Atrial natriuretic peptides: the role of phenylalanine on biological activity.

Abstract:

:Previous studies have shown that atrial natriuretic peptides (ANPs) inhibit the secretion of aldosterone by isolated rat adrenal glomerulosa cells stimulated by angiotensin II, ACTH, and potassium. Structure-function studies have concentrated on the significance of the C- and N-terminal chains for the biological activity of the peptide. We investigated the role of phenylalanine at positions 8 and 26 by using [Ala8]human (h) ANP or [Ala26]hANP analogs to inhibit potassium-stimulated aldosterone secretion in granulosa cells. hANP-(1-28) inhibited potassium-stimulated aldosterone secretion with an IC50 of 0.48 nM. Synthetic [Ala26]hANP inhibited the aldosterone response to potassium with an inhibitory curve relative to hANP-(1-28) (rIC50) of 6.0 nM, which was significantly greater than that for hANP (P less than 0.001). Synthetic [Ala8]hANP was markedly less effective as an inhibitor, with an estimated rIC50 of 3.0 microM (P less than 0.0001). To determine whether the analogs act as competitive antagonists to hANP-(1-28), experiments were performed in which a fixed concentration (0.1 microM) of the analog was incubated in the presence of increasing concentrations of hANP-(1-28). When hANP-(1-28) was incubated with [Ala8]hANP, the rIC50 (0.2 nM) was significantly less than that for hANP-(1-28) alone (P less than 0.02). When hANP-(1-28) was incubated with [Ala26]hANP, the rIC50 was 0.1 nM. In summary, [Ala8]hANP and [Ala26]hANP were significantly less potent than hANP-(1-28) as inhibitors of aldosterone production from granulosa cells. Both analogs shifted the hANP-(1-28) dose-response curve to the left. Neither analog functioned as a competitive antagonist to hANP-(1-28). Our results indicate that the hydrophobic phenyl groups at these two positions are required for full biological potency of ANP as an inhibitor of aldosterone production.

journal_name

Endocrinology

journal_title

Endocrinology

authors

Craven TG,Kem DC,Schiebinger RJ

doi

10.1210/endo-122-3-826

subject

Has Abstract

pub_date

1988-03-01 00:00:00

pages

826-30

issue

3

eissn

0013-7227

issn

1945-7170

journal_volume

122

pub_type

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