An Anomalous Effect of Theophylline on ACTH and Adenosine 3',5'-Monophosphate Stimulation.

Halkerston, I. D. K.; Feinstein, Maurice B.; Hechter, Oscar

doi:10.3181/00379727-122-31283

Cited by 40 publications

(16 citation statements)

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“…1). This agrees qualitatively with the previous findings of Halkerston et al (1966), who demonstrated that 1 mM theophylline enhanced ACTH stimulation of adrenal steroidogenesis by protection of the cAMP formed intracellularly, and that 10mM theophylline inhibited it by means of partial inhibition of protein synthesis.…”

Section: Discussionsupporting

confidence: 93%

Gonadotropic effects of cholera enterotoxin in the rat testis slices: Stimulation of adenylate cyclase activity and testosterone synthesis from cholesterol.

Sato

Ohsawa

1977

Endocrinol Japon

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SynopsisThe effects of cholera enterotoxin (CET) on the male gonad was investigated using testis slices of the rat.CET stimulated adenylate cyclase activity of the interstitial tissue of the rat testis, increased cyclic AMP (cAMP) production and testosterone release from the interstitial tissue in vitro, thus mimicking effects of LH and human chorionic gonadotropin (hCG). CET also stimulated adenylate cyclase activity of the seminiferous tubules and increased cAMP production, whereas hCG did not exhibit such an effect.The stimulatory effect of CET on adenylate cyclase activity of the rat testis occurred with a lag time of about 30 min, reached the maximum level after 2-hr incubation and continued over 6 hr. Testosterone release by CET was observed within 1-to 2-hr incubation, when the increase in cAMP was already demonstrated.The steroidogenic effect of CET was enhanced at low concentration (1 mM) of theophylline and inhibited at high concentration (20mM) of theophylline. Protein synthesis inhibitors (puromycin and cycloheximide) abolished these steroidogenic effect completely, but not cAMP production.Tracer studies of active site(s) of CET in testicular steroidogenesis revealed that the stimulation of testosterone synthesis by CET was, like hCG, due to the stimulation of the conversion of cholesterol to testosterone.These results suggest that CET stimulates the adenylate cyclase/cAMP system of the interstitial tissue (probably of Leydig cells) and stimulates testosterone synthesis from cholesterol, and that once the adenylate cyclase of Leydig cells has been stimulated, the biosynthetic pathway leading to testosterone is quite similar to that caused by gonadotropins (LH and hCG), although the activation mechanism of adenylate cyclase seems to be different each other.

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Section: Discussionsupporting

confidence: 93%

Gonadotropic effects of cholera enterotoxin in the rat testis slices: Stimulation of adenylate cyclase activity and testosterone synthesis from cholesterol.

Sato

Ohsawa

1977

Endocrinol Japon

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“…Nevertheless, some discrepancies exist. Halkerston et al (1966) reported theophylline (10 mM) to have two antagonistic adrenal actions, a small potentiation of ACTH simulated steroidogenesis, and inhibition of such in addition to inhibition of protein synthesis. Further, theophylline (Bieck et al 1969) and caffeine (Kitabchi et al 1971) have antagonistic effects upon ACTH and cAMP stimulated steroidogenesis.…”

Section: Discussionmentioning

confidence: 99%

IN VITRO EFFECTS OF THEOPHYLLINE AND AMINOGLUTHETIMIDE UPON BASAL AND ACTH INDUCED cAMP LEVELS AND STEROID OUTPUT BY THE NORMAL HUMAN ADRENAL GLAND

Honn¹,

Chavin

1978

Acta Endocrinologica

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The in vitro effects of theophylline and aminogluthetimide upon basal and ACTH stimulated cAMP, cortisol and aldosterone responses of normal human adrenocortical tissue were evaluated. Theophylline increased basal cAMP levels and cortisol output, however, basal aldosterone output was depressed. Theophylline in concert with ACTH depressed cortisol and aldosterone output. Aminogluthetimide alone did not affect basal cAMP levels, however, the normal cAMP response to ACTH was delayed in aminogluthetimide pre-treated adrenals. Aminogluthetimide also depressed basal and ACTH stimulated cortisol and aldosterone output with the latter being more sensitive. The findings indicate that both theophylline and aminogluthetimide produce effects upon the adrenal in addition to inhibition of phosphodiesterase and cholesterol side-chain cleavage, respectively. Further, theophylline depression of ACTH stimulated steroid output may be helpful in understanding the interplay between a number of factors in the control of adrenal steroid biosynthesis and release. Numerous inhibitory drugs have been employed to help elucidate the mecha¬ nism of ACTH action upon adrenocortical tissue. Two commonly used drugs in this regard are theophylline, a phosphodiesterase inhibitor (Halkerston 1975), and aminogluthetimide, a competitive inhibitor of adrenal cholesterol side chain cleavage activity (Kahnt

