The rapid release of corticosterone from the adrenal induced by ACTH is mediated by nitric oxide acting by prostaglandin E2

doi:10.1073/pnas.0502136102

The rapid release of corticosterone from the adrenal induced by ACTH is mediated by nitric oxide acting by prostaglandin E₂

^*Centro de Estudios Farmacológicos y Botánicos, Consejo Nacional de Investigaciones Científicas y Técnicas, Serrano 669, 1414 Buenos Aires, Argentina; ^†Department of Physiology, Dental School, University of Buenos Aires, 1122 Buenos Aires, Argentina; ^‡Department of Medicine, Faculty of Anatomy, University of Dresden, 01307 Dresden, Germany; and ^§Department of Medicine, Faculty of Endocrinology, Diabetes, and Metabolism, University of Dresden, 01307 Dresden, Germany

Contributed by Samuel M. McCann, March 16, 2005

Abstract

The adrenal cortex is a major stress organ in mammals that reacts rapidly to a multitude of external and internal stressors. Adrenocorticotropin (ACTH) is the main stimulator of the adrenal cortex, activating corticosteroid synthesis and secretion. We evaluated the mechanism of action of ACTH on adrenals of male rats, preserving the architecture of the gland in vitro. We demonstrated that both sodium nitroprusside (NP), a nitric oxide (NO) donor, and ACTH stimulate corticosterone release. NO mediated the acute response to ACTH because Nω-nitro-l-arginine methyl ester, a NO synthase inhibitor, and hemoglobin, a NO scavenger, blocked the stimulation of corticosterone release induced by ACTH. NP stimulated prostaglandin E release, which in turn stimulated corticosterone release from the adrenal. Additionally, indomethacin, which inhibits cyclooxygenase, and thereby, prostaglandin release, prevented corticosterone release from the adrenal induced by both NP and ACTH, demonstrating that prostaglandins mediate acute corticosterone release. Corticosterone content in adrenals after incubation with ACTH or NP was lower than in control glands, indicating that any de novo synthesis of corticosterone during this period was not sufficient to keep up with the release of the stored hormone. The release induced by ACTH or NP depleted the corticosterone content in the adrenal by ≈40% compared with the content of glands incubated in buffer. The mechanism of rapid release is as follows: NO produced by NO synthase activation by ACTH activates cyclooxygenase, which generates PGE₂, which in turn releases corticosterone stored in microvesicles and other organelles.

Footnotes

↵ ¶ To whom correspondence should be addressed. E-mail: vrettori{at}yahoo.com.
Author contributions: C.E.M., S.M.M., and V.R. designed research; J.F.-S., A.D.L., J.P.P., C.d.l.C., R.F., and S.R.B. performed research; C.E.M., S.R.B., S.M.M., and V.R. analyzed data; and C.E.M., S.R.B., S.M.M., and V.R. wrote the paper.
Abbreviations: ACTH, adrenocorticotropin; AG, adrenal gland; NP, sodium nitroprusside;l-NAME, Nω-nitro-l-arginine methyl ester; NOS, NO synthase; Hb, hemoglobin; COX, cyclooxygenase; Indo, indomethacin; PG, prostaglandin; mbcAMP, N⁶-monobutyryladenosine 3′,5′cyclic monophosphate (sodium salt); FRSK, forskolin; StAR, steroidogenic acute regulatory protein; AA, arachidonic acid.