Promising effects of xanthine oxidase inhibition by allopurinol on autonomic heart regulation estimated by heart rate variability (HRV) analysis in rats exposed to hypoxia and hyperoxia

• Published in: PloS one 2018-02, Vol.13 (2), p.e0192781-e0192781
• Main Authors: Zajączkowski, Stanisław, Ziółkowski, Wiesław, Badtke, Piotr, Zajączkowski, Miłosz A, Flis, Damian J, Figarski, Adam, Smolińska-Bylańska, Maria, Wierzba, Tomasz H
• Format: Article
• Language: English
• Subjects: Activation; Allopurinol; Antioxidants; Autonomic nervous system; Bioenergetics; Biology and Life Sciences; Carbonyl compounds; Carbonyl groups; Carbonyls; Cardiovascular diseases; Catalase; Chemoreception (internal); Chemoreceptors; Chemoreceptors (internal); Complications and side effects; Control; Diabetes; Dosage and administration; Echocardiography; EKG; Enzymatic activity; Enzymes; Erythrocytes; Exposure; Gene expression; Genetic aspects; Glutathione; Glutathione peroxidase; Health risks; Heart failure; Heart rate; Hydrogen peroxide; Hyperoxia; Hypoxia; Inhibition; Intervals; Kinesiology; Lysates; Medicine and Health Sciences; Oxidases; Oxidative stress; Oxygen; Peroxidase; Physical education; Physiological aspects; Physiology; Rats; Reactive oxygen species; Research and Analysis Methods; Rhythm; Rodents; Studies; Superoxide dismutase; Uric acid; Vagus nerve; Variability; Xanthine oxidase
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0192781

It has long been suggested that reactive oxygen species (ROS) play a role in oxygen sensing via peripheral chemoreceptors, which would imply their involvement in chemoreflex activation and autonomic regulation of heart rate. We hypothesize that antioxidant affect neurogenic cardiovascular regulation through activation of chemoreflex which results in increased control of sympathetic mechanism regulating heart rhythm. Activity of xanthine oxidase (XO), which is among the major endogenous sources of ROS in the rat has been shown to increase during hypoxia promote oxidative stress. However, the mechanism of how XO inhibition affects neurogenic regulation of heart rhythm is still unclear. The study aimed to evaluate effects of allopurinol-driven inhibition of XO on autonomic heart regulation in rats exposed to hypoxia followed by hyperoxia, using heart rate variability (HRV) analysis. 16 conscious male Wistar rats (350 g): control-untreated (N = 8) and pretreated with Allopurinol-XO inhibitor (5 mg/kg, followed by 50 mg/kg), administered intraperitoneally (N = 8), were exposed to controlled hypobaric hypoxia (1h) in order to activate chemoreflex. The treatment was followed by 1h hyperoxia (chemoreflex suppression). Time-series of 1024 RR-intervals were extracted from 4kHz ECG recording for heart rate variability (HRV) analysis in order to calculate the following time-domain parameters: mean RR interval (RRi), SDNN (standard deviation of all normal NN intervals), rMSSD (square root of the mean of the squares of differences between adjacent NN intervals), frequency-domain parameters (FFT method): TSP (total spectral power) as well as low and high frequency band powers (LF and HF). At the end of experiment we used rat plasma to evaluate enzymatic activity of XO and markers of oxidative stress: protein carbonyl group and 8-isoprostane concentrations. Enzymatic activity of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) were measures in erythrocyte lysates. Allopurinol reduced oxidative stress which was the result of hypoxia/hyperoxia, as shown by decreased 8-isoprostane plasma concentration. XO inhibition did not markedly influence HRV parameters in standard normoxia. However, during hypoxia, as well as hyperoxia, allopurinol administration resulted in a significant increase of autonomic control upon the heart as shown by increased SDNN and TSP, with an increased vagal contribution (increased rMSSD and HF), whereas sympathovagal indexes