Hypoxic ventilatory response and respiratory chemosensitivity in differing rat models of female sex hormone loss

Abstract

Respiratory function is modulated by circulating sex steroids. Specifically, concentrations of circulating 17β-estradiol and progesterone regulate the responsiveness of the respiratory system in adult female rats. Progesterone was first noted to influence breathing following the observation that pregnancy impacted blood gasses. 17β-estradiol is the most abundant and neuroactive form of estrogen, and female respiratory neuroplasticity is dependent on its presence. Circulating sex hormone levels fluctuate across the normal estrus cycle and gradually decline as part of the natural aging process. The specific influences of sex hormones on hypoxic ventilatory response (HVR) and chemosensitivity are slowly emerging in the literature. A developing pattern is that short-term hormone fluctuations, such as estrus cycle, do not appear to significantly change basic respiratory responsiveness. However, less is known about larger hormone shifts, such as those following the loss of gonads or with natural aging. We hypothesized that the loss of sex hormones would differentially impact HVR and chemosensitivity in an ovariectomy (OVX) model versus a naturally aged female rat. Specifically, we theorized that aged rats would demonstrate reduced sensitivity to hypoxia and reduced dynamic range within ventilatory output, as compared to OVX and intact female rats. Three experimental groups of female rats were used: young rats (3 mos old; n=4), young OVX rats (n=5), and aged rats (>24 mos old; n=5). Chemosensitivity was measured during progressive hypoxic challenges at 15%, 12%, and 9% oxygen (O 2 ) using unrestrained barometric plethysmography. Serum samples were taken for measurement of estrogen (E 2 ) and progesterone (P) using ELISA assays. At the highest level of hypoxia (9% O 2 ), all groups exhibited intact chemosensitivity as demonstrated by significant changes in minute ventilation (V E ; < 0.05), V E controlling for metabolism (V E / VCO 2 ; < 0.05), and respiratory neural drive (calculated as the ratio of tidal volume (T V ) to inspiratory time (Ti), controlling for metabolism; T V /T i /VCO 2 ; < 0.05). Further analysis showed that young and OVX groups demonstrated greater sensitivity to hypoxia as compared to the aged group. Using analyses targeting rate of change, the young and OVX groups had a faster rate of change in V E , V E / VCO 2 , and T V /T i /VCO 2 (< 0.05) as the hypoxia intensity increased. ELISA analyses suggest that E 2 , but not P, concentration is significantly correlated with these results (< 0.05). Collectively, these data indicate that aging impacts respiratory function in complex and unique ways that differ from OVX in female rats. This may be significant since OVX is commonly used as a model of age-related physiological changes. University of Minnesota BIRCWH/Women's Health Research Program Seed Grant, National Heart Lungs Brain Institute R01HL146477, Rehabilitation Science Graduate Program, UMN Medical School This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.