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Reduced Hypothalamic Vasopressin Secretion Underlies Attenuated Adrenocorticotropin Stress Responses in Pregnant Rats

Centre for Integrative Physiology (S.M., M.J.S., J.A.R.) School of Biomedical and Clinical Laboratory Sciences, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, Scotland EH8 9XD, United Kingdom; and Department of Pharmacology (D.M.), University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229-3900

Address all correspondence and requests for reprints to: Prof. John A Russell, Centre for Integrative Physiology, School of Biomedical and Clinical Laboratory Sciences, College of Medicine and Veterinary Medicine, Hugh Robson Building, George Square, Edinburgh, Scotland EH8 9XD, United Kingdom. E-mail: j.a.russell{at}ed.ac.uk.

We sought to explain decreased ACTH secretory responses to stress in pregnant rats by investigating hypothalamic CRH and vasopressin secretion and actions on anterior pituitary corticotrophs. In late pregnancy median eminence, CRH content was reduced (by 12%). Anterior pituitary proopiomelanocortin mRNA expression, measured by in situ hybridization but not radioimmunoassayed ACTH content, was also reduced (by 45% on d 21); CRH receptor (CRHR)1 mRNA expression was unaltered in pregnancy, but V1b receptor mRNA expression was reduced (by 19%). ACTH secretory responses, measured in jugular blood, to CRH (200 ng/kg iv) or vasopressin (1.7 µg/kg, iv) were reduced on d 21 vs. virgins (49% and 44%), but the response to combined CRH and vasopressin injection was intact. Either antalarmin (CRHR1 antagonist; 20 mg/kg ip) or dP(Tyr(Me)²),Arg-NH₂⁹)AVP (V1a/b antagonist; 10 µg/kg, iv) pretreatment reduced the ACTH secretory response to forced swimming (90 sec) in virgin rats (by 57% and 40%), but only antalarmin was effective in pregnant rats (53% decrease).

In vitro, measuring ACTH secretion from acutely dispersed anterior pituitary cells showed increased corticotroph sensitivity in pregnancy to CRH and to CRH augmentation by vasopressin, attributable to increased intracellular cAMP action. Hence, in late pregnancy, reduced anterior pituitary CRHR1 or V1b receptor expression did not impair corticotroph responses to CRH or vasopressin. Rather, diminished secretagogue secretion in vivo accounts for reduced action of stress levels of exogenous CRH or vasopressin alone; the late pregnancy attenuated ACTH secretory response to swim stress is deduced to be due to reduced vasopressin release by parvocellular paraventricular nuclei neurones.

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