Effects of urate-lowering agents on arrhythmia vulnerability in post-infarcted rat hearts

Abstract

Hyperuricemia has been shown to be associated with ventricular arrhythmias. However, the mechanisms remained unknown. We assessed whether different urate-lowering agents can attenuate arrhythmias through lowering urate itself or inhibiting xanthenes oxidize (XO) activity in infarcted rats. Male Wistar rats after ligating coronary artery were randomized to either allopurinol, or febuxostat, chemically unrelated inhibitors of XO, benzbromarone or vehicle for 4 weeks. Post-infarction was associated with increased oxidant stress, as measured by myocardial superoxide, isoprostane, XO activity and dihydroethidine fluorescence staining. Measurement of myocardial norepinephrine levels revealed a significant elevation in vehicle-treated infarcted rats compared with sham-operated rats. Sympathetic hyperinnervation was blunted after administering both XO inhibitors, assessed by immunofluorescent analysis, Western blotting and real-time quantitative RT-PCR. Besides, the XO inhibitors-attenuated nerve growth factor levels were reversed in the presence of peroxynitrite generator. Arrhythmic scores in the XO inhibitors-treated infarcted rats were significantly lower than that in vehicle. For similar levels of urate lowering, the uricosuric agent benzbromarone had no beneficial effects on oxidative stress, sympathetic hyperinnervation or arrhythmia vulnerability. Chronic use of XO inhibitors, but not uricosuric agent, down-regulated sympathetic innervation probably through a superoxide-dependent pathway and plays a role in the beneficial effect on arrhythmogenic response.

Discovery of new therapeutic redox targets for cardioprotection against ischemia/reperfusion injury and heart failure

“…NCT00181155 Phase II, NCT00997542 Phase IV) are presented in [146]. Mechanistically, febuxostat improved oxidative stress parameters, adverse protein kinase signaling (phospho-Erk and phospho-mTOR), mitochondrial as well as cardiac function, apoptosis parameters and arrhythmia in animal models of cardiac hypertrophy, myocardial infarction and heart failure [198][199][200][201].…”

The Key Role of Uric Acid in Oxidative Stress, Inflammation, Fibrosis, Apoptosis, and Immunity in the Pathogenesis of Atrial Fibrillation

“…Autonomic nervous system activation can induce significant and heterogeneous changes of atrial electrophysiology and induce atrial tachyarrhythmias, including atrial tachycardia and AF (38). Recently, some researchers showed that a continuous 4 weeks inhibition of XO in infarcted rats down-regulated sympathetic innervation (39). This suggests that UA involves in sympathetic nerve activity via sympathetic innervation probably through a superoxide-dependent pathway, which eventually contributes to arrhythmia.…”

Hyperuricemia is associated with an increased prevalence of ventricular tachycardia and fibrillation in patients with ST-elevation myocardial infarction after primary percutaneous coronary intervention

“…But it is controversial whether hyperuricemia is only a marker of oxidative stress or directly induce VT/VF in STEMI patients. Use of allopurinol significantly decreased the inducibility of ventricular tachycardia and ventricular fibrillation in infarcted rats by down-regulating sympathetic innervation through a superoxide-dependent pathway, but the uricosuric agent benzbromarone had no beneficial effects on oxidative stress, sympathetic hyperinnervation or arrhythmia vulnerability at the similar levels of uric acid [ 27 ], indicating that uric acid functions only as an indicator of xanthine oxidase (XO) activity and is not directly involved in the arrhythmogenic process. However, there are well-established interspecies differences in intrinsic levels of myocardial XO activity [ 28 ].…”