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Abstract

Allopurinol, a competitive inhibitor of xanthine oxidase, was found to have a protective effect on ischemic myocardium. Its mechanism of action is still controversial. We used Langendorff isolated rat heart preparation to test the hypothesis that allopurinol could maintain a level of the adenine nucleotide pool (ATP, ADP, and AMP) that would protect and improve the functional activity of the heart during a period of hypoxia. Hearts were initially perfused for 30 min until steady state was attained. This was followed by 20 min of experimental perfusion divided into 5 min of control perfusion followed by 15 min of hypoxic perfusion with or without allopurinol in the perfusate. Hearts were quick-frozen and enzymatically analyzed for adenine nucleotides and creatine phosphate at the end of the hypoxic period. Left ventricular pressure, heart rate, and coronary flow were measured in all preparations. Allopurinol (0.1 mM) treated hearts had greater levels of ATP (12.3 +/- 0.8 vs. 9.3 +/- 0.8 micromol/g dry weight; p < 0.01). This improvement occurred in the presence as well as the absence of glucose. Total adenine nucleotides improved from 17 +/- 1 to 20.3 +/- 2.4 micromol/g dry weight (p < 0.01). This improvement also occurred in the presence as well as in the absence of glucose in the perfusate. It also improved cell energy state significantly in the presence as well as the absence of glucose. There was insignificant change in creatine phosphate. Allopurinol improved left ventricular pressure from 38 +/- 7% to 55 +/- 9% (p < 0.002) in the presence of glucose and from 8 +/- 3% to 27 +/- 6.3% (p < 0.001) in the absence of glucose. Coronary flow improved from 110 +/- 5% to 120 +/- 8% (p < 0.04) in the presence of glucose. These results support the suggestion that allopurinol at 0.1 mM exerts its protective effect on rat heart during hypoxia by enhancing the adenine nucleotide pool.

Metabolomics analysis elucidates unique influences on purine / pyrimidine metabolism by xanthine oxidoreductase inhibitors in a rat model of renal ischemia-reperfusion injury

“…One possible alternate answer to the question is that XOR inhibitors might exhibit organ-protective effects by affecting purine metabolism. Indeed, administration of allopurinol maintained tissue concentrations of ATP, adenosine diphosphate (ADP), and adenosine 5′-monophosphate (AMP), and preserved functional organ activity (Cunningham et al 1974; Lasley et al 1988; Khatib et al 2001). As XOR is a key player in purine metabolism, exhaustive metabolic analysis would contribute to elucidate the beneficial organ-protective effect of XOR inhibitors.…”

“…Animal models of I/R injury have long been used to evaluate metabolic fluctuations in organ disorders (Cunningham et al 1974; Lasley et al 1988; Khatib et al 2001; Stromski et al 1986; Stromski et al 1988; Okabe 1996). By investigating the influence of renal I/R on the metabolome, I/R-induced metabolic changes can be elucidated.…”

Shortage of Cellular ATP as a Cause of Diseases and Strategies to Enhance ATP

“…In animals, at least 11 papers reported that heart failure and ischemic heart disease were improved by the administration of allopurinol or febuxostat (DeWall et al, 1971; Arnold et al, 1980; Hopson et al, 1995; Pérez et al, 1998; Ekelund et al, 1999; Khatib et al, 2001; Ukai et al, 2001; Stull et al, 2004; Hou et al, 2006; Xu et al, 2008; Zhao et al, 2008; Yao and Seko, 2017; El-Bassossy et al, 2018). In humans, at least 20 papers, including randomized controlled trials (RCTs) and meta-analyses, reported that heart failure and ischemic heart disease were improved by the administration of allopurinol or febuxostat (Saugstad, 1996; Cappola et al, 2001; Gavin and Struthers, 2005; Pacher et al, 2006; Noman et al, 2010; Rentoukas et al, 2010; Thanassoulis et al, 2010; Kelkar et al, 2011; Gotsman et al, 2012; Hirsch et al, 2012; Agarwal and Messerli, 2013; Agarwal et al, 2013; Larsen et al, 2016; MacIsaac et al, 2016; Singh and Yu, 2016, 2017; Ansari-Ramandi et al, 2017; Foody et al, 2017; Singh et al, 2017; Bredemeier et al, 2018).…”

“…One such study in the early 2000s of allopurinol’s impact on mitochondrial function examined rat livers under ischemic/hypoxic conditions and found that decreases in ATP levels after ischemia/reperfusion were attenuated with allopurinol treatment (Jeon et al, 2001). Another study around the same time-period examined prepared rat hearts under hypoxic conditions, and the authors reported that both ATP and total adenine nucleotide pools were enhanced after allopurinol administration (Khatib et al, 2001). Later, a report on canines examined the impact of XOIs on cardiac bioenergetics under conditions simulating myocardial ischemia, with subjects examined at rest and then with/without XOI under either basal cardiac work (BCW) or high cardiac work (HCW) after catecholamine administration (Lee et al, 2011).…”

Multicentre, prospective, randomised, open-label, blinded end point trial of the efficacy of allopurinol therapy in improving cardiovascular outcomes in patients with ischaemic heart disease: protocol of the ALL-HEART study

“…Extra ATP and oxygen availability produced by allopurinol might prevent downstream ischaemic cardiomyocytes from infarcting and thereby leading to heart failure during an ischaemic insult such as acute coronary syndrome (ACS). 31 32 …”