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Biomedical subjects

H Lefebvre

Publications and source records attributed to H Lefebvre.

At least 37 records · Page 2Linked to original sources
PubMed1998

[Adrenal insufficiency].

Adrenal insufficiency can be either primitive as the result of a destruction of the glands or secondary to a corticotropic failure. Adrenal insufficiency can appear as an acute event or in contrast arise progressively. An acute adrenal insufficiency can occur any time and threatens the vital prognosis. It should be prevented by adapted treatment and education of the patient. The treatment of adrenal insufficiency includes substitutive doses of mineralo and/or glucocorticoids and, as often as possible, etiologic therapy. For this reason, as soon as the diagnosis of adrenal insufficiency has been done, a main point is to determine the cause of the endocrine failure. Indeed, some diseases responsible for adrenal deficiency, among a progressively extending list of etiologic factors, can benefit for a specific treatment.

Acute Disease↗
PubMed1997

Effect of the serotonin 5-HT4 receptor agonist cisapride on aldosterone secretion in corticotropic insufficiency and primary hyperaldosteronism.

Serotonin (5-HT) stimulates aldosterone secretion in man through activation of 5-HT4 receptors coupled to adenylyl cyclase via a Gs regulatory protein. In adrenocortical cells, the levels of expression of the Gs protein and ACTH receptor are decreased when the cells are deprived of ACTH and angiotensin II (ANG II). In order to examine the possible influence of ACTH and ANG II on the responsiveness of human glomerulosa cells to 5-HT, we have investigated the effect of cisapride, a 5-HT4 receptor agonist, on plasma aldosterone in patients with suppressed plasma ACTH, i.e. patients with corticotropic insufficiency (CI), and in patients with suppressed renin-ANG II activity, i.e. patients with primary hyperaldosteronism (PH) including both aldosterone-producing adenoma and idiopathic hyperaldosteronism. After 2 h of recumbency, all patients received a single oral dose of 10 mg cisapride. In the CI group, cisapride induced a 5-fold increase in plasma aldosterone levels without any modification of plasma renin, potassium or cortisol levels. Combined administration of cisapride and ACTH caused an increase in plasma aldosterone similar to that produced by ACTH alone. In the PH group, cisapride was still able to cause a 3.6-fold increase in plasma aldosterone levels while renin remained suppressed throughout the study. Taken together, these data show that cisapride stimulates aldosterone secretion in CI and PH patients, indicating that prolonged suppression of plasma ACTH or renin-ANG II activity does not affect the sensitivity of glomerulosa cells to 5-HT. The present study also demonstrates that the stimulatory effects of 5-HT and ACTH on aldosterone secretion are not additive.

Adrenocorticotropic Hormone↗
PubMed1996

Lack of effect of the serotonin4 receptor agonist zacopride on ACTH secretion in normal men.

OBJECTIVE: In the present study, we investigated the effect of zacopride on corticotropin (ACTH) and cortisol secretion in healthy volunteers. Male subjects received a single oral dose of placebo, 10 micrograms zaco-pride or 400 micrograms zacopride. Plasma ACTH, cortisol and aldosterone concentrations were measured before and during the 3 h following the administration of the drug. RESULTS: For none of the doses did zacopride cause any modification of plasma ACTH or cortisol levels. In contrast, administration of 400 micrograms zacopride induced a significant increase in plasma aldosterone levels. CONCLUSION: Our results indicate that in humans serotonin-evoked stimulation of ACTH secretion is not mediated through serotonin4 (5-HT4) receptors. Together with previous findings, these data indicate that the stimulatory effect of 5-HT4 receptor agonists on aldosterone secretion in man can be ascribed solely to a direct action on glomerulosa cells.

Adolescent↗
PubMed1996

Activation of 5-hydroxytryptamine4 receptors causes calcium influx in adrenocortical cells: involvement of calcium in 5-hydroxytryptamine-induced steroid secretion.

