A study of gender influence on the pattern of cardiorespiratory response to transient and unrelenting acute severe hypoxemia in adult rats
Authors: Van Maele Nicholas J , Hosner Conner James , Bell Harold James 
Published: November 2023

Males are known to be at greater risk of sudden death across the spectrum of life stages. Conditions such as sudden infant death during sleep (SIDS), sudden unexplained death in epilepsy (SUDEP), and sudden death in adulthood are all biased towards a preponderance of male victims. The pathogenesis for this gender difference may in part be related to gender differences in the control of breathing responses to asphyxia. Differences in the eupneic breathing responses have been well‐documented during neonatal to adult life stages in animals and human subjects. We hypothesized that gender‐related differences would also be present in the pattern of cardiorespiratory responses elaborated during autoresuscitation from acute severe hypoxemia. We studied age‐matched adult male (n=9, 702 ± 86 g) and female (n=9, 342 ± 49 g) Sprague‐Dawley rats, which were anesthetized with pentobarbital and instrumented to directly measure spontaneous breathing and intravascular arterial blood pressure. Respiratory variables were determined from the tracheal flow trace, and cardiovascular variables from the arterial blood pressure waveform. All animals underwent identical protocols, including assessment of cardiorespiratory responses to mild hypoxia (10% inspired), hypercapnia (7% inspired CO2). To examine responses during autoresuscitation animals breathed 100% nitrogen. In the first transient exposure to asphyxia, animals were switched back to room air exposure upon demonstrating hypoxia‐induced respiratory arrest, allowing for the potential of a spontaneous autoresuscitation. In the second unrelenting exposure to asphyxia, animals remained in 100% N2 during respiratory arrest, and gasping. There were no significant gender‐related differences in the respiratory or cardiovascular responses to mild hypoxia or hypercapnia challenge. During the respiratory autoresuscitation in response to transient asphyxia, systolic blood pressure (SBP) was significantly lower in females (141 ± 14 mmHg) vs. males (162 ± 29mmHg) at the point where the first gasping breath was observed (p=0.038), as well as at the point where eupneic breathing resumed (p<0.001). During this same autoresuscitation process, there were also gender differences observed in the duration of primary apnea (97.8 ± 15.5 in males, vs. 81.8 ± 8.0 sec in females, p<0.01). Gender‐related differences in the number of gasping breaths, and the cumulative volume of gasping breaths narrowly missed the threshold for significance (p=0.08 for both comparisons). There were no other gender differences with respect to cardiorespiratory responses to transient or unrelenting asphyxia in the animals we studied, and all animals in both gender groups successfully restored eupneic breathing in the former condition. We conclude that adult male rats experience a longer primary apnea in response to transient asphyxia, and sustain higher SBP during the gasping and recovery phases of autoresuscitation. These differences equate to a delay in the process of reoxygenation upon gasping in male animals, and potentially less flexibility in their ability to alter blood flow distribution and facilitate oxygen delivery during respiratory autoresuscitation.Support or Funding InformationNVM and CH were recipients of a College of Medicine Summer Scholars Research Program award. HB received research support from a CMU Early Career Grant through the Office of Research and Sponsored Programs.