Atrial natriuretic peptide in physiological doses does not inhibit the ACTH or cortisol response to corticotrophinreleasing hormone-41 in normal human subjects E.

Ur, M. Faria, S. Tsagarakis, J. V. Anderson, G. M. Besser and A. Grossman

Department of Endocrinology, St Bartholomew's Hospital, received

London

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26 March 1991

ABSTRACT

Whilst it has been postulated that atrial natriuretic peptide (ANP) may modulate pituitary hormone release, several investigations in non-human species have reported conflicting results when looking for an effect on the hypothalamo-pituitary-adrenal axis. However, in a recent study significant inhibition of corticotrophin-releasing hormone (CRH)-stimulated ACTH in cultured rat anterior pituitary cells occurred only with the complete peptide \g=a\-ANP(1\p=n-\28). We have therefore investigated whether this form of ANP can inhibit CRH-stimulated ACTH and cortisol release in human subjects. Six healthy male volunteers received human \g=a\-ANPor placebo, and human CRH or placebo, on four separate occasions. ANP was infused at a rate of 0\m=.\01\g=m\g/kgper min in order to achieve levels in the high physiological range. CRH was given as a bolus dose of 100 \g=m\g30 min into

the ANP infusion. Cortisol and ANP were measured by radioimmunoassay, the latter after extraction. ACTH was measured by immunoradiometric assay. The data were analysed by Student's paired t-test on basal, peak and incremental levels. Basal levels of ANP were within the normal range (2\p=n-\5pmol/l). With ANP infusion, mean \m=+-\s.e.m. peak ANP levels were 29\m=.\6\m=+-\ 3\m=.\1pmol/l.There were no significant differences in mean basal cortisol and ACTH levels on each of the 4 study days. Mean peak cortisol and ACTH levels after CRH and ANP did not significantly differ from those achieved with CRH and placebo ANP. We thus conclude that at high physiological doses, circulating ANP does not inhibit CRH-stimulated ACTH or cortisol release. Journal ofEndocrinology (1991) 131, 163\p=n-\167

INTRODUCTION

Skofitsch, Keiser et al. (1985), which suggest that nuclei involved in the regulation of anterior pituitary hormone secretion contain cells which are immunoreactive for ANP. ANP has been shown to be released from rat hypothalamic fragments by potassium depolarization (Shibasaki, Naruse, Naruse et al. 1986), to bind specifically to anterior pituitary cells (Quirion, Dalpe, De Lean et al. 1984) and to increase cyclic GMP (Abou Samra, Catt & Aguilera, 1987) and decrease cyclic AMP (Anand-Srivastava, Cantin & Genest, 1985) in the pituitary gland. Furthermore, under appropriate conditions, ANP and its analogues have been reported to inhibit the release of adrenocorticotrophic hormone (ACTH) stimulated by corticotrophin-releasing hormone-41 (CRH) (Antoni

Mammalian cardiac atria have been shown to elabor¬ ate peptides which exert profound renal and haemodynamic effects. A subgroup of these peptides has been shown to have significant natriuretic and diuretic activities; these have been termed atrial natriuretic peptides (ANPs). Molecular analysis of these peptides suggests that they are mostly derived from a common precursor. The human precursor molecule has 151 amino acid residues, while the predominant biologi¬ cally active peptide is made up of the 28 C-terminal amino acids of this molecule, ANP (1-28). Immunoreactive ANP-positive nerve fibres and cell bodies have been found to be widely distributed throughout the central nervous system. There is also evidence that ANP-containing neurones innervate the preoptic area, mesencephalon and hypothalamus of the rat (Zamir, Skofitsch, Eskay & Jacobowitz, 1986). Of particular interest are the findings of Jacobowitz,

&Dayanithi 1990).

Previous studies in human subjects have found inhibitory effect of ANP(99-126) on ACTH and cortisol responses to insulin-induced hypoglycaemia (Jungmann, Konzok, Holl et al. 1989) or no

angiotensin-stimulated aldosterone and ACTHstimulated cortisol responses (Cuneo, Espiner, Nicholls et al. 1987). We have examined in vivo the effect of an increase in circulating ANP concentrations on CRH-stimulated ACTH release in normal human volunteers, using an

(White, Smith, Hoadley et al. 1987). The sensi¬ of tivity the assay is 2-8 ng/1, with intra- and interassay coefficients of variation of 9 and 12% respectively. ANP was measured as previously described (Anderson, Christofides, Vinas et al. 1986). For a given subject, all

whether the inhibition of ACTH release observed in vitro has relevance to human physiology.

increments for ACTH and cortisol after bolus CRH with either placebo or active ANP. Unless otherwise stated, all values given are means ± s.e.m.. Significance is taken as

Atrial natriuretic peptide in physiological doses does not inhibit the ACTH or cortisol response to corticotrophin-releasing hormone-41 in normal human subjects.

Whilst it has been postulated that atrial natriuretic peptide (ANP) may modulate pituitary hormone release, several investigations in non-human specie...
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