5-Hydroxytryptamine (5-HT) stimulates corticosteroid secretion from adrenal cells through activation of 5-HT4 receptors positively coupled to adenylyl-cyclase. In the present study, we investigated in frog adrenocortical cells the effect of 5-HT4 receptor agonists on cytosolic calcium concentration ([Ca2+]i) and determined the sequence of events associated with 5-HT4 receptor agonist zacopride (10[-8] to 10[-5]M each in the vicinity of cultured adrenocortical cells caused a dose-dependent increase in [Ca2+]i. Preincubation of the cells with the selective 5-HT4 receptor antagonist [1-[2-(methylsulfonylamino)ethyl]-4- piperidinyl]methyl-1-methyl-1H-indole-3-carboxylate maleate totally blocked the 5-HT-induced stimulation of [Ca2+]i. Chelation of extracellular calcium with ethylene glycol bis (beta-aminoethyl ether)-N,N,N', N'-tetraacetic acid (10 MM) suppressed the stimulatory effect of 5-HT on [Ca2+]i. Conversely, thapsigargin, an inhibitor of calcium ATPase activity, had no effect on the [Ca2+]i rise. The calcium influx induced by 5-HT4 receptor agonists was not affected by nifedipine and omega-conotoxin GVIA but was totally blocked by pimozide, a T-type calcium channel antagonist. The [Ca2+]i response to zacopride was potentiated by the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine and markedly reduced by the protein kinase A inhibitor adenosine-3',5'-cyclic monophosphorothioate. We studied in perifused frog adrenal slices the involvement of [Ca2+]i rise and cAMP formation in the mechanism of action of 5-HT4 receptor agonists. Zacopride-induced steroidogenesis was significantly reduced in the presence of adenosine-3'5'-cyclic monophosphorothioate or after suppression of calcium in the perifusion medium. The stimulatory effect of zacopride on corticosteroid secretion was not affected by nifedipine and omega-conotoxin GVIA but was significantly inhibited by pimozide. Taken together, these data indicate that activation of 5-HT4 receptors in adrenocortical cells causes stimulation of adenylyl cyclase and subsequently increases calcium influx through a T-type calcium channel. Both the increased in cAMP formation and the calcium rise are involved in the stimulatory effect of 5-HT on corticosteroid secretion.

Adrenal Cortex↗
PubMed1995

Pseudo-phaeochromocytoma after multiple drug interactions involving the selective monoamine oxidase inhibitor selegiline.

A patient presented with paroxysmal hypertension and typical clinical features of phaeochromocytoma, but with a normal adrenal computed tomographic scan and much higher plasma noradrenaline than adrenaline concentrations. Urinary vanillylmandelic acid concentrations were only moderately elevated. This syndrome probably arose as a consequence of an interaction between the monoamine oxidase inhibitor selegiline, the sympathomimetic agent ephedrine, and a tricyclic antidepressant. The mechanism of the interaction is thought to be related to increased sympathetic release of noradrenaline by ephedrine, inhibition of catabolism by selegiline, and inhibition of reuptake of noradrenaline by the tricyclic. Although newer selective monoamine oxidase inhibitors are considered to be safer than earlier non-selective inhibitors, they can also contribute to drug interactions mimicking phaeochromocytoma.

Bronchial Spasm↗
PubMed1995

The serotonin-4 receptor agonist cisapride and angiotensin-II exert additive effects on aldosterone secretion in normal man.

In animals and man, serotonin (5-HT) exerts a direct stimulatory action on adrenocortical cells through activation of 5-HT4 receptors. In rats, 5-HT also potentiates the stimulatory effect of angiotensin-II (Ang II) on aldosterone secretion. The aim of the present study was to investigate the effect of concomitant administration of the 5-HT4 receptor agonist, cisapride, and Ang II on aldosterone secretion in normal human subjects. Eight healthy male volunteers pretreated with dexamethasone received, at 1-week intervals in random order and simple blind fashion, the following treatments: 1) a single oral dose of 10 mg cisapride, 2) a single oral dose of placebo, 3) a perfusion of graded doses of Ang II (from 1-4 ng/kg.min), 4) a perfusion of placebo, and 5) a single oral dose of 10 mg cisapride associated with a perfusion of Ang II. The oral doses of cisapride and placebo were also administered after a 3-day period of a low sodium diet (10 mmol/day). Plasma aldosterone levels increased significantly within 90 min after the administration of cisapride without any change in renin levels. The comparison between the net increase in aldosterone production induced by cisapride, Ang II, and cisapride plus Ang II showed that the stimulatory effects of cisapride and Ang II on aldosterone secretion were only additive. Similarly, the increase in plasma aldosterone levels induced by a sodium-restricted diet was just additive with the cisapride-evoked stimulation of aldosterone secretion. These results provide further evidence that the action of 5-HT on glomerulosa cells is mediated through activation of 5-HT4 receptors. The data also indicate that in humans, 5-HT does not potentiate the stimulatory effect of Ang II on aldosterone secretion.