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“…In addition to the substances listed in the preceding paper [l 1, neurotensin, substance P, Leu-enkephalin and Leu" human gastrin I (with leucine at residue 15) were purchased from Beckman and synthetic somatostatin from Serono. Synthetic octapeptide of cholecystokinin was generously supplied by M. Ondetti (Squibb) and bovine pancreatic peptide by R. E. Chance (Lilly).…”

Section: Methodsmentioning

confidence: 99%

“…lowering the magnitude of the vasoactive intestinal peptide stimulation. Furthermore, high concentrations of methylxanthine derivatives are known to induce undesirable side effects on other enzyme activities [14] or on protein synthesis [15].…”

Section: Effect Of Time Temperature Phosphodiesterase Inhibitor Andmentioning

confidence: 99%

Interaction of Vasoactive Intestinal Peptide with Isolated Intestinal Epithelial Cells from Rat

Laburthe

Amiranoff

et al. 1979

European Journal of Biochemistry

132

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Porcine vasoactive intestinal peptide stimulated adenosine 3' : 5'-monophosphate (cyclic AMP) production in rat intestinal epithelial cells. The stimulation was dependent on time and temperature and was potentiated by the phosphodiesterase inhibitor 3-isobutyl-1 -methylxanthine. Under optimal conditions (at 15 "C, with 0.2 mM 3-isobutyl-l-methylxanthine, at a cell concentration up to 18 pg DNA/ml), the cyclic AMP production produced by vasoactive intestinal peptide was constant for 10 min and stopped after 15 min incubation, at either low (1 nM) or high (30 nM) concentration of the peptide. This plateau effect was demonstrated not to be due to an inactivation of vasoactive intestinal peptide in the medium nor to an alteration of receptors for the peptide. Cyclic AMP production was sensitive to a concentration as low as 0.1 nM vasoactive intestinal peptide. Maximal stimulation of cyclic AMP levels by vasoactive intestinal peptide was observed with 30 nM vasoactive intestinal peptide and represented an 1 1-fold increase above basal. The dose-response curve was monophasic with a K , of 2.3 x lo-' M. No cooperative effects were detected by Hill analysis. The positive non-linear relationship observed between stimulation of cyclic AMP production and occupancy of binding sites was not time-dependent as indicated by experiments performed after 15, 45 and 120 min incubation. Maximal and half-maximal responses were obtained at about 70% and 7 % occupation of binding sites, respectively.Chicken vasoactive intestinal peptide and porcine secretin were agonists of porcine vasoactive intestinal peptide with a 6-times higher and a 120-times lower potency, respectively. Among secretin analogs that were found to have low affinity for vasoactive intestinal peptide binding sites, [Calanine,secretin, that resembles vasoactive intestinal peptide at the first seven amino acids at the N-terminal end, was a partial agonist of vasoactive intestinal peptide and others failed to stimulate cyclic AMP production. Glucagon (10 pM), gastric inhibitory peptide (0.1 pM), substance P, neurotensin, octapeptide of cholecystokinin, bovine pancreatic polypeptide, human gastrin I with leucine at residue 15, Leu-enkephalin and somatostatin (1 pM) did not alter cyclic AMP levels. Non-peptide mediators such as dopamine, serotonin, acetylcholine and histamine, tested at 10 pM, were also ineffective. Prostaglandins Ez, El and isoproterenol, tested at 10 pM, induced an increase of cyclic AMP levels above basal but were 9.5, 13.7 and 17.5 times less efficient than vasoactive intestinal peptide, respectively. Thus vasoactive intestinal peptide is a unique stimulus of cyclic AMP production in rat intestinal epithelial cells.

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An Anomalous Effect of Theophylline on ACTH and Adenosine 3',5'-Monophosphate Stimulation.

Cited by 40 publications

References 0 publications

Gonadotropic effects of cholera enterotoxin in the rat testis slices: Stimulation of adenylate cyclase activity and testosterone synthesis from cholesterol.

Gonadotropic effects of cholera enterotoxin in the rat testis slices: Stimulation of adenylate cyclase activity and testosterone synthesis from cholesterol.

IN VITRO EFFECTS OF THEOPHYLLINE AND AMINOGLUTHETIMIDE UPON BASAL AND ACTH INDUCED cAMP LEVELS AND STEROID OUTPUT BY THE NORMAL HUMAN ADRENAL GLAND

Interaction of Vasoactive Intestinal Peptide with Isolated Intestinal Epithelial Cells from Rat

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