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PubMed2002

Sleep processes exert a predominant influence on the 24-h profile of heart rate variability.

Adverse cardiovascular events are known to exhibit 24-h variations with a peak incidence in the morning hours and a nonuniform distribution during the night. The authors examined whether these 24-h variations could be related to circadian or sleep-related changes in heart rate (HR) and in HR variability (HRV). To differentiate the effect of circadian and sleep-related influences, independent of posture and of meal ingestion, seven normal subjects were studied over 24 h, once with nocturnal sleep from 2300 to 0700 h and once after a night of sleep deprivation followed by 8 h of daytime sleep from 0700 to 1500 h. The subjects were submitted to constant conditions (continuous enteral nutrition and bed rest). HRV was calculated every 5 min using two indexes: the standard deviation of normal R-R intervals (SDNN) and the ratio of low-frequency to low-frequency plus high-frequency power. Sleep processes exerted a predominant influence on the 24-h profiles of HR and HRV, with lowest HRV levels during slow wave sleep, high levels during REM sleep and intrasleep awakenings, and abrupt increases in HR at each transition from deeper sleep to lighter sleep or awakenings. The circadian influence was smaller, except for SDNN, which displayed a nocturnal increase of 140% whether the subjects slept or not. This study demonstrates that 24-h variations in HR and HRV are little influenced by the circadian clock andare mainly sleep-stage dependent. The results suggest an important role for exogenous factors in the morning increase in cardiovascular events. During sleep, the sudden rises in HR at each transition from deeper sleep to lighter sleep or awakenings might precipitate the adverse cardiac events.

Adult↗
PubMed1989

The effect of bracket type and ligation method upon forces exerted by orthodontic archwires.

The effects of bracket type and ligation method upon the forces exerted at 1.5-mm deflection by three archwire materials were measured in a simulated clinical situation. Significant force differences were found when archwires were used in standard edgewise or straightwire brackets, respectively, and also when Alastik modules were used for ligation instead of steel ligatures.

Alloys↗
PubMed2002

Soluble HLA class I molecules induce natural killer cell apoptosis through the engagement of CD8: evidence for a negative regulation exerted by members of the inhibitory receptor superfamily.

Herein, we show that CD8(dull), CD8(intermediate), and CD8(bright) natural killer (NK) cell clones can be identified. Triggering of CD8 with its natural ligand(s), represented by soluble HLA class I (sHLA-I), isolated either from serum of healthy donors or from HLA-I(-) 721.221 lymphoblastoid cell line transfected with HLA-A2, -Cw4, and -Bw46 alleles, or HLA-G1 leads to NK cell apoptosis. The magnitude of this effect directly correlated with the level of CD8 expression. sHLA-I-induced apoptosis depends on the interaction with CD8, as it was inhibited by masking this molecule with specific monoclonal antibodies (mAbs). Moreover, sHLA-I or CD8 cross-linking with specific mAbs elicited intracellular calcium increases, Fas ligand (FasL) messenger RNA transcription, and FasL secretion, which were needed for delivering the death signal. Indeed, this apoptosis was inhibited by preincubation of NK cell clones with Fas or FasL antagonist mAbs, indicating that the Fas/FasL pathway is involved. Furthermore, members of the inhibitory receptor superfamily, such as CD94/NKG2 complex or killer inhibitory receptors, were shown to exert an inhibitory effect on sHLA-I-mediated apoptosis and secretion of FasL. These findings suggest that interaction between sHLA-I and CD8 evokes an apoptotic signal that is down-regulated by inhibitory receptor superfamily that function as survival receptors in NK cells.

Apoptosis↗
PubMed2004

Sam68 exerts separable effects on cell cycle progression and apoptosis.

