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H Lefebvre

Publications and source records attributed to H Lefebvre.

At least 55 records · Page 3Linked to original sources
PubMed1993

Effect of the serotonin-4 receptor agonist zacopride on aldosterone secretion from the human adrenal cortex: in vivo and in vitro studies.

We have recently shown that serotonin (5-HT) stimulates cortisol secretion from human adrenocortical tissue in vitro through activation of 5-HT4 receptors. The aim of the present study was to investigate the effect of the 5-HT4 agonist racemic zacopride on aldosterone secretion from the human adrenal gland in vivo and in vitro. In vivo studies were conducted on 28 healthy volunteers pretreated with dexamethasone. The subjects received a single oral dose of placebo, 10 micrograms zacopride, or 400 micrograms zacopride. Plasma aldosterone levels increased significantly within 90 min after the administration of 400 micrograms zacopride, remained elevated for 60 min, and gradually returned to the baseline within 180 min. In contrast, the administration of 10 micrograms zacopride or placebo did not modify the aldosterone concentration. No significant changes were observed in renin, ACTH, or cortisol levels. In vitro studies were conducted on perifused human adrenocortical slices. Administration of 20-min pulses of zacopride (from 10(-11) - 10(-6) mol/L) induced a dose-dependent increase in aldosterone secretion. The minimal effective dose was 10(-10) mol/L, and half-maximal stimulation was obtained with a dose of 7 x 10(-8) mol/L. Zacopride was 100 times more potent in stimulating aldosterone than cortisol release. Taken together, the present data suggest that 5-HT-evoked aldosterone secretion involves the activation of 5-HT4 receptors.

Adolescent↗
PubMed1992

Serotonin-induced stimulation of cortisol secretion from human adrenocortical tissue is mediated through activation of a serotonin4 receptor subtype.

The occurrence of serotonin in the human adrenal gland was demonstrated both by immuno-histochemical and biochemical approaches. Using specific polyclonal antibodies to serotonin, the presence of numerous immunoreactive cells was revealed by means of the peroxidase-antiperoxidase technique. These cells exhibited the morphological characteristics of mast cells. Combination of high performance liquid chromatography and electrochemical detection showed the presence of substantial amounts of both serotonin and its metabolite 5-hydroxyindolacetic acid in adrenocortical extracts. The role of serotonin in the regulation of steroidogenesis from human adrenocortical slices was studied in vitro using a perifusion system technique coupled to a specific radioimmunoassay for cortisol. Graded doses of serotonin (from 10(-8) M to 3 x 10(-7) M) increased cortisol production in a dose-dependent manner. Prolonged exposure of adrenal fragments to serotonin (10(-7) M) induced a biphasic response, i.e. a rapid and transient increase in cortisol secretion followed by a plateau phase, suggesting the existence of a desensitization phenomenon. The stimulatory effect of serotonin (10(-7) M) was not altered during infusion of the serotonin1 and/or serotonin2 receptor antagonists methysergide (10(-6) M) and ketanserin (10(-6) M), respectively. In contrast, ICS 205 930 (10(-6) M), a non-selective serotonin3/serotonin4 antagonist, totally abolished the response of adrenal slices to serotonin (10(-7) M). The benzamide derivative zacopride, considered as a serotonin4 agonist, induced a robust stimulation of cortisol secretion. In addition, the corticotropic effects of serotonin (10(-7) M) and zacopride (10(-6) M) were not additive. Incubation of adrenocortical fragments with zacopride (10(-6) M) or serotonin (10(-6) M) caused a significant increase in cAMP formation. Taken together, these data suggest that serotonin, locally released by intra-adrenal mast-like cells, may act as a paracrine factor to stimulate cortisol secretion in man. Our results also indicate that serotonin-induced corticosteroid production is mediated through activation of a serotonin4 receptor subtype positively coupled to adenylate cyclase.

Adrenal Cortex↗
PubMed1992

Glucocorticoids, transmitters and stress.

Many kinds of stress stimulate the neuroendocrine systems controlling catecholamine and glucocorticoid secretion. Stress-induced stimulation of CRF-containing neurons appears to be mediated by serotonergic, noradrenergic, and possibly other neuronal pathways. Stress can alter various neurobiological and endocrine functions, two essential components of the neuroendocrine responses being release of adrenalin from chromaffin cells of the adrenal medulla and secretion of glucocorticoids from adrenocortical cells. Activation of adrenal steroid secretion is mainly by a reflex activation of hypothalamic neurons, which stimulate ACTH secretion from the anterior pituitary. While the neuropeptide CRF plays a major role in the neuroendocrine response to stress, the neuronal signals which are responsible for the regulation of CRF neurons have not been completely elucidated. A number of other regulatory substances may also participate, alone or with CRF, in the control of ACTH secretion by pituitary corticotrophs, and there is increasing evidence that classical neurotransmitters or neuropeptides may act directly on adrenocortical cells to modulate corticosteroid secretion. We review the neuronal, neuroendocrine, and humoral pathways which participate in the regulation of stress-induced corticosteroid secretion, and present preliminary data on the effect of the tricyclic antidepressant, tianeptine in the response of the HPA axis to stress.

