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Biomedical subjects

R Giordano

Publications and source records attributed to R Giordano.

At least 55 records · Page 3Linked to original sources
PubMed2001

Mineralocorticoid receptor blockade by canrenoate increases both spontaneous and stimulated adrenal function in humans.

Animal studies indicate that mineralocorticoid receptors (MR) in the hippocampus play a major role in the glucocorticoid feedback control of the hypothalamo-pituitary-adrenal (HPA) axis. Specifically, MR mediate the proactive feedback of glucocorticoids in the maintenance of basal HPA activity. The stimulatory effect of intracerebroventricular and intrahippocampal MR blockade on the HPA axis in animals has been clearly shown, whereas the effect of systemic administration of mineralocorticoid antagonists in humans is still contradictory. To clarify this point, in seven normal young women (aged 25-32 yr; body mass index, 19.0-23.0 kg/m(2)) we studied the effects of canrenoate (CAN; 200 mg as iv bolus at 2000 h, followed by 200 mg infused in 500 mL saline over 4 h up to 2400 h) or placebo (saline, 1.0 mL as iv bolus at 2000 h, followed by 500 mL over 4 h up to 2400 h) on the spontaneous ACTH, cortisol, dehydroepiandrosterone (DHEA) and aldosterone secretion as well as on the ACTH, cortisol, and DHEA responses to human CRH (2.0 microg/kg as iv bolus at 2200 h) or arginine vasopressin (AVP; 0.17 U/kg as im bolus at 2200 h). Blood samples were taken every 15 min from 2000-2400 h. During placebo, spontaneous ACTH and cortisol levels showed progressive decreases (P < 0.05) from 2000-2400 h (baseline vs. nadir, mean +/- SEM, 2.0 +/- 0.3 vs. 1.4 +/- 0.2 pmol/L and 115.1 +/- 23.7 vs. 63.5 +/- 24.3 nmol/L), whereas DHEA and aldosterone levels did not change. CRH induced clear increases in ACTH, cortisol, and DHEA levels (peaks, mean +/- SEM, 7.1 +/- 1.1 vs. 1.6 +/- 0.2 pmol/L, 322.9 +/- 19.5 vs. 92.8 +/- 24.5 nmol/L, and 44.2 +/- 2.7 vs. 20.0 +/- 3.0 nmol/L; P < 0.05). Similarly, AVP elicited significant increases in ACTH, cortisol, and DHEA levels (3.8 +/- 0.3 vs. 1.5 +/- 0.1 pmol/L, 211.9 +/- 27.2 vs. 67.7 +/- 9.7 nmol/L, and 51.6 +/- 4.0 vs. 16.3 +/- 2.0 nmol/L; P < 0.05). During CAN treatment, ACTH, cortisol, and DHEA levels showed progressive rises, which begun at approximately 60 min and peaked between 2300 and 2400 h (ACTH, 3.4 +/- 0.4 vs. 1.1 +/- 0.3 pmol/L; cortisol, 314.5 +/- 49.6 vs. 123.3 +/- 13.2 nmol/L; DHEA, 52.0 +/- 8.8 vs. 21.0 +/- 2.3 nmol/L; P < 0.05 vs. baseline as well as vs. the same time points during placebo). Aldosterone secretion was not modified by CAN. The ACTH, cortisol, and DHEA responses to human CRH were enhanced by CAN (10.0 +/- 1.7 pmol/L, 462.2 +/- 36.9 nmol/L, and 66.3 +/- 8.8 nmol/L), although statistical significance (P < 0.05) was obtained for cortisol and DHEA only. Also the ACTH, cortisol and DHEA responses to AVP were amplified by CAN (8.0 +/- 2.6 pmol/L, 324.0 +/- 34.8 nmol/L, and 77.8 +/- 4.0 nmol/L); again, statistical significance (P < 0.05) was obtained for cortisol and DHEA only. In conclusion, our study shows that the blockade of MR by CAN significantly enhances the activity of the HPA axis in humans, indicating a physiological role for MR in its control. These results also suggest that the stimulatory effect of CAN on HPA axis is mediated by concomitant modulation of CRH and AVP release.

