ACTH response to a low dose but not a high dose of bacterial endotoxin in rats is completely mediated by corticotropin- releasing hormone

Karel Schotanus, Gábor B. Makar, Fred J.H. Tilders, Frank Berkenbosch

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22 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)300-307
Number of pages8
Issue number5
Publication statusPublished - Jan 1 1994


  • Adrenocorticotropic hormone
  • Corticosterone
  • Corticotropin-releasing hormone
  • Endotoxin
  • Hypothalamus lesions
  • Lipopolysaccharide
  • Passive immunization

ASJC Scopus subject areas

  • Immunology
  • Endocrinology
  • Neurology
  • Endocrine and Autonomic Systems

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