PubMed · 14360608
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A PUCK, C SIEVERT. 1954. [Adrenal cortex function and laparotomy].. https://pubmed.ncbi.nlm.nih.gov/14360608/
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Racemic 2-O-[4'(9''-N-purinyl)butyl] myo-inositol 1,4,5-tris(phosphate) 8 was synthesized starting from myo-inositol. Substitution of position 2 by an alkyl side chain was rendered possible by inversion of the chair conformation of the inositol ring by means of an orthoester. The final compound is a full agonist with the same order of potency as d-myo-inositol 1,4,5-tris(phosphate).
To study the effects of decreased amounts or absence of aldosterone on development and endocrine function, we have disrupted the mouse gene, Cyp11b2, coding for aldosterone synthase (AS) by replacing its first two exons with sequences coding for enhanced green fluorescent protein. The null pups fail to thrive postnatally, and about 30% die between d 7 and 28. Aldosterone in plasma and AS mRNA in adrenal glands are undetectable in the null mice. Adult AS-null mice are small, weigh 75% of wild type, are hypotensive, have increased concentrations of plasma K(+) and corticosterone, and a decreased concentration of plasma Cl(-). Their plasma renin and angiotensin II concentrations are 45x and 4x wild type. The adrenal cortex is disorganized and has cells that contain marked accumulations of lipid. The zona glomerulosa is widened and includes easily detectable renin-containing cells, not seen in the wild-type adrenal gland. In the AS-/- adrenals, the level of mRNA for Cyp11b1, coding for 11beta-hydroxylase, is 150% wild type. The adrenal glands of the null mice consequently show evidence of a greatly activated renin-angiotensin system and up-regulation of glucocorticoid production. In the AS-null mice enhanced green fluorescent protein fluorescence is mainly at the boundary between the cortex and medulla, where apoptotic cells are numerous. These data are consistent with the absence of aldosterone in the AS-null mice inducing an increased cell-turnover of cells in the adrenals that normally become AS expressing and their migration to the medullary boundary where they apoptose.
CONTEXT: Cortisol secretion is usually under the control of ACTH. However, cortisol secretion occurs in response to gastric inhibitory polypeptide (GIP) in rare cases of food-dependent Cushing's syndrome (CS). OBJECTIVE: We have investigated whether chronic ACTH stimulation or activation of the ACTH signaling pathway might be associated with GIP receptor (GIPR) expression. DESIGN: RT-PCR analysis and primary culture of hyperplastic adrenals. PATIENTS: All patients presented with CS: 20 unilateral adrenal adenomas, five Cushing's disease, one food-dependent CS. RESULTS: RT-PCR revealed GIPR expression in all hyperplastic adrenals studied. No RT-PCR product could be detected in two normal adrenals or 20 hyperfunctioning adrenal adenomas. Primary culture revealed a significant cAMP response to ACTH in all adrenals available for study (EC50, 8.1 x 10(-10) M in normals, 4.7 x 10(-10) M in Cushing's disease, and 4.4 x 10(-10) M in food-dependent disease). However, cultures taken from all four ACTH-dependent and the one food-dependent hyperplastic adrenals studied were also responsive to GIP (EC50 for cAMP, 1.3 x 10(-9) M in Cushing's disease and 4.1 x 10(-10) M in food-dependent disease). Fasting cortisol levels were low in the case of food-dependant Cushing's, rising postprandially as predicted. However, there was no trend toward low fasting or high postprandial cortisol in the other cases, suggesting that the presence of detectable GIPR alone, albeit with definite function in vitro, is not sufficient to cause clinically food-dependent CS. CONCLUSIONS: These data are consistent with the hypothesis that chronic ACTH stimulation or constitutive activation of the ACTH signaling pathway may be associated with aberrant GIPR expression, and suggest one mechanism for the pathogenesis of this phenomenon.