Adrenal Glands↗
PubMed2001

Growth hormone-releasing hormone and growth hormone secretagogue-receptor ligands: focus on reproductive system.

Growth hormone-releasing hormone (GHRH) and somatostatin are the most important hypothalamic neurohormones controlling growth hormone (GH) secretion. Several neurotransmitters and neuropeptides also play an important role in the control of GH secretion, mainly acting via modulation of GHRH and somatostatin. In the past two decades, particular attention has been given to a new family of substances showing a strong GH-releasing effect: GH secretagogues (GHSs). GHSs increase GH secretion in a dose- and age-related manner after iv and even oral administration. The endocrine effects of GHSs, are not fully specific for GH; they show, in fact, prolactin- (PRL), adenocorticotropic hormone- and cortisol-releasing effects. Specific GHS receptors are present in both the central nervous system and peripheral tissues, where they mediate several extraendocrine effects of GHSs. The isolation of these "orphan" receptors suggested the existence of an endogenous GHS-like ligand that could be represented by a recently discovered gastric peptide, named ghrelin. The interaction between GHSs and GHRH at the central level and in the pituitary gland, but not at peripheral level, has clearly been shown. Because GHRH and GHS receptors share the same localization in some peripheral tissues, they may have some interactions even at this level.

Adrenocorticotropic Hormone↗
PubMed2001

Biologic activities of growth hormone secretagogues in humans.

Growth hormone secretagogues (GHSs) are synthetic peptidyl and nonpeptidyl molecules with strong, dose-dependent, and reproducible growth hormone (GH)-releasing activity even after oral administration. GHSs release GH via actions on specific receptors (GHS-R) at the pituitary and, mainly, at the hypothalamic levels. GHSs likely act as functional somatostatin antagonists and meantime enhance the activity of GH-releasing hormone (GHRH)-secreting neurons. The GH-releasing effect of GHSs is independent of gender but undergoes marked age-related variations. Estrogens play a major role in enhancing the GH response to GHSs at puberty, which GHRH hypoactivity, somatostatinergic hyperactivity and impaired activity of the putative GHS-like ligand and receptors probably explain the reduced GH-releasing effect of GHSs in aging. The activity of GHSs is not fully specific for GH. Their slight prolactin-releasing activity probably comes from direct pituitary action. In physiological conditions, the ACTH-releasing activity of GHSs is dependent on central actions; a direct action on GHS-R in pituitary ACTH-secreting tumors likely explains the peculiar ACTH and cortisol hyperresponsiveness to GHSs in Cushing disease. GHSs have specific receptor subtypes in other central and peripheral endocrine and nonendocrine tissues mediating GH-independent biologic activities. GHSs influence sleep pattern, stimulate food intake, and have cardiovascular activities. GHs have specific binding in normal and neoplastic follicular derived human thyroid tissue and inhibit the proliferation of follicular-derived neoplastic cell lines. The discovery of ghrelin, a 28 amino acid peptide synthesized in the stomach but also in other tissues, has opened new fascinating perspectives of research in this field.

Age Factors↗
PubMed2001

Choosing new adsorbents for endogenous ultrapure infusion fluid: performances, safety and flow distribution.

Adsorption may notably contribute to the removal of uremic toxins and to the efficiency of hemodialysis. We examined different uncoated stationary matrixes, charcoals and synthetic resins to establish their adsorptive capacities in relation to low (urea, creatinine) and high molecular weight (beta2-microglobulin, myoglobin) compounds in in vitro conditions (steady state and flow-through) using isotonic solutions or uremic ultrafiltrate. Trace metal, particle release analyses and scanning electron microscopy of different adsorbents were performed. Dynamic flow-distribution studies were made using 99Technetium and analysing the different regions of interest by single head gamma-camera. We show that adsorbents may differ greatly as to their adsorptive capacity depending on flow rate, nature, and total mass of the compounds to be removed from the ultrafiltrate. These studies suggest a methodological approach for screening stationary matrixes for possible application in hemodialysis.

Adsorption↗
PubMed2000

Reverse transcriptase activity in mature spermatozoa of mouse.

We show here that a reverse transcriptase (RT) activity is present in murine epididymal spermatozoa. Sperm cells incubated with human poliovirus RNA can take up exogenous RNA molecules and internalize them in nuclei. Direct PCR amplification of DNA extracted from RNA-incubated spermatozoa indicate that poliovirus RNA is reverse-transcribed in cDNA fragments. PCR analysis of two-cell embryos shows that poliovirus RNA-challenged spermatozoa transfer retrotranscribed cDNA molecules into eggs during in vitro fertilization. Finally, RT molecules can be visualized on sperm nuclear scaffolds by immunogold electron microscopy. These results, therefore, reveal a novel metabolic function in spermatozoa, which may play a role during early embryonic development.

Animals↗
PubMed2000

Nucleosomal domains of mouse spermatozoa chromatin as potential sites for retroposition and foreign DNA integration.

Exogenous DNA molecules are spontaneously taken up by sperm cells, internalized in nuclei, and eventually integrated in the sperm genome. The actual occurrence of the integration suggests that the sperm chromosomal DNA is not uniformly and tightly packed with protamines, implying the existence of genomic sites where the chromosomal DNA is accessible to foreign molecules. We have characterized a hypersensitive, nucleosomal subfraction of mouse sperm chromatin that is highly enriched in unmethylated retroposon DNA from a variety of families. Here we propose that both the integration of exogenous DNA molecules, and the endogenous retroposition activity, occur in the same site(s) of sperm chromatin.

Animals↗
PubMed2000

DNA dose and sequence dependence in sperm-mediated gene transfer.

We have tested three parameters in sperm-mediated gene transfer assays with mice and pigs: (i) the epididymal versus ejaculated origin of sperm cells, (ii) the primary structure, and (iii) the amount of the challenging foreign DNA. We have found that the pVLCNhGH construct, of retrotransposon origin, causes a massive embryo lethality and yet increases the yield of genetic transformation among born animals of both species compared to viral constructs. Arrest of embryonic development is a DNA dose-dependent effect, which is observed with high DNA doses, while lower doses are compatible with development. Finally, the overall efficiency of sperm-mediated gene transfer is higher when ejaculated, versus epididymal, spermatozoa are used. We suggest that this difference is related to the highly efficient apoptotic response in epididymal compared to ejaculated spermatozoa, triggered by the interaction of exogenous DNA molecules with the sperm membrane.

Animals↗
PubMed2000

E2F transcription factors are differentially expressed in murine gametes and early embryos.

We have examined the murine genes encoding transcription factors E2F1, -3, -5 and -6 in gametes and early embryos. All genes are expressed as maternal transcripts and all are efficiently transcribed after the blastocyst stage. Between those two stages, each E2F mRNA is transcribed with a distinctive and unique pattern. E2F proteins are also differentially expressed and compartmentalized in pre-implantation embryos.

3T3 Cells↗
PubMed2000

Glucagon is an ACTH secretagogue as effective as hCRH after intramuscolar administration while it is ineffective when given intravenously in normal subjects.

It is widely accepted that glucagon stimulates GH, ACTH and cortisol release in humans, though the mechanisms underlying these effects are unclear. Aim of the present study was to evaluate the stimulatory effect of intramuscolar (i.m.) and intravenous (i.v.) glucagon (GLU) administration on ACTH, cortisol (F) and GH release in normal adult subjects and to compare its effect on hypothalamo-pituitary adrenal (HPA) axis with that of hCRH. To this goal, in 6 normal young women (26-32 yrs, 50-58 kg) we studied the ACTH and F responses to either i.m. or i.v. GLU (1 mg, approximately 0.017 mg/kg in subjects of 54.1 +/- 1.6 kg) administration as well as to i.v. hCRH (2.0 micrograms/kg) or placebo administration. The GH and glucose variations after GLU administration were also studied. I.v. GLU did not modify the spontaneous decrease of ACTH and cortisol levels observed after placebo. Conversely, i.m. GLU elicited clear-cut ACTH and F responses (peak vs baseline, mean +/- SEM: 53.0 +/- 15.2 vs 19.0 +/- 1.5 pg/ml, p < 0.05 and 222.3 +/- 23.8 vs 158.3 +/- 7.0 micrograms/l, p < 0.05) which were higher than those recorded after hCRH (28.1 +/- 4.6 vs 17.4 +/- 3.1 pg/ml, p < 0.02 and 182.7 +/- 22.8 vs 114.8 +/- 12.3 micrograms/l p < 0.02), though this difference did not attain statistical significance. Also GH rise was recorded after i.m. but not after i.v. GLU administration (11.6 +/- 3.4 vs 3.3 +/- 0.7 micrograms/l, p < 0.05). Thirty min after both i.v. and i.m. GLU administration glucose levels showed a similar increase followed by similar decrease. The intramuscular administration of GLU induced negligible side-effects in some subject (mild and transient nausea) which, on the contrary, were clear in all subjects after its intravenous administration (nausea, vomiting, tachycardia). In conclusion, glucagon "per se" is not an ACTH, cortisol and GH secretagogue. After intramuscular administration glucagon is a stimulus of HPA axis at least as effective as hCRH. The mechanisms underlying the ACTH, cortisol and GH responses to i.m. glucagon unlikely include glucose variations or stress.

Adrenocorticotropic Hormone↗
PubMed2000

Alprazolam, a benzodiazepine, blunts but does not abolish the ACTH and cortisol response to hexarelin, a GHRP, in obese patients.

GH secretagogues (GHS) act on specific receptors at the pituitary and hypothalamic level and possess potent GH-releasing activity but also stimulate prolactin (PRL), ACTH and cortisol (F) secretion. However, hyperactivity of the HPA axis in obesity has been reported. The objective of this study was to clarify the endocrine activity of GHS in obesity. In nine obese patients (obese OB), 9 F, age, (34.8 +/- 3.7 y, body mass index (BMI), 35.0 +/- 2.2 kg/m2; WHR, 0.9 +/- 0.02), 14 controls (normal subjects, NS), 14 F, 30.4 +/- 0.9 y, 20.0 +/- 0.4 kg/m2), we studied the ACTH, F and GH responses to hexarelin (HEX, 2.0 microg/kg), a peptidyl GHS, alone and preceded by alprazolam (ALP, 0.02 mg/kg), and a benzodiazepine which has an inhibitory effect on corticotroph secretion. The HEX-induced ACTH response in OB was higher than that in n.s., but this difference did not attain statistical significance. In n.s. the HEX-induced ACTH response was abolished by ALP (P < 0.03) which, however, only blunted that in OB (P < 0.02). The GH response to HEX in OB was lower (P < 0.02) than that in n.s.. ALP blunted the GH response to HEX in n.s. (P < 0.03) while it did not modify that in OB. The GABAergic activation by alprazolam abolishes the ACTH response to hexarelin in normal subjects, while it only blunts that in obese subjects. Moreover, alprazolam blunts the GH response to hexarelin in normal but not in obese subjects. Thus, obese patients show partial refractoriness to the inhibitory effect of alprazolam on both corticotroph and somatotroph function.

Adrenocorticotropic Hormone↗
PubMed2000

Interaction between glucagon and human corticotropin-releasing hormone or vasopressin on ACTH and cortisol secretion in humans.

OBJECTIVE: It is known that glucagon administration elicits ACTH and cortisol responses in humans, although this effect takes place after intramuscular or subcutaneous but not after the intravenous route of administration. The mechanisms underlying this stimulatory effect on corticotroph secretion are unknown but they are unrelated to glucose variations and stress-mediated actions. DESIGN AND METHODS: To throw further light on the stimulatory effect of i.m. glucagon on the pituitary-adrenal axis, using six normal young female volunteers (26-32 years, body mass index 19.7-22.5 kg/m(2)) we studied the interaction between glucagon (GLU; 0.017 mg/kg i.m.) and human corticotropin-releasing hormone (hCRH; 2.0 microg/kg i.v.) or vasopressin (AVP; 0.17 U/kg i.m.). The interactions between hCRH and AVP on the hypothalamo-pituitary-adrenal (HPA) axis and the GH response to GLU alone or combined with hCRH or AVP were also studied. RESULTS: GLU i.m. administration elicited a clear increase in ACTH (peak vs baseline, means+/-s.e.m.: 11.6+/-3.3 vs 4.2+/-0.3 pmol/l, P<0.05), cortisol (613.5+/-65.6 vs 436.9+/-19.3 nmol/l, P<0.05) and GH levels (11.6+/-3.4 vs 3.3+/-0.7 microg/l, P<0.05). The ACTH response to GLU (area under the curve: 426.4+/-80.9 pmol/l per 120 min) was higher than that to AVP (206.3+/-38.8 pmol/l per 120 min, P<0.02) and that to hCRH (299.8+/-39.8 pmol/l per 120 min) although this latter difference did not attain statistical significance. The GLU-induced cortisol response (28336.9+/-2430.7 nmol/l per 120 min) was similar to those after hCRH (24099.2+/-2075.2 nmol/l per 120 min) and AVP (21808.7+/-1948.2 nmol/l per 120 min). GLU and hCRH had an additive effect on ACTH (964.9+/-106.6 pmol/l per 120 min, P<0.02) and a less than additive effect on cortisol levels (35542.5+/-2720. 2 nmol/l per 120 min). Similarly, GLU and AVP had an additive effect on ACTH (825.6+/-139.6 pmol/l per 120 min, P<0.02) and an effect less than additive on cortisol levels (33059.2+/-1965.3 nmol/l per 120 min). The effects of GLU co-administered with hCRH or AVP were similar to those of the combined administration of hCRH and AVP on ACTH (906. 0+/-152.7 pmol/l per 120 min) and cortisol (34383.5+/-1669.2 nmol/l per 120min) levels. The GH response to GLU was not modified by hCRH or AVP. CONCLUSIONS: These results show that i.m. glucagon administration is a provocative stimulus of ACTH and cortisol secretion, at least as potent as hCRH and AVP. The ACTH-releasing effect of i.m. glucagon is not mediated by selective CRH or AVP stimulation but the possibility that both neurohormones play a role could be hypothesized.

Adrenocorticotropic Hormone↗
PubMed2000

Interaction between glucagon and hexarelin, a peptidyl GH secretagogue, on somatotroph and corticotroph secretion in humans.

OBJECTIVE: Glucagon administration stimulates both somatotroph and corticotroph secretion in humans, although this happens only if glucagon is administered by the intramuscular route and not by the intravenous route. On the other hand, GH secretagogues (GHS) strongly stimulate GH and also possess ACTH-releasing activity. DESIGN AND METHODS: To clarify the mechanisms underlying the stimulatory effects of both glucagon and GHS on somatotroph and corticotroph secretion, we studied the GH, ACTH and cortisol responses to glucagon (GLU, 0.017 mg/kg i.m.) and Hexarelin, a peptidyl GHS (HEX, 2.0 microg/kg i.v.) given alone or in combination in 6 normal young volunteers (females, aged 26-32 years, body mass index 19.7-22.5 kg/m). RESULTS: GLU administration elicited a clear increase in GH (peak vs baseline, mean+/-S.E.M.: 11.6+/-3.4 vs 3. 3+/-0.7 microg/l, P<0.02), ACTH (11.6+/-3.3 vs 4.1+/-0.3 pmol/l, P<0. 02) and cortisol (613.5+/-65.6 vs 436.9+/-19.3 nmol/l, P<0.05) levels. HEX induced a marked increase in GH levels (55.7+/-19.8 vs 3. 7+/-1.9 microg/l, P<0.005) and also significant ACTH (5.7+/-1.1 vs 3. 4+/-0.6 pmol/l, P<0.01) and cortisol (400.2+/-31.4 vs 363.4+/-32.2 nmol/l, P<0.05) responses. The GH area under the curve (AUC) after HEX was clearly higher than after GLU (1637.3+/-494.0 vs 479.1+/-115. 7 microg/l/120 min, P<0.04) while HEX and GLU coadministration had a true synergistic effect on GH release (3243.8+/-687.5 microg/l/120 min, P<0.02). The ACTH and cortisol AUCs after HEX were lower (P<0. 02) than those after GLU (208.3+/-41.3 vs 426.3+/-80.9 pmol/l/120 min and 18 874.5+/-1626.1 vs 28 338.5+/-2430.7 nmol/l/120 min respectively). The combined administration of HEX and GLU had an effect which was less than additive on both ACTH (564.02+/-76.5 pmol/l/120 min) and cortisol (35 424.6+/-5548.1 nmol/l/120 min) secretion. CONCLUSIONS: These results show that the intramuscular administration of glucagon releases less GH but more ACTH and cortisol than Hexarelin. The combined administration of glucagon and Hexarelin has a true synergistic effect on somatotroph secretion but a less than additive effect on corticotroph secretion; these findings suggest that these stimuli act via different mechanisms to stimulate somatotrophs while they could have a common action on the hypothalamo-pituitary-adrenal axis.

