allopurinol and Hypercapnia

Based on the fact that erythropoietin (Epo) administration in rodents protects against spatial learning and cognitive deficits induced by chronic intermittent hypoxia (CIH)-mediated oxidative damage, here we tested the hypothesis that Epo in the brain protects against cardiorespiratory disorders and oxidative stress induced by CIH in adult mice.. Adult control and transgenic mice overexpressing Epo in the brain only (Tg21) were exposed to CIH (21%-10% O2-10 cycles/hour-8 hours/day-7 days) or room air. After CIH exposure, we used the tail cuff method to measure arterial pressure, and whole-body plethysmography to assess the frequency of apneic episodes at rest, minute ventilation, and ventilatory responses to hypoxia and hypercapnia. Finally, the activity of pro-oxidant (XO-xanthine oxidase, and NADPH) and antioxidant (super oxide dismutase) enzymes was evaluated in the cerebral cortex and brainstem.. Exposure of control mice to CIH significantly increased the heart rate and arterial pressure, the number of apneic events, and the ventilatory response to hypoxia and hypercapnia. Furthermore, CIH increased the ratio of pro-oxidant to antioxidant enzymes in cortex and brainstem tissues. Both physiological and molecular changes induced by CIH were prevented in transgenic Tg21 mice.. We conclude that the neuroprotective effect of Epo prevents oxidative damage in the brain and cardiorespiratory disorders induced by CIH. Considering that Epo is used in clinics to treat chronic kidney disease and stroke, our data show convincing evidence suggesting that Epo may be a promising alternative drug to treat sleep-disorder breathing.

Topics: Animals; Apnea; Arterial Pressure; Brain; Brain Stem; Cerebral Cortex; Erythropoietin; Heart Rate; Hypercapnia; Hypoxia; Male; Mice; Mice, Transgenic; NADP; Oxidative Stress; Plethysmography, Whole Body; Pulmonary Ventilation; Reactive Oxygen Species; Rest; Sleep Apnea Syndromes; Superoxide Dismutase; Xanthine Oxidase

We tested the hypothesis that estradiol (E2) protects against cardiorespiratory disorders and oxidative stress induced by chronic intermittent hypoxia (CIH) in adult female rats.. Sprague-Dawley female rats (230-250 g) were ovariectomized and implanted with osmotic pumps delivering vehicle or E2 (0.5 mg/kg/d). After 14 days of recovery, the rats were exposed to CIH (21%-10% O2: 8 h/d, 10 cycles per hour) or room air (RA). After 7 days of CIH or RA exposure, we measured arterial pressures (tail cuff), metabolic rate (indirect calorimetry), minute ventilation, the frequency of sighs and apneas at rest, and ventilatory responses to hypoxia and hypercapnia (whole body plethysmography). We collected the cerebral cortex, brainstem, and adrenal glands to measure the activity of NADPH and xanthine oxidase (pro-oxidant enzymes), glutathione peroxidase, and the mitochondrial and cytosolic superoxide dismutase (antioxidant enzymes) and measured lipid peroxidation and advanced oxidation protein products (markers of oxidative stress).. CIH increased arterial pressure, the frequency of apnea at rest, and the hypoxic and hypercapnic ventilatory responses and reduced metabolic rate. CIH also increased oxidant enzyme activities and decreased antioxidant activity in the cortex. E2 treatment reduced body weight and prevented the effects of CIH.. E2 prevents cardiorespiratory disorders and oxidative stress induced by CIH. These observations may help to better understand the underlying mechanisms linking menopause and occurrence of sleep apnea in women and highlight a potential advantage of hormone therapy.

Topics: Animals; Antioxidants; Blood Pressure; Body Weight; Estradiol; Female; Glutathione Peroxidase; Heart; Hypercapnia; Hypoxia; NADP; Oxidative Stress; Rats; Rats, Sprague-Dawley; Respiration; Rest; Sleep Apnea Syndromes; Superoxide Dismutase; Xanthine Oxidase

Hypoventilation, associated with hypercapnic acidosis (HCA), may improve outcome in acute lung injury (ALI). We have recently reported that HCA per se protects against ALI. The current study explored whether the mechanisms of protection with HCA were related to acidosis versus hypercapnia. Because CO(2) equilibrates rapidly across cell membranes, we hypothesized that (1) HCA would afford greater protection than metabolic acidosis. We further hypothesized that (2) buffering HCA would attenuate its protection. Forty isolated perfused rabbit lung preparations were randomized to: control (normal pH, PCO(2)); HCA; metabolic acidosis; or buffered hypercapnia. After ischemia-reperfusion (IR) injury wet:dry ratio was greatest with control and buffered hypercapnia, and rank order of capillary filtration coefficient was: control approximately buffered hypercapnia > metabolic acidosis > HCA. Isogravimetric pressure reduction was greatest with buffered hypercapnia. Despite comparable injury, pulmonary artery pressure elevation was less with buffered hypercapnia versus control. In vitro xanthine oxidase (XO) activity depended on pH, not PCO(2). We conclude that: (1) HCA and metabolic acidosis are protective, but HCA is the most protective; (2) buffering HCA attenuates its protection; (3) buffering HCA causes pulmonary vasodilation; (4) because metabolic acidosis and HCA similarly inhibit in vitro XO activity, the differential effects cannot be explained solely on the basis of extracellular XO activity.

Topics: Acidosis, Respiratory; Animals; Blood Gas Analysis; Capillary Permeability; Disease Models, Animal; Hydrogen-Ion Concentration; Hypercapnia; Hyperventilation; In Vitro Techniques; Lung; Male; Rabbits; Reperfusion Injury; Respiratory Distress Syndrome; Vasodilation; Xanthine Oxidase

Relative hypoventilation, involving passively-or "permissively"-generated hypercapnic acidosis (HCA), may improve outcome by reducing ventilator-induced lung injury. However, the effects of HCA per se on pulmonary microvascular permeability (Kf,c) in noninjured or injured lungs are unknown. We investigated the effects of HCA in the isolated buffer-perfused rabbit lung, under conditions of: (1) no injury; (2) injury induced by warm ischemia-reperfusion; and (3) injury induced by addition of purine and xanthine oxidase. HCA (fraction of inspired carbon dioxide [FICO2] 12%, 25% versus 5%) had no adverse microvascular effects in uninjured lungs, and prevented (FICO2 25% versus 5%) the increase in Kf,c following warm ischemia-reperfusion. HCA (FICO2 25% versus 5%) reduced the elevation in Kf,c, capillary (Pcap), and pulmonary artery (Ppa) pressures in lung injury induced by exogenous purine/xanthine oxidase; inhibition of endogenous NO synthase in the presence of 25% FICO2 had no effect on Kf,c, but attenuated the reduction of Pcap and Ppa. HCA inhibited the in vitro generation of uric acid from addition of xanthine oxidase to purine. We conclude that in the current models, HCA is not harmful in uninjured lungs, and attenuates injury in free-radical-mediated lung injury, possibly via inhibition of endogenous xanthine oxidase.

Topics: Acidosis; Analysis of Variance; Animals; Blood Pressure; Capillaries; Capillary Permeability; Carbon Dioxide; Free Radicals; Hydrostatic Pressure; Hypercapnia; Lung; Male; Microcirculation; Nitric Oxide Synthase; Pulmonary Artery; Purines; Rabbits; Reperfusion Injury; Respiration, Artificial; Respiratory Distress Syndrome; Uric Acid; Vascular Resistance; Xanthine Oxidase