Sex Differences In the PVN Orexin Mediated Sympathoexcitatory and Pressor Responses

The orexin system, through activation of its receptors, plays a critical role in regulating multiple physiological functions, including the sleep–wake cycle, feeding behavior, neuroendocrine and stress responses, and reward-seeking behavior. In addition, orexins modulate cardiovascular function via their excitatory actions on neurons within the hypothalamic paraventricular nucleus (PVN). Despite or this, the intracellular mechanisms underlying orexin-mediated cardiovascular regulation remain poorly understood. In this study, we tested the hypothesis that hyperactivity of orexin system in the PVN enhances neuronal activity, leading to sympathoexcitatory and pressor responses via activation of the ERK1/2 signaling pathway, and investigated the sex difference of Orexin mediated sympathoexcitatory responses. Adult male and female Sprague–Dawley rats received bilateral PVN injections of orexin A (OXA) (25 pmol/side), after which mean arterial pressure (MAP), heart rate (HR), and renal sympathetic nerve activity (RSNA) were recorded. To assess the role of ERK1/2 signaling, a subset of animals received PVN pretreatment with the ERK1/2 inhibitor PD98059 (20 mg/side), prior to OXA administration, then their MAP, HR and RSNA were measured. The results showed that PVN microinjection of OXA significantly increased MAP, HR, and RSNA in both males and females. No significant sex differences were observed in the pressor response (males: n = 5, 16.30 ± 2.73 mmHg; females: n = 8, 17.63 ± 2.24 mmHg; p = 0.7178) or heart rate response (males: 12.20 ± 9.16 bpm; females: 12.88 ± 7.66 bpm; p = 0.9565). In contrast, females exhibited a significantly greater RSNA response to OXA compared with males (males: n = 5, 84.82 ± 8.30%; females: n = 6, 296.8 ± 82.34%; p = 0.0227). Pretreatment with PD98059 significantly attenuated the RSNA response to OXA in both males (n = 6, 39.42 ± 8.26%; p = 0.0039) and females (n = 5, 42.15 ± 7.81%; p = 0.0105) relative to OXA alone, abolishing the sex difference in sympathetic activation. However, despite similar RSNA attenuation, females displayed a significantly smaller MAP increase following OXA + PD98059 pretreatment (n = 6, 4.33 ± 0.99 mmHg; p = 0.0007) compared with males (n = 7, 14.39 ± 2.01 mmHg). These findings indicate that ERK1/2 signaling in the PVN is a central mechanism underlying orexin A–induced sympathoexcitatory responses in both sexes. Although orexin A elicits similar increases in MAP and HR in males and females, sex-specific differences in sympathoexcitatory and pressor responses emerge following ERK1/2 inhibition. Further studies are needed to define the downstream signaling mechanisms responsible for this sex-dependent modulation of cardiovascular responses. Funding: NIHR15HL122952 and NIHR01HL163159. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.