Animals↗
PubMed1991

Benzamide derivatives provide evidence for the involvement of a 5-HT4 receptor type in the mechanism of action of serotonin in frog adrenocortical cells.

We have previously shown that serotonin (5-HT) is a potent stimulator of corticosterone and aldosterone secretion by frog adrenocortical cells and we have demonstrated that the action of 5-HT is not mediated by the classical 5-HT receptor subtypes i.e. 5-HT1, 5-HT2 and 5-HT3. Recently, a non-classical 5-HT receptor (termed 5-HT4) has been characterized using 4-amino-5-chloro-2-methoxy-benzamide derivatives as serotonergic agonists. In the present report, we have investigated the possible involvement of the 5-HT4 receptor subtype in the mechanism of action of 5-HT on steroid secretion. Increasing concentrations of benzamide derivatives (zacopride, cisapride and BRL 24924) gave rise to a dose-related stimulation of corticosteroid production, zacopride being the most potent compound of this series to enhance steroidogenesis. Prolonged administration (230 min) of zacopride induced a rapid increase in corticosterone and aldosterone output followed by a gradual decline of corticosteroid secretion. During prolonged exposure of adrenal tissue to zacopride (10(-5) M), the corticotropic activity of 5-HT (10(-6) M) was totally abolished. The stimulatory effects of 5-HT and zacopride were abolished by the non-selective 5-HT3 antagonist ICS 205 930. In contrast methysergide, a 5-HT1 receptor antagonist, and MDL 72222, a selective 5-HT3 antagonist did not block zacopride-induced corticosteroid secretion. Both 5-HT and zacopride induced a dose-related increase in cAMP production by frog adrenal slices. Taken together, these results indicate that the stimulatory effect of 5-HT on frog adrenocortical tissue is mediated by activation of a 5-HT4 receptor subtype positively coupled to adenylate cyclase.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1989

Mechanism of action of serotonin on frog adrenal cortex.

The mechanism of action of serotonin (5-HT) on frog adrenal cortex has been investigated in vitro using the perifusion system technique. The direct effect of 5-HT on corticosteroid secreting cells was demonstrated, using enzymatically dispersed adrenocortical cells. Melatonin and 5-HTP appeared to be less potent than 5-HT to enhance corticosteroid secretion. In contrast Trp and 5-HIAA were totally devoid of effect on steroid secretion. To investigate the type of receptor involved in the stimulatory effect of 5-HT on adrenocortical cells, adrenal slices were stimulated with 5-HT in absence or presence of various antagonists. We observed that classical antagonists of 5-HT1, 5-HT2 and 5-HT3 type receptors failed to block 5-HT-induced corticosteroid secretion in our model. These results show that 5-HT exerts a direct effect on corticosteroid-secreting cells. Our data also indicates that the type of receptor involved in the action of 5-HT in frog adrenal cortex differs from mammalian 5-HT receptors.

5-Hydroxytryptophan↗
PubMed1989

hCG test in gynaecomastia: further study.

In adult men referred with gynaecomastia, the prolonged plasma oestradiol (E2) response to hCG appears to be a useful tool in the diagnosis of feminizing Leydig cell tumour (LCT) of the testis. However, its specificity is uncertain. The hormonal status was therefore studied in 85 men with gynaecomastia including 17 with LCT, 52 with clinically isolated gynaecomastia and 16 hypogonadal men (13 with Klinefelter's syndrome and three with hypogonadotrophic hypogonadism). The data obtained after hCG (5000 IU i.m., n = 85) or GnRH (100 micrograms i.v., n = 70) administration were compared to those of a group of control men. Means of basal gonadotrophin and of gonadotrophin responses to GnRH were similar in LCT and controls but were significantly (P less than 0.001) higher than controls in patients with either Klinefelter's syndrome or isolated gynaecomastia. Half the patients with isolated gynaecomastia had normal gonadotrophin parameters (NGG) while half had significantly (P less than 0.001) higher levels (EGG) than controls, suggesting either primary testicular failure or androgen resistance. The T responses to hCG did not differentiate patients with LCT from either isolated gynaecomastia or controls. A prolonged E2 response (greater than 300 pmol/l on day 3 following hCG) was observed in all patients with LCT, in 10/21 EGG patients and in 3/13 patients with Klinefelter's syndrome. Such a response was observed in only one NGG patient. We conclude that a prolonged E2 response to hCG does not appear to be specific to LCT but that specificity is greatly improved (from 80 to 98%) when the gonadotrophin pattern (basal and/or responses to GnRH) is also taken into account.

