Atriopeptin Inhibits Stimulated Secretion of Adrenocorticotropin in Rats: Evidence for a Pituitary Site of Action*

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Abstract
The aim of this study was to resolve previous controversies regarding the effect of atriopeptin on the secretion of ACTH in vivo. Male Wistar rats were used throughout. The animals were subjected to lesioning of the hypothalamic paraventricular nucleus (PVN) or sham operation and implanted with indwelling jugular cannulae 5 days later for blood sampling and drug infusion. Two days after the insertion of the cannulae the animals were treated with saline or 103-126 amino acid residue atriopeptin iv: a bolus injection was given (200 or 40 pmol/rat) followed by an infusion (40 or 8 pmol/min) which was maintained for the entire duration of the experiment (70 min). Ten minutes after the bolus of atriopeptin the animals received iv a combination of 1 pmol 41-residue CRF and 10 pmol arginine vasopressin (CRF/AVP) to stimulate ACTH secretion. Serial blood samples (0.1 ml) were obtained at -10 min and immediately before the injection of CRF/AVP and at 5, 10, 20, 30, and 60 min afterwards. Plasma ACTH concentration was measured by RIA. In sham-operated rats CRF/AVP caused a 4-fold increase in plasma ACTH which peaked at 5 min and returned to baseline by 60 min. In sham-operated rats the higher dose of atriopeptin (200 pmol bolus, 40 pmol/min infusion) did not alter the effect of the stimulus between 5 and 30 min, and augmented plasma ACTH at 60 min. The smaller dose of atriopeptin reduced plasma ACTH at 10 and 20 min by 54% and 48%, respectively, and also decreased by 48% the net amount of ACTH released over 30 min in response to CRF/AVP. When given alone, the higher dose of atriopeptin caused a persistent (60 min) 10-13% reduction of mean arterial blood pressure, while the lower dose decreased blood pressure by about 9% for less than 10 min. In parallel, the higher dose of atriopeptin increased plasma ACTH concentration while the lower dose produced no change. In PVN-lesioned rats the CRF/AVP induced ACTH response was similar to that seen in sham-operated controls. Only the higher dose of atriopeptin was tested, and this markedly reduced CRF/AVP stimulated ACTH secretion at 5-60 min after CRF/AVP. Given alone, atriopeptin had no marked effect on plasma ACTH in PVN-lesioned rats, while its hypotensive action was similar to that in sham-operated animals. It is concluded that: 1) Atriopeptin inhibits stimulated ACTH secretion in rats; 2) High systemic doses of atriopeptin that cause persistent hypotension release endogenous ACTH-releasing factors of paraventricular nucleus origin, and this may mask an inhibitory action of the peptide at the pituitary level; 3) Atriopeptin may function as a hypothalamic corticotropin release-inhibiting factor.

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