Testosterone Supplementation Induces Age-Dependent Augmentation of the Hypoxic Ventilatory Response in Male Rats With Contributions From the Carotid Bodies

Abstract

Excessive carotid body responsiveness to O2 and/or CO2/H+ stimuli contributes to respiratory instability and apneas during sleep. In hypogonadal men, testosterone supplementation may increase the risk of sleep-disordered breathing; however, the site of action is unknown. The present study tested the hypothesis that testosterone supplementation potentiates carotid body responsiveness to hypoxia in adult male rats. Because testosterone levels decline with age, we also determined whether these effects were age-dependent. In situ hybridization determined that androgen receptor mRNA was present in the carotid bodies and caudal nucleus of the solitary tract of adult (69 days old) and aging (193–206 days old) male rats. In urethane-anesthetized rats injected with testosterone propionate (2 mg/kg; i.p.), peak breathing frequency measured during hypoxia (FiO2 = 0.12) was 11% greater vs. the vehicle treatment group. Interestingly, response intensity following testosterone treatment was positively correlated with animal age. Exposing ex vivo carotid body preparations from young and aging rats to testosterone (5 nM, free testosterone) 90–120 min prior to testing showed that the carotid sinus nerve firing rate during hypoxia (5% CO2 + 95% N2; 15 min) was augmented in both age groups as compared to vehicle (<0.001% DMSO). Ventilatory measurements performed using whole body plethysmography revealed that testosterone supplementation (2 mg/kg; i.p.) 2 h prior reduced apnea frequency during sleep. We conclude that in healthy rats, age-dependent potentiation of the carotid body’s response to hypoxia by acute testosterone supplementation does not favor the occurrence of apneas but rather appears to stabilize breathing during sleep.

Etonogestrel promotes respiratory recovery in an in vivo rat model of central chemoreflex impairment

“…However, female cats in the Bayliss study showed variable phrenic responses to acute progesterone, with many showing little or no response. In fact, ETO has androgenic effects 94 and may partially mimic the stimulatory effects of acute testosterone supplementation on ventilation 95,96 . It will be key to test in our SP‐saporin lesion protocol if male rats also display recovery of respiratory function in order to further investigate mechanisms.…”

“…On the day of the experiment, rats were placed in the chamber and testing commenced once the animals were quiet (typically 30–40 min). Although we did not record EEG/EMG to determine sleep/wake state, rat behavior (head movement and body position) was continuously monitored along with respiratory data ( ƒ R and V T variability) 96 to exclude periods of REM sleep that may impact the chemoreflex 100 . Gas mixtures were delivered at 1.5 L/min using a GSM‐3 (CWE, Inc., Ardmore, PA, USA) and monitored using a Gas Analyzer (AD Instruments, Sydney, Australia).…”

Extracellular vesicles in the pathogenesis and treatment of acute lung injury

“…Mortality rate in men appears to correlate with testosterone level since male SARS-CoV-2 patients with lower total and free testosterone levels have poor prognoses [ 13 ]. This may be because that testosterone could enhance the responsiveness of the carotid body to hypoxia [ 14 ] and attenuate tissue inflammation, fibrosis, and hypoxia induced in response to a systemic pro-inflammatory syndrome [ 15 ]. However, unlike that in men, higher total and free testosterone levels are associated with more severe inflammatory states in women with SARS-CoV-2 pneumonia [ 16 ].…”