Adult↗
PubMed1995

Characterization of the somatostatin receptor subtype in a bronchial carcinoid tumor responsible for Cushing's syndrome.

Small ACTH-secreting carcinoid tumors responsible for Cushing's syndrome are often difficult to localize using available radiological investigations. Somatostatin receptors have been found in about 90% of carcinoid tumors studied, leading to a new approach for the localization of tumors or metastasis by using radiolabeled somatostatin analogs. We report a case of Cushing's syndrome due to an ACTH-secreting bronchial carcinoid tumor, completely suppressible with octreotide treatment and evidenced by body scintigraphy with 111In-labeled pentreotide. After removal, which led to patient recovery, the tumor was studied in vitro. In situ hybridization, using a complementary DNA probe, revealed POMC messenger ribonucleic acid in a subpopulation of tumor cells. These cells were labeled by immunochemistry using an antiserum directed against ACTH. Confocal laser scanning microscopy analysis showed that the ACTH-immunoreactive peptide was sequestered in secretory granules. Autoradiographic labeling using [125I-Tyrzero,D-Trp8]somatostatin-14 demonstrated the presence of somatostatin-binding sites in the whole tumor tissue. The relative affinities of various selective somatostatin analogs and the ability of GTP to inhibit radioligand binding suggested that the receptor expressed in the tumor cells belonged to the SSTR-2 subtype.

Adult↗
PubMed1994

Effect of a series of 5-HT4 receptor agonists and antagonists on steroid secretion by the adrenal gland in vitro.

We have previously shown that serotonin (5-hydroxytryptamine, 5-HT) stimulate corticosterone and aldosterone secretion from perifused frog adrenal gland in vitro through activation of 5-HT4 receptors. In the present study, we have used this model to investigate the effect of newly discovered 5-HT4 receptor agonists and antagonists on corticosteroid secretion. Serotonin, the benzamide derivatives (R,S)-zacopride ((R,S)-4-amino-N-(1- azabicyclo[2.2.2]oct-3-yl)-5-chloro-2-methoxybenzamide, HCI) and its enantiomers, the azabicycloalkyl benzimidazole derivatives BIMU 1 (endo-N- (8-methyl-8-azabicyclo-[3.2.1]oct-3-yl)-2,3-dihydro-3-ethyl-2-oxo- 1H-benzimidazole-1-carboxamide, HCl) and BIMU 8 (endo-N-(8-methyl-8- azabicyclo-[3.2.1]oct-3-yl)-2,3-dihydro-(1-methyl)ethyl-2-oxo-1H- benzimidazole-1-carboxamide, HCl) were all capable of enhancing corticosterone and aldosterone secretion in a dose-dependent manner. Serotonin was the most potent stimulator of steroidogenesis (EC50 = 1.5 x 10(-7) M) while the potency of the benzamide and the benzimidazolone derivatives was approximately 10 times lower. The rank order of efficacy of the different 5-HT4 receptor agonists was: (S)-zacopride > BIMU 8 = (R,S)-zacopride > BIMU 1 = (R)-zacopride = 5-HT. The stimulatory effects of 5-HT and the benzimidazolone derivatives on corticosteroid secretion were not additive, suggesting that they activated the same receptor.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Glands↗
PubMed1994

Creatine kinase in dog plasma: preanalytical factors of variation, reference values and diagnostic significance.

In the dog, plasma creatine kinase (CK) activity was stable up to one week at +4 degrees C and one month at -20 degrees C. Activity was higher in serum than in plasma due to interference by CK from the platelets. The reference values were determined in 232 dogs using the IFCC recommended method. There was a significant decrease in activity with age but no effect of sex. In adults, plasma CK exhibited a log-normal distribution ranging from 20 to 104 U per litre. In 510 dogs with various diseases, the overall sensitivity and specificity of CK determination were 40 per cent and 98 per cent, respectively. The numerous false negatives could result from the relatively short half-life of the enzyme, while the false positives could be due to secondary muscle damage.

Animals↗
PubMed1994

Effects of selective disruption of cytoskeletal elements on steroid secretion by human adrenocortical slices.