Adolescent↗
PubMed1989

Identification of vasotocin-like immunoreactivity in chromaffin cells of the frog adrenal gland: effect of vasotocin on corticosteroid secretion.

The presence of neurohypophyseal nonapeptides in the adrenal gland of nonmammalian vertebrates and the possible action of these regulatory peptides on corticosteroid secretion have never been investigated. We have applied the indirect immunofluorescence technique to examine whether vasotocin (AVT) and/or mesotocin (MT) are located in frog adrenal (interrenal) tissue. Using antisera against AVT and tyrosine hydroxylase, we found that all chromaffin cells contain an AVT-like peptide. Labeling of consecutive sections with phenylethanolamine-N-methyltransferase or AVT antibodies showed that both noradrenaline- and adrenaline-storing cells contain AVT-like immunoreactivity. In contrast no labeling of frog adrenal slices was observed using a MT antiserum. At the ultrastructural level, the immunogold technique revealed that the AVT-immunoreactive peptide is sequestered in chromaffin granules with varying electron densities. Filtration of frog adrenal tissue extracts on Sep-Pak C-18 cartridges showed that the elution profile of the AVT-like peptide was similar to that of synthetic AVT. The apparent concentration of AVT in the adrenal was 2.7 ng/g tissue. Since chromaffin cells represent approximately one third of all interrenal cells, the actual concentration of AVT in chromaffin tissue was about 8 ng/g tissue. The role of AVT in the regulation of frog adrenal steroidogenesis was studied in vitro using perifused frog interrenal slices. Graded doses of AVT (10(-10)-10(-7) M) induced a dose-dependent stimulation of both corticosterone and aldosterone secretion. The other neurohypophyseal peptides (vasopressin, oxytocin, and MT) were also able to enhance corticosteroid secretion, but AVT was by far the most potent stimulator of steroidogenesis. Prolonged administration (4 h) of AVT induced a rapid increase in corticosterone and aldosterone output, followed by a gradual decline of corticosteroid secretion. These results show that an AVT-like peptide is stored in chromaffin granules of frog adrenal gland. Our data also indicate that synthetic AVT is a potent stimulator of corticosteroid secretion by frog interrenal cells. Since in amphibians adrenocortical and chromaffin cells are intimately intermingled, these results suggest that AVT produced by chromaffin cells may regulate corticosteroid release locally, through a cell to cell mode of communication.

Adrenal Cortex↗
PubMed1988

Serotonin stimulates corticosteroid secretion by frog adrenocortical tissue in vitro.

The mode of action of serotonin (5-HT) in the regulation of frog adrenal steroidogenesis was studied in vitro using the perifusion system technique. Graded doses of 5-HT (from 10(-8) to 10(-6) M) increased both corticosterone and aldosterone production in a dose-dependent manner. Short pulses (20 min) of 10(-6) M 5-HT, administered at 130 min intervals within the same experiment, did not cause any desensitization phenomenon. Indomethacin (IDM; 5 microM), a cyclooxygenase inhibitor which induced a dramatic decrease in the spontaneous secretion of corticosteroids, did not impair the stimulatory effect of 5-HT on corticosterone and aldosterone production. In the absence of calcium, 5-HT (10(-6) M) was still able to stimulate corticosteroid production. Dantrolene (5 x 10(-5) M), a blocker of calcium mobilization from intracellular pools which significantly inhibited the spontaneous production of corticosteroids, did not suppress 5-HT-evoked corticosteroid secretion. These results show that 5-HT, stored in adrenal chromaffin cells, may act as a paracrine factor to stimulate adrenal steroidogenesis in the frog. Our data also indicate that the mechanism of action of 5-HT does not depend on prostaglandin biosynthesis.

6-Ketoprostaglandin F1 alpha↗
PubMedDate not supplied

Serotonergic regulation of adrenocortical function.

