In experimental animals and humans, bacterial endotoxin activates the hypo- thalamus-pituitary-adrenal (HPA) axis. The pathways by which endotoxin stimulates adrenocorticotropic hormone (ACTH) and corticosterone secretion are uncertain. In the present study we compared the role of hypothalamic cor-ticotropin-releasing hormone (CRH) in the activation of the HPA axis by a low (2.5 μg/kg) and a high (2.5 mg/kg) dose of bacterial endotoxin. Two exper-imental models were applied using chronically cannulated male Wistar rats. In the first model, rats were subjected to lesions of the hypothalamus that inter-rupted dorsal, lateral and frontal input to the median eminence (anterolateral deafferentation) or to sham operation and rats were used 7 days later. Before and at hourly intervals after endotoxin (2.5 μg/kg i.p.), blood samples were taken for the determination of plasma ACTH and corticosterone concentrations. Deafferentation of the hypothalamus strongly attenuated the elevations in plasma ACTH and corticosterone concentrations by a low dose of endotoxin compared to the responses in sham-operated animals. The second model involved passive immunization to CRH using a monoclonal antibody to rat/ human CRH (PFU83). PFU83 (90 nmol/rat) abolished the elevation of plasma ACTH concentrations and attenuated corticosterone responses to a low dose of endotoxin (2.5 μg/kg i.p.) compared to that in control IgG-treated rats. Since the corticosterone responses to endotoxin were less effectively inhibited by the antibody than the ACTH responses, we postulate that non-ACTH- dependent mechanisms may contribute to the corticosterone response to endotoxin. The same dose of PFU83 attenuated the endotoxin-induced ACTH responses to a high dose of endotoxin (2.5 mg/kg i.p.) by ± 45% but did not affect plasma corticosterone concentrations. We conclude that the ACTH responses to a low dose of endotoxin in rats are completely mediated by secretion of CRH from hypothalamic CRH-producing neurons that project to the median eminence, whereas the ACTH response induced by high doses of endotoxin is only partially dependent on CRH.
- Adrenocorticotropic hormone
- Corticotropin-releasing hormone
- Hypothalamus lesions
- Passive immunization
ASJC Scopus subject areas
- Endocrine and Autonomic Systems