Adrenocorticotropic Hormone↗
PubMed2000

[Peripheral blood stem cell collection in pediatric oncohematology. Experience with patients weighing less than 15 kg].

BACKGROUND: Leukapheresis for peripheral blood stem cell collection is increasingly being carried out in pediatric cancer patients. Aim of this study was to report experience of the Padua Apheresis Unit on a series of children weighting < 15 kg who have undergone such an apheresis procedure. METHODS: This retrospective study includes 15 pediatric patients affected with various malignancies (neuroblastoma: 7; acute myelogenous leukemia: 3; rhabdomyosarcoma: 2; PNET: 1; retinoblastoma: 1; Burkitt's lymphoma: 1) collecting peripheral blood stem cells by a Cobe Spectra blood cell separator. Main procedure parameters, including vascular access, leukapheresis duration, blood flow rate, processed blood volumes, side effects, mononuclear and CD34+ cell yields, have been registered. RESULTS: Altogether 22 sessions have been carried out, by processing a mean of 2.8 blood volumes. No leukapheresis related complications have been recorded, such as hypotension, hypocalcemia and hypothermia. Noteworthy, in 4 procedures two or more peripheral venipunctures have been performed to ensure an adequate blood flow. CONCLUSIONS: Leukapheresis for peripheral blood stem cell collection can be safely and efficaciously carried out in pediatric patients, even weighing < 15 kg, on the condition that certain aspects of apheresis practice in children (vascular access, volume shifts, anticoagulation, side effects) are carefully considered.

Antibodies, Monoclonal↗
PubMed1999

Cloning of a surface membrane glycoprotein specific for the infective form of Trypanosoma cruzi having adhesive properties to laminin.

Trypomastigotes of Trypanosoma cruzi express a set of surface glycoproteins known, collectively, as Tc-85. A monoclonal antibody to these proteins, named H1A10, inhibits (50-90%) in vitro parasite interiorization into host cells, thus implicating these glycoproteins in the infection process. Two DNA inserts, a genomic DNA fragment and a full-length cDNA encoding the H1A10 epitope, have now been cloned and characterized. Results show that both have high sequence identity with all reported members of the gp85/trans-sialidase gene family, although the H1A10 epitope exists only in the Tc-85 subset of the family. The epitope has been mapped by competition of antibody binding to a Tc-85 recombinant protein with peptides having sequences predicted by the Tc-85 DNA sequence, which contains also putative N-glycosylation sites and COOH-terminal glycosylphosphatidylinositol anchor insertion sites, as expected, since an N-glycan chain and a glycosylphosphatidylinositol anchor have been characterized previously in the Tc-85 subset. The protein encoded by the full-length cDNA insert binds to cells and in vitro to laminin, but not to gelatin or fibronectin, in a saturable manner. For the first time it was possible to assign a defined ligand to a sequenced glycoprotein belonging to the gp85 family. This fact, together with the reported binding of family members to cell surfaces, reinforces the hypothesis that this family encodes glycoproteins with similar sequences but differing enough as to bind to different ligands and thus forming a family of adhesion glycoproteins enabling the parasite to overcome the barriers interposed by cell membranes, extracellular matrices, and basal laminae.

Amino Acid Sequence↗
PubMed1999

Effects of the combined administration of hexarelin, a synthetic peptidyl GH secretagogue, and hCRH on ACTH, cortisol and GH secretion in patients with Cushing's disease.

Hexarelin (HEX) is a peptidyl GH secretagogue (GHS) which markedly stimulates GH release but, like other GHS, possesses also CNS-mediated ACTH- and cortisol-releasing activity. Interestingly, the stimulatory effect of HEX on ACTH and cortisol release is exaggerated and higher than that of hCRH in patients with Cushing's disease (CD). To further clarify the mechanisms by which HEX stimulates the activity of hypothalamo-pituitary-adrenal (HPA) axis in man, in 6 patients with CD (6 women, 38-68 yr old) and in 7 control subjects (CS, 7 women, 22-29 yr old) we studied the effects of HEX (2.0 microg/kg i.v.) and/or hCRH (2.0 microg/kg i.v.) on ACTH and cortisol (F) secretion. The GH responses to HEX alone and combined with hCRH were also studied in all subjects. Basal ACTH and F levels in CD were higher than in CS (66.3+/-5.1 vs 16.5+/-0.6 pg/ml and 217.8+/-18.5 vs 134.4+/-4.6 microg/l, respectively; p<0.02). In CS, the ACTH and F responses to HEX, evaluated as deltaAUC (mean+/-SE: 128.7+/-39.2 pg x min/ml and 328.5+/-93.2 microg x min/l, respectively) were lower, though not significantly, than those after hCRH (375.8+/-128.4 pg x min/ml and 1714.2+/-598.0 microg x min/l, respectively), though the peak ACTH and F responses to both stimuli were similar. The co-administration of HEX and hCRH had an additive effect on both ACTH (1189.6+/-237.2 pg x min/ml) and F secretion (3452.9+/-648.6 microg x min/l). In fact, the ACTH and F responses to HEX+/-hCRH were significantly higher (p<0.01) than those elicited by single stimuli. In CD, HEX induced ACTH and F responses (3603.8+/-970.7 pg x min/ml and 10955.9+/-6184.6 microg x min/l, respectively) clearly higher (p<0.002) than those in CS. The HEX-induced ACTH and F responses in CD were higher, though not significantly, than those recorded after hCRH (1432.7+/-793.5 pg x min/ml and 4832.7+/-2146.5 microg x min/l, respectively). On the other hand, the hCRH-induced ACTH and F responses in CD were similar to those in CS. In CD, the coadministration of HEX and hCRH had an additive effect on ACTH (8035.7+/-1191.1 pg x min/ml) but not on F (10985.4+/-3900.8 microg x min/l) secretion. In fact, the ACTH, but not the F response to HEX+hCRH was significantly higher (p<0.02) than that elicited by single stimuli. In conclusion, the present study demonstrates that in patients with Cushing's disease as well as in subjects control Hexarelin and hCRH have an additive effect on ACTH secretion. Considering that, at least in humans, differently from hCRH, GHS have no interaction with AVP, our present findings further agree with the hypothesis that the ACTH-releasing activity of GHS is, at least partially, independent of CRH-mediated mechanisms.

Adrenocorticotropic Hormone↗
PubMed1999

Tyr-Ala-Hexarelin, a synthetic octapeptide, possesses the same endocrine activities of Hexarelin and GHRP-2 in humans.

Hexarelin (HEX) and GHRP-2 are two synthetic hexapeptides, superanalogs of GHRP-6, belonging to GH secretagogue (GHS) family. GHS act via specific receptors at both the pituitary and the hypothalamic level to stimulate GH release both in animals and in humans. However, GHS also possess significant PRL- and ACTH/cortisol-releasing activity. Tyr-Ala-HEX as well as Tyr-Ala-GHRP-6 are, in turn, synthetic octapeptides generally used to perform binding studies because of their easy iodination. However, their endocrine activities have never been studied in humans. To clarify the endocrine activities of Tyr-Ala-HEX, in 7 young adult volunteers we compared the effects of the maximal effective dose of HEX (2.0 microg/kg i.v.) or GHRP-2 (2.0 microg/kg i.v.) with the same one of Tyr-Ala-HEX on GH, PRL, ACTH and cortisol levels. Basal GH, PRL, ACTH and cortisol levels in all testing sessions were similar. The administration of placebo did not modify hormonal levels. HEX and GHRP-2 administration induced the well known strong GH response (Cmax, mean+/-SE: 77.3+/-6.0 and 74.1+/-12.1 microg/l; AUC, mean+/-SE: 2596.7+/-251.1 and 2480.0+/-343.6 microg*min/l). These responses were similar to that induced by Tyr-Ala-HEX (63.7+/-18.5 microg/l; 1986.6+/-622.4 microg*min/l). Moreover, HEX, GHRP-2 and Tyr-Ala-HEX had the same significant stimulatory effect on PRL (14.9+/-2.5, 12.3+/-2.0 and 10.0+/-1.5 microg/l; 497.8+/-61.8, 480.4+/-66.9 and 415.8+/-58.5 microg*min/l), ACTH (48.0+/-10.1, 51.4+/-10.6 and 44.9+/-12.2 pg/ml; 1531.6+/-235.7, 1586.7+/-277.0 and 1338.1+/-164.5 pg*min/ml) and cortisol (179.9+/-10.0, 181.2+/-14.1 and 149.7+/-20.1 microg/l; 8465.0+/-406.6, 8689.2+/-788.1 and 6295.2+/-797.0 microg*min/l). Also the mean Tmax of the endocrine responses to HEX, GHRP-2 and Tyr-Ala-HEX were similar. In conclusion, the present results demonstrate that in humans Tyr-Ala-HEX is a GH secretagogue as potent as HEX and GHRP-2, two GHRP-6 superanalogs. Tyr-Ala-HEX also shares with HEX and GHRP-2 the same PRL- ACTH- and cortisol-releasing activity.

Adrenocorticotropic Hormone↗
PubMed1999

Effects of alprazolam, a benzodiazepine, on the ACTH-, GH- and PRL-releasing activity of hexarelin, a synthetic peptidyl GH secretagogue (GHS), in patients with simple obesity and in patients with Cushing's disease.

GH secretagogues (GHS) possess potent GH-releasing activity but also stimulate PRL, ACTH and cortisol (F) secretion. To further clarify the endocrine activities of GHS, in 9 obese patients, 9 patients with Cushing's disease and 14 controls we studied the ACTH, F, GH and PRL responses to hexarelin (HEX, 2.0 micrograms/kg i.v.), a peptidyl GHS, alone and preceeded by alprazolam (ALP, 0.02 mg/kg p.o.), a benzodiazepine. The HEX-induced ACTH response in controls was similar to that in obese patients (delta peak: 9.9 +/- 1.9 and 24.7 +/- 7.6 ng/L, respectively) and both were lower (p < 0.002) than that in Cushing's patients (peak: 210.7 +/- 58.4 ng/L). The GH response to HEX in controls (peak: 58.1 +/- 10.3 x g/L) was higher (p < 0.001) than those in obese and Cushing's patients (18.2 +/- 3.8 and 12.6 +/- 5.4 x g/L, respectively) which, in turn, were similar. The PRL responses to HEX in controls, obese and Cushing's patients (peak: 11.9 +/- 1.6, 18.0 +/- 4.5 and 12.4 +/- 1.4 x g/L, respectively) were similar. In controls the HEX-induced ACTH response was abolished by ALP (peak: 8.6 +/- 2.4 vs 28.0 +/- 6.7 ng/L, p < 0.03) which, on the other hand, only blunted that in obese (peak: 12.7 +/- 2.1 vs 42.4 +/- 8.4 ng/L, p < 0.02) and did not modify that in Cushing's patients (205.6 +/- 55.4 vs 175.9 +/- 47.6 ng/L). ALP blunted the GH response to HEX in controls (peak: 31.0 +/- 7.1 x g/L, p < 0.03) while did not modify those in obese and in Cushing's patients (14.5 +/- 5.3 and 13.3 +/- 11.1 x g/L, respectively). ALP did not modify the HEX-induced PRL response in controls, obese and Cushing's patients (peak: 13.8 +/- 0.9, 16.3 +/- 2.4 and 19.2 +/- 1.1 x g/L, respectively). In conclusion, alprazolam inhibits the ACTH response to hexarelin in normal and obese subjects while fails to modify the exaggerated ACTH response in Cushing's Disease suggesting that GHS activate the HPA axis via the hypothalamus in normal and obese subjects but not in patients with Cushing's disease. Alprazolam is also able to blunt the GH-releasing activity of hexarelin in normal subjects but not the low GH response to the hexapeptide in obese and Cushing's patients. The PRL-releasing activity of hexarelin in controls, obese and hypercortisolemic patients is similar and is not modified by alprazolam pretreatment.

Adrenocorticotropic Hormone↗