Julie M. Wenninger

Sex steroidal hormones and respiratory control.

There is a growing public awareness that sex hormones can have an impact on a variety of physiological processes. Yet, despite almost a century of research, we still do not have a clear picture as to the effects of sex hormones on the regulation of breathing. Considerable data has accumulated showing that estrogen, progesterone and testosterone can influence respiratory function in animals and humans. Several disorders of breathing such as obstructive sleep apnea (OSA) and sudden infant death syndrome (SIDS) show clear sex differences in their prevalence, lending weight to the importance of sex hormones in respiratory control. This review focuses on questions such as: how early do sex hormones influence breathing? Which is the most effective? Where do sex hormones exert their effects? What mechanisms are involved? Are there age-associated changes? A clearer understanding of how sex hormones influence the control of breathing could enable sex- and age-specific therapeutic interventions for diseases of the respiratory control system.

Respiratory plasticity after perinatal hyperoxia is not prevented by antioxidant supplementation

Perinatal hyperoxia attenuates the hypoxic ventilatory response in rats by altering development of the carotid body and its chemoafferent neurons. In this study, we tested the hypothesis that hyperoxia elicits this plasticity through the increased production of reactive oxygen species (ROS). Rats were born and raised in 60% O(2) for the first two postnatal weeks while treated with one of two antioxidants: vitamin E (via milk from mothers whose diet was enriched with 1000 IU vitamin E kg(-1)) or a superoxide dismutase mimetic, manganese(III) tetrakis (1-methyl-4-pyridyl) porphyrin pentachloride (MnTMPyP; via daily intraperitoneal injection of 5-10 mg kg(-1)); rats were subsequently raised in room air until studied as adults. Peripheral chemoreflexes, assessed by carotid sinus nerve responses to cyanide, asphyxia, anoxia and isocapnic hypoxia (vitamin E experiments) or by hypoxic ventilatory responses (MnTMPyP experiments), were reduced after perinatal hyperoxia compared to those of normoxia-reared controls (all P<0.01); antioxidant treatment had no effect on these responses. Similarly, the carotid bodies of hyperoxia-reared rats were only one-third the volume of carotid bodies from normoxia-reared controls (P <0.001), regardless of antioxidant treatment. Protein carbonyl concentrations in the blood plasma, measured as an indicator of oxidative stress, were not increased in neonatal rats (2 and 8 days of age) exposed to 60% O(2) from birth. Collectively, these data do not support the hypothesis that perinatal hyperoxia impairs peripheral chemoreceptor development through ROS-mediated oxygen toxicity.

Carotid chemoafferent plasticity in adult rats following developmental hyperoxia

Developmental hyperoxia impairs carotid chemoreceptor development and induces long-lasting reduction in carotid sinus nerve (CSN) responses to hypoxia in adult rats. Studies were carried out to determine if CSN responses to acute hypoxia would exhibit hypoxia-induced plasticity in adult 3-5-months-old rats previously treated with postnatal hyperoxia (60% O2, PNH) of 1, 2, or 4 weeks duration. CSN responses to acute hypoxia were assessed in adult rats exposed to 1 week of sustained hypoxia (12% O2, SH). In normal adult rats and adult rats treated with 1 week of PNH, CSN responses to acute hypoxia were significantly increased in urethane-anesthetized rats when studied 3-5 h after SH. Apparent increases in CSN responses to hypoxia were not significant in rats treated with 2 weeks of PNH and were clearly absent after 4 weeks of PNH, but exponential analysis suggests a PNH duration-dependent plasticity of the CSN response to acute hypoxia after SH. In a second study rats exposed to 2 weeks of PNH were treated with SH for 1 week as adults and acute hypoxic responses were tested 4-5 months later. CSN responses in these rats were unaffected by SH suggesting a lack of persistent SH-induced functional plasticity. We conclude that rats treated with 1 week of PNH retain the capacity for hypoxia-induced plasticity of carotid chemoafferent function and some potential for plasticity may be present after 2 weeks of PNH, whereas 4 weeks of PNH impairs the capability of rats to exhibit plasticity following 1 week of SH.

Environmental Hyperoxia and Development of Carotid Chemoafferent Function

Exposure to hyperoxia in the first few weeks of life causes life-long impairment of carotid chemoreceptor function in rats, e.g., depressed carotid sinus nerve (CSN) and phrenic nerve responses to acute hypoxia. We determined the maximal CSN responses of anesthetized adult rats to severe hypoxia (ventilation with 100% N2) or asphyxia (stopped ventilator) after 1, 2, and 4 weeks of postnatal hyperoxia (60% O2) (PNH). As with acute responses to hypoxic stimuli, we find that maximal CSN responses are significantly attenuated with severity of attenuation dependent on duration of PNH. We suggest that impaired carotid chemoafferent input produced by PNH could play a role in failure of arousal in severely hypoxic states occurring in infants and adults.