Serotonin (5-HT) plays a pivotal role in the regulation of the hypothalamo-pituitary-adrenal axis. In particular, 5-HT is involved in the stimulation of ACTH secretion during stress. Recent data indicate that, at the adrenal level, 5-HT acts as a local regulator of corticosteroid secretion. The presence of 5-HT in the adrenal gland has been demonstrated immunohistochemically and biochemically in various species including frog, mouse, rat and human. In the mouse, 5-HT has been detected in nerve fibers while, in the frog and rat, 5-HT appears to be sequestered in chromaffin cells. In man, 5-HT is stored in perivascular mast cells. In vivo and in vitro studies have shown that 5-HT stimulates mineralo- and glucocorticoid secretion from adrenal cells. In rat, the type of receptor involved in the corticotropic effect of 5-HT is still controversial. In the frog and the human, the effect of 5-HT on the adrenal cortex is mediated through a 5-HT4 receptor subtype positively coupled to adenylyl cyclase and calcium influx. Clinical studies indicate that 5-HT4 receptor agonists stimulate aldosterone secretion in healthy volunteers and in patients with aldosterone disorders. The 5-HT4 receptor agonist cisapride and angiotensin II exert additive effects on aldosterone secretion. In contrast, cisapride has no influence on ACTH-induced aldosterone release. Collectively, these findings suggest that intra-adrenal 5-HT stimulates the secretory activity of adrenocortical cells through a paracrine mode of communication involving a 5-HT4 receptor type. Serotonergic control of corticosteroid production may be involved in the physiological control of the activity of the adrenal cortex, in particular during inflammatory stress. 5-HT may also be implicated in the pathophysiology of aldosterone disorders.

Adrenal Cortex↗
PubMedDate not supplied

A hCG-secreting testicular seminoma revealed by male infertility: mechanism of hCG-evoked endocrine disturbances.

We report a case of a hCG-producing testicular seminoma revealed by a male infertility due to oligozoospermia. No palpable tumour was found at clinical examination and the diagnosis was established on hormonal data and the echography of the testis. The endocrine patterns associated high levels of beta-hCG and 17 beta-oestradiol contrasting with low levels of LH and FSH and normal levels of testosterone. Immunohistochemical studies confirmed the ectopic production of hCG. Histological findings and the evolution of hormonal parameters suggested that hyperoestradiolaemia was probably the consequence of a hCG-evoked Leydig cells hyperplasia involving a paracrine mechanism. In fact, after removal of the tumour, a dramatic decrease of plasma sex steroid levels was observed before recovery of normal testicular endocrine and exocrine functions.

Adult↗
PubMedDate not supplied

Pharmacological profile of serotonergic receptors in the adrenal gland.

The secretory activity of the adrenal gland is mainly regulated by peptidergic hormones (ACTH, angiotensin II) and ions. However, there is now increasing evidence that local factors, including neuropeptides and neurotransmitters, can also participate in the control of adrenocortical cells. In particular, serotonin (5-HT), produced by adrenochromaffin cells in frog and rat as well as by mast cells in the adrenal gland of rat and human, stimulates corticosteroid secretion. In both frog and human adrenal gland, the benzamide derivative (R,S)-zacopride induces a robust increase in corticosteroid release suggesting that the effect of 5-HT on steroidogenesis is mediated through activation of 5-HT4 receptors. In contrast, in rat, the stimulatory effect of 5-HT on aldosterone secretion is clearly not mediated by 5-HT4 receptors. In all three species, incubation of adrenocortical fragments with 5-HT induces a significant increase in cAMP formation. Our data suggest that 5-HT, released within the adrenal cortex, may act as a paracrine factor to stimulate steroid secretion. Although the corticotropic effect of 5-HT has been conserved from amphibians to primates, the type of receptors involved in the action of 5-HT markedly differs across species.

Adrenal Cortex Hormones↗
PubMedDate not supplied

Effect of prolonged administration of the serotonin4 (5-HT4) receptor agonist cisapride on aldosterone secretion in healthy volunteers.

In man, serotonin (5-HT) has been shown to stimulate aldosterone secretion through activation of 5-HT4 receptors, In particular, we have observed that oral administration of a single dose of the 5-HT4 receptor agonist cisapride (10 mg) induces a 5-fold increase in plasma aldosterone levels in healthy volunteers. Surprisingly, the usual disorders associated with hyperaldosteronism, i.e. hypertension and hypokalemia, have never been reported during chronic treatment with cisapride. In the present study, we have investigated the effect of prolonged oral administration of cisapride (10 mg, 3 times/day during 7 days) on aldosterone secretion in 12 healthy volunteers, in a simple blind fashion versus placebo. On day 1 of the treatment, cisapride induced a significant increase in plasma aldosterone levels (PAL) which returned to the values observed after placebo treatment within 10 hrs. On days 2 and 3, PAL were similar in cisapride- and placebo-treated subjects. Urinary aldosterone, kalemia and reninemia were not influenced by cisapride during the 7 days of the treatment. The present study shows that cisapride only exerts a transient stimulatory effect on aldosterone secretion in healthy volunteers. These data explain why long-term administration of 5-HT4 agonists does not affect blood pressure in man. They also indicate that prolonged stimulation of adrenal 5-HT4 receptors in vivo yields to a rapid desensitization phenomenon, as previously observed in vitro.

Aldosterone↗