Sex difference in the activation of central autonomic control regions in chronic intermittent hypoxia

Abstract

Obstructive sleep apnea (OSA) results in sustained daytime hypertension. Chronic intermittent hypoxia (CIH) mimics the repetitive bouts of arterial hypoxemia associated with OSA. Male Sprague Dawley rats treated with CIH develop sustained hypertension and increased activation of central autonomic regions that regulate mean arterial pressure (MAP). However, gonadally intact female rats exposed to modest CIH treatment are not hypertensive. In male rats, lesions of the median preoptic nucleus (MnPO) prevent CIH-induced increase of MAP. We hypothesize that activation of MnPO and other autonomic control regions may contribute to the sex differences in the MAP response to CIH. To test this hypothesis, adult gonadally intact male and female rats (250-300 g bw) were exposed to either continuously normoxic (CON) or treated with CIH (10% O2 every 3 mins alternating with 21% O2 every 3 mins, 8 h/day) for 7 days. One week before the experiment started, some rats were instrumented with radiotelemetry transmitters to measure MAP and heart rate (HR). After one week of baseline recording, the rats were exposed to either normoxia or CIH and were euthanized (inactin 100 mg/kg ip) on the 8th day for immunohistochemistry. Forebrain and brainstem sections were stained for FosB/ΔFosB. Forebrain sections were also stained for neuronal nitric oxide synthase (NOS1) while brainstem sections were processed for dopamine-β-hydroxylase (DBH). The numbers of cells positive for NOS1 and FosB neurons in MnPO were counted and DBH and FosB positive neurons were counted in the hindbrain autonomic regions. CIH was associated with increased FosB staining in males but not females. Male exhibited an increase in the average number of FosB positive neurons (CON male 20 ± 2 cells/section, CIH male 35 ± 3; CON female 11 ± 1, CIH female 12 ± 2,) and colocalization of FosB and NOS1 (CON male 10 ± 1 cells/section, CIH male 18 ± 4; CON female 5 ± 1, CIH female 6 ± 1) in the MnPO. CIH females (n = 3) did not demonstrate increases in the numbers of FosB positive cells or DBH positive neurons in the commissural nucleus tractus solitarius (CON 7 ± 2, CIH 8 ± 2), rostral ventrolateral medulla (CON 2 ± 1, CIH 3 ± 1), caudal ventrolateral medulla (CON 5 ± 1, CIH 6 ± 2), and area postrema (CON 2 ± 1, CIH 2 ± 1) compared to CON females (n = 2). These preliminary results suggests that CIH is associated with increased FosB staining in the autonomic regions of male rats as opposed to female rats which is consistent with our working hypothesis. In addition, CIH was associated with increased FosB staining in NOS1 positive MnPO neurons suggesting that they may play a role in the sustained hypertension reported in male rats. The research is funded by NIH grant RO1 HL155977 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.