The role of the cytoskeleton in corticosteroid secretion in normal human adrenal gland was investigated in vitro, using the perifusion technique and confocal laser scanning microscopy. Vinblastine, which selectively disrupted microtubules in adrenocortical cells, did not modify the basal release of cortisol but induced a 58% inhibition of the response to adrenocorticotropic hormone (ACTH). In contrast, vinblastine did not alter dibutyryl adenosine 3',5'-cyclic monophosphate (DBcAMP)-induced steroid secretion. Cytochalasin B treatment caused disappearance of microfilaments and blocked the stimulatory action of ACTH and DBcAMP on cortisol secretion. beta,beta'-Iminodipropionitrile disorganized the cytokeratin intermediate filaments but did not alter spontaneous and ACTH-evoked cortisol release. These results, which provide the first evidence for an action of cytoskeleton inhibitors on cortisol release from normal human adrenocortical cells, show that microtubules are involved in the mechanism of action of ACTH at a step preceding adenosine 3',5'-cyclic monophosphate formation, whereas microfilaments are involved in a late and common step of adrenal steroidogenesis.

Adrenal Cortex↗
PubMed1994

[Protein S deficiency in necrotizing cellulitis of the penis].

INTRODUCTION: The pathogenesis of necrotizing cellulitis remains uncertain. Factors that enhance clot formation may contribute to tissue necrosis. CASE REPORT: A case of necrotizing cellulitis of the penis in a patient with a transient protein S deficiency, is reported. CONCLUSION: The responsibility of this transient hypercoagulable state in the occurrence of tissue necrosis in this patient is discussed.

Adult↗
PubMed1993

Kidney tubule enzymes and extracellular DNA in urine as markers for nephrotoxicity in the guinea pig.

Guinea pigs were given a single intraperitoneal injection of 1.35 mg/kg body weight of mercuric chloride; then various kidney enzymes and extracellular DNA were assayed in urine. Dramatic increases of all studied markers were observed on the first day following treatment. Sequential collection of urines allowed for kinetic studies: membrane markers alkaline phosphatase and gamma-glutamyltransferase were first released, then cytosolic lactate dehydrogenase and mitochondrial glutamate dehydrogenase, finally extracellular DNA; DNA release is equated with cell death. The features of kidney damage revealed by comparative and quantitative studies of these noninvasive markers suggest that brush border erasure was more extensive than cell necrosis.

Alkaline Phosphatase↗
PubMed1993

Vasopressin stimulates cortisol secretion from human adrenocortical tissue through activation of V1 receptors.

It has previously been shown that arginine vasopressin (AVP) exerts a direct stimulatory action on rat adrenocortical cells. In the present study, we have investigated the possible effect of AVP on cortisol secretion by normal human adrenocortical tissue. The occurrence of endogenous AVP in the human adrenal gland has been studied by means of the indirect immunofluorescence technique. The presence of AVP-containing cells was observed in both cortex and medulla. The action of AVP on corticosteroidogenesis has been investigated in vitro using a perifusion system technique coupled to a specific RIA for cortisol. Graded doses of AVP (from 10(-11)-10(-9) M) increased cortisol secretion in a dose-dependent manner (ED50, 4.5 x 10(-11) M). AVP also induced a significant stimulation of cortisol release from acutely dispersed adrenocortical cells. Prolonged administration of AVP (3 h) induced a rapid and transient increase in cortisol output, followed by a gradual decline in cortisol secretion. Repeated pulses of AVP, given at 90-min intervals, resulted in reproducible stimulations of cortisol output. Selective agonists and antagonists have been used to determine the type of receptor involved in the response of adrenocortical cells to AVP. Oxytocin at doses up to 10(-7) M had virtually no effect on cortisol secretion. The stimulatory effect of AVP was blocked by the V1 antagonist [beta-mercapto-beta,beta-cyclopentamethylene propionyl 1, OMe-Tyr2, Arg8]AVP. In contrast, the V2 antagonist [d(CH2)5D-Phe2,Ile4,Ala9-NH2]AVP did not affect the response of the adrenal gland to AVP. The selective V2 agonist [deamino-Cys1,D-Arg8]AVP did not mimic the stimulatory effect of AVP on cortisol secretion. Taken together, these results suggest that AVP, locally released by intracortical cells, may act as a paracrine factor to stimulate adrenal steroidogenesis in man. The effect of AVP on cortisol secretion appears to be mediated through activation of typical V1 receptors.

Adrenal Cortex↗