG-9928) before ischemia decreased IF after regional left arterior descending coronary artery (LAD) occlusion (2). That study also demonstrated that pretreatment with three different A 1 AR antagonists failed to prevent IF reduction by IPC (2).…”

“…Another study in anesthetized dogs (2) further supported this theory by demonstrating that pretreatment with either of two A 1 AR antagonists (DPCPX and BG-9928) before ischemia decreased IF after regional left arterior descending coronary artery (LAD) occlusion (2). That study also demonstrated that pretreatment with three different A 1 AR antagonists failed to prevent IF reduction by IPC (2). The discrepancy between all of the above findings may be due to differences in the selectivity of the antagonists for multiple adenosine receptor subtypes.…”

Adenosine receptors as therapeutic targets

“…However, BG9719 contains an epoxide group, which is potentially chemically reactive. However, a non-epoxide-containing antagonist in the same series, BG9928, improves renal function and congestive heart failure without exacerbating cardiac injury 161 . BG9928, now in Phase II clinical trials, was found to improve sodium excretion in heart failure patients.…”

The A2a/A2b receptor antagonist ZM-241385 blocks the cardioprotective effect of adenosine agonist pretreatment in in vivo rat myocardium

“…Additional reports support the hypothesis that adenosine receptor subtype interactions may occur in the heart. Sympathetic nerve-mediated coronary constriction in stunned canine myocardium is induced by the infusion of a combination of adenosine A 1 and A 2a agonists but not by either agonist alone (3). It has been reported that cardiac adenosine A 2a receptors modulate the adenosine A 1 receptor anti-adrenergic effect (22,34).…”