BACKGROUND: The RNA-binding protein Sam68 has been implicated in a number of cellular processes, including transcription, RNA splicing and export, translation, signal transduction, cell cycle progression and replication of the human immunodeficiency virus and poliovirus. However, the precise impact it has on essential cellular functions remains largely obscure. RESULTS: In this report we show that conditional overexpression of Sam68 in fibroblasts results in both cell cycle arrest and apoptosis. Arrest in G1 phase of the cell cycle is associated with decreased levels of cyclins D1 and E RNA and protein, resulting in dramatically reduced Rb phosphorylation. Interestingly, cell cycle arrest does not require the specific RNA binding ability of Sam68. In marked contrast, induction of apoptosis by Sam68 absolutely requires a fully-functional RNA binding domain. Moreover, the anti-cancer agent trichostatin A potentiates Sam68-driven apoptosis. CONCLUSIONS: For the first time we have shown that Sam68, an RNA binding protein with multiple apparent functions, exerts functionally separable effects on cell proliferation and survival, dependent on its ability to bind specifically to RNA. These findings shed new light on the ability of signal transducing RNA binding proteins to influence essential cell function. Moreover, the ability of a class of anti-cancer therapeutics to modulate its ability to promote apoptosis suggests that Sam68 status may impact some cancer treatments.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Rubia cordifolia, Fagonia cretica linn and Tinospora cordifolia exert neuroprotection by modulating the antioxidant system in rat hippocampal slices subjected to oxygen glucose deprivation.

BACKGROUND: The major damaging factor during and after the ischemic/hypoxic insult is the generation of free radicals, which leads to apoptosis, necrosis and ultimately cell death. Rubia cordifolia (RC), Fagonia cretica linn (FC) and Tinospora cordifolia (TC) have been reported to contain a wide variety of antioxidants and have been in use in the eastern system of medicine for various disorders. However, their mechanism of action was largely unknown. We therefore selected these herbs for the present study to test their neuroprotective ability and the associated mechanism in rat hippocampal slices subjected to oxygen-glucose deprivation (OGD). METHODS: Hippocampal Slices were subjected to OGD (oxygen glucose deprivation) and divided into 3 groups: control, OGD and OGD + drug treated. Cytosolic Cu-Zn superoxide dismutase (Cu-Zn SOD), reduced glutathione (GSH), glutathione peroxidase (GPx), nitric oxide (NO) was measured as nitrite (NO2) in the supernatant and protein assays were performed in the respective groups at various time intervals. EPR was used to establish the antioxidant effect of RC, FC and TC with respect to superoxide anion (O2.-), hydroxyl radicals (. OH), nitric oxide (NO) radical and peroxynitrite anion (ONOO) generated from pyrogallol, menadione, DETA-NO and Sin-1 respectively. RT-PCR was performed for the three groups for GCLC, iNOS, Cu-Zn SOD and GAPDH gene expression. RESULTS: All the three herbs were effective in elevating the GSH levels, expression of the gamma-glutamylcysteine ligase and Cu-Zn SOD genes. The herbs also exhibited strong free radical scavenging properties against reactive oxygen and nitrogen species as studied by electron paramagnetic resonance spectroscopy. In addition all the three herbs significantly diminished the expression of iNOS gene after 48 hours which plays a major role in neuronal injury during hypoxia/ischemia. CONCLUSIONS: RC, FC and TC therefore attenuate oxidative stress mediated cell injury during OGD and exert the above effects at both the cytosolic as well as at gene expression level and may be an effective therapeutic tool against ischemic brain damage.

Animals↗
PubMed2006

Interleukin-1beta and anaphylatoxins exert a synergistic effect on NGF expression by astrocytes.

C3a and C5a anaphylatoxins are proinflammatory polypeptides released during complement activation. They exert their biological activities through interaction with two G protein-coupled receptors named C3aR and C5aR, respectively. In the brain, these receptors are expressed on glial cells, and some recent data have suggested that anaphylatoxins could mediate neuroprotection. In this study, we used RT-PCR and ribonuclease protection assays (RPA) to investigate the role of anaphylatoxins on neurotrophin expression by the human glioblastoma cell line T98G and by rat astrocytes. Our data show that for both cell types, anaphylatoxins upregulate expression of NGF mRNA. This response depended on a G protein-coupled pathway since pre-treatment of cells with pertussis toxin (PTX) completely blocked NGF mRNA increases. This effect was anaphylatoxin-specific since pre-incubation with anti-C3a or anti-C5aR antibodies abolished the effects of C3a and C5a, respectively. The regulation of NGF mRNA by anaphylatoxins was not accompanied by translation into protein expression, but there was a significant synergic effect of anaphylatoxins/IL-1b costimulation. Our demonstration of involvement of anaphylatoxins in the NGF release process by astrocytes suggests that C3a and C5a could modulate neuronal survival in the CNS.

Journal Article↗
PubMedDate not supplied

Strength capabilities and subjective limits in repetitive manual exertions: task and hand dominance effects.

Strength and subjectively determined exertion limits are used widely for ergonomic evaluation. Although compilations of such data for the hand and finger exist, several important limitations include the use of inexperienced participants and constrained postures. In this study both strength and maximum acceptable limits (MAL, 2-hour duration) were obtained from both industrial workers and inexperienced volunteers in 10 simulated hand-intensive automotive assembly tasks. To expand the applicability of the results, the effects of hand-dominance were also determined. Results were compared with existing recommendations (by Kodak and the American Conference of Governmental Industrial Hygienists threshold limit value for hand-intensive activities), and showed that across the diverse tasks the former yields values slightly below the 1st percentile of MAL, whereas the latter values are slightly higher than the 25th percentile. MALs were found to be approximately 50% of strength, consistent with earlier reports, and suggesting that acceptable limits are strongly influenced by physical capacity. Substantial differences ( approximately 30%) in strength and MALs were found between the two participant groups, emphasizing that participants should resemble the target population. Hand-dominance effects were statistically significant though of moderate size ( approximately 5%). Strength and MAL distributions are provided that can be used for evaluation and design of a variety of hand-intensive occupational tasks.

Adult↗
PubMed2005

T helper type 1 and type 2 cytokines exert divergent influence on the induction of prostaglandin E2 and hyaluronan synthesis by interleukin-1beta in orbital fibroblasts: implications for the pathogenesis of thyroid-associated ophthalmopathy.

Thyroid-associated ophthalmopathy (TAO) is an autoimmune component of Graves' disease characterized by intense inflammation in the setting of volume expansion. At the heart of orbital susceptibility to Graves' disease appears to be the peculiar phenotype of orbital fibroblasts that, when activated by IL-1beta and other proinflammatory cytokines, produce excess prostaglandin E2 (PGE2) and hyaluronan. T helper type 1 (Th1) cytokines predominate early in TAO, whereas Th2 cytokines are more abundant later. It is currently unknown whether this transition might promote changes in tissue reactivity associated with disease progression. We report here that interferon-gamma and IL-4, representative of these respective classes of cytokines, attenuate IL-1beta-provoked PGE2 production. This down-regulation is mediated by blocking the induction of prostaglandin endoperoxide H synthase-2 (PGHS-2), the inflammatory cyclooxygenase. The mechanism involves blockade by IL-4 and interferon-gamma of the IL-1beta-dependent activation of PGHS-2 gene promoter activity. In addition, interferon gamma inhibits IL-1beta-provoked PGHS-2 mRNA stability. The actions of interferon-gamma and IL-4 are mediated through the Janus kinase 2/signal transducer and activator of transcription signaling pathway and could be abolished by treating with AG490, a specific inhibitor of Janus kinase 2. In contrast, the up-regulation of hyaluronan synthesis by IL-1beta is enhanced by either IL-4 or interferon-gamma. The latter two cytokines enhance the induction by IL-1beta of hyaluronan synthase-2 expression. These unexpected findings indicate that the Th1-->Th2 cytokine transition exerts equivalent influence on PGE2 and hyaluronan production as TAO progresses from early to late stage.

Cyclooxygenase 2↗
PubMed1985

Glucose exerts opposite effects on muscarinic receptor binding to A and B cells of the endocrine pancreas.

Ambient glucose stimulates insulin but inhibits glucagon secretion. We investigated whether mirror-image regulation pertains also to glucose effects on muscarinic receptor binding to B and A cells. We compared binding of [3H]methylscopolamine to islets from normal guinea pigs and to A-cell rich islets from streptozotocin-treated animals. Binding was assessed in intact islets at 37 C after previous culture for 72 h in 3.3, 5.5, or 11 mM glucose. For both types of islets, specific binding was observed after 1 min and reached a plateau after 10 min of incubation. Half-maximal displacement of 2.8 X 10(-9) M [3H] methylscopolamine occurred with 10(-9) - 10(-8) M unlabeled methylscopolamine. In normal islets, specific binding was significantly higher after culture in 11 mM than after 3.3 or 5.5 mM glucose. Conversely, in A-cell rich islets, binding was significantly higher at 3.3 or 5.5 than at 11 mM glucose. Glucagon release induced by acetylcholine (10(-5) M) was half-maximally suppressed by methylscopolamine at a concentration of 10(-9) - 10(-8) M. Acetylcholine-stimulated glucagon release was higher from A-cell rich islets when cultured at 3.3 mM than when cultured at 11 mM glucose. It is concluded: 1) that both A and B cells appear to contain muscarinic receptors, 2) that long term glucose environment exerts opposite effects on binding of methylscopolamine to A and B cells, and 3) that inhibition of binding to A cells is correlated with reduction of acetylcholine-induced glucagon release.

Animals↗
PubMed1988

Triiodothyronine exerts direct cell-specific regulation of thyrotropin-releasing hormone gene expression in the hypothalamic paraventricular nucleus.

Thyroid hormone administered systemically exerts negative feedback control of biosynthesis of the TRH pro-hormone in the hypothalamic paraventricular nucleus (PVN), the origin of neurons that regulate anterior pituitary TSH secretion, but not in any other group of TRH-synthesizing neurons in the brain. To determine whether this response is mediated by direct effects on PVN neurons, we studied the effect of unilateral stereotaxic implants of L-T3 into the anterior hypothalamus on the concentration of pro-TRH mRNA and pro-TRH in the PVN of hypothyroid rats. Because hypothalamic-pituitary-thyroid function is also regulated by central catecholamines, we also determined the effect of unilateral ablation of ascending catecholaminergic fibers to one side of the PVN by stereotaxic injection of 6-hydroxydopamine or transection of ascending catecholaminergic pathways. T3-implanted hypothyroid animals showed a marked reduction in pro-TRH mRNA and immunoreactive pro-TRH in medial parvocellular neurons of the PVN on the same side as the implant, but not in contralateral PVN neurons or TRH-synthesizing neurons in other hypothalamic regions. In contrast, hypothyroid animals implanted with pellets of hormonally inactive 3,5-diiodo-L-thyronine showed intense symmetric hybridization and immunoreaction product in both wings of the PVN. Despite marked unilateral reduction in the catecholamine innervation to the PVN, no reduction in pro-TRH mRNA or immunoreactive pro-TRH was observed in the PVN on the affected side compared to that on the unaffected side. These studies demonstrate that negative feedback regulation of thyroid hormone occurs directly on TRH neurons and is restricted only to those in the PVN tuberoinfundibular system.

Animals↗
PubMed1994

Evidence that growth hormone stimulates milk synthesis by direct action on the mammary gland and that prolactin exerts effects on milk secretion by maintenance of mammary deoxyribonucleic acid content and tight junction status.

Both PRL and GH play a role in maintaining lactation in the rat, although GH can only maintain pup weight gain at around 50% of the control value, whereas PRL can maintain weight gain close to 90% in the absence of GH. In this study we examined the effects of PRL and GH deficiency (using bromocriptine and an antiserum to rat GH) on milk yield and composition in lactating rats. Treatment with bromocriptine to suppress PRL secretion for 48 h led to a 57% decrease in milk yield with a concomitant decrease in milk protein and lactose yields, but no decrease in fat output. This led to the production of milk with a lower lactose concentration but increased concentrations of protein and particularly fat (increased 100%), which suggests that GH serves an auxiliary role by maintaining an energy-rich milk for the neonate when PRL secretion is reduced. This decrease in milk synthesis was accompanied by decreases in total mammary DNA content and increased milk sodium concentrations. The latter indicates the opening of tight junctions between mammary epithelial cells, which normally occurs during dedifferentiation and involution of the mammary gland. This suggests that PRL maintains milk synthesis at least in part by inhibiting epithelial cell loss and maintaining cellular differentiation. A deficiency in GH, by contrast, caused only a small decrease (24%) in milk yield and had no effect on the major constituents of milk or on milk sodium concentrations or total mammary DNA content. When animals were made deficient in both PRL and GH, however, there was a further marked decrease (88%) in milk volume along with the yields of all major milk constituents, confirming our previous findings that PRL and GH are the major regulators of milk synthesis. Recent studies have indicated that GH exerts direct effects on mammary gland growth, but its actions on milk secretion have been proposed to be mediated indirectly via insulin-like growth factor-I (IGF-I). We, therefore, inhibited lactation by inducing PRL and GH deficiency for 48 h and then attempted to reinitiate it by administering GH either systemically or by local oil-based implants into the mammary gland. Oil-based GH implants were as effective in stimulating milk secretion in the treated (but not contralateral, control) gland as was systemic GH treatment. Thus, GH does act directly on the mammary gland to stimulate milk synthesis, although this does not rule out the possibility that GH acts by stimulating local production of IGF-I.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1994

1,25-Dihydroxy-24-OXO-16ene-vitamin D3, a renal metabolite of the vitamin D analog 1,25-dihydroxy-16ene-vitamin D3, exerts immunosuppressive activity equal to its parent without causing hypercalcemia in vivo.

The hormone, 1,25-(OH)2D3, is metabolized into 1,25-(OH)2-24-OXO-D3, in kidney prior to conversion to its final inactive product, calcitroic acid. Similarly, 1,25-(OH)2-24OXO-16eneD3, is produced in the kidney from the Vitamin D analog, 1,25-(OH)2-16eneD3, but resists further hydroxylation. The analog's metabolite was synthesized and its biologic activity compared to the parent compound. Naive SJL/J mice, 4 weeks old, were immunized with neuroantigen in adjuvant to induce experimental autoimmune encephalomyelitis [EAE]. Treatment with 1,25-(OH)2-24OXO-16eneD3 was given at 0.05, 0.15 and 0.3 microgram I.P., on alternate days, starting 3 days prior and for up to 5 days post immunization and compared to a similar treatment with 0.1 microgram 1,25-(OH)2D3 or 1,25-(OH)2-16eneD3. Suppression of EAE was observed with 0.15 microgram 1,25-(OH)2-24OXO-16eneD3, comparable to the suppression induced with the parent compound and more potent than 1,25-(OH)2D3. However, no hypercalcemia was seen in mice treated with 0.15 microgram of OXO-metabolite (9.7 +/- 0.6 vs 9.3 +/- 1.1 mg/dl, treated vs controls), in contrast to 1,25-(OH)2D3 and 1,25-(OH)2-16eneD3 (11.2 +/- 1.0 and 11.0 +/- 0.9 mg/dl respectively; p < 0.001). In summary, our results suggest that 1,25-(OH)2-24OXO-16eneD3, a stable intermediary metabolite of the vitamin D analog, 1,25-(OH)2-16eneD3 exerts immunosuppressive activity equal to its parent without causing hypercalcemia in vivo.

Animals↗
PubMed1996

Sex steroid binding protein exerts a negative control on estradiol action in MCF-7 cells (human breast cancer) through cyclic adenosine 3',5'-monophosphate and protein kinase A.

Estradiol is considered to be a critical factor in the growth induction of some breast cancer cells, like MCF-7 cell line. Among other compounds involved in the control of neoplastic mammary cell growth, cAMP has been suggested, on the other hand, to exert an antiproliferative effect. Sex steroid binding protein (SBP) sex hormone binding globulin (SHBG), the plasma carrier for both androgens and estradiol, recognizes a specific receptor located on membranes of estrogen- and androgen-sensitive tissue and cultured cells (e.g. MCF-7 cell). The interaction of estradiol with the receptor-bound SBP has been reported to induce a significant accumulation of cAMP in MCF-7 cells; in addition, a negative modulation of estradiol induced proliferation of these cells has been described after treatment with SBP. We report here a more detailed observation about the effect of SBP on MCF-7 cell estradiol-induced growth as well as the possible linkage between SBP and its membrane receptor and protein kinase A activity. MCF-7 cell growth was induced by estradiol, but the effect of estradiol was completely abolished by cell treatment with both SBP and estradiol. The inhibitory effect of SBP was highly specific. Because it was suggested that SBP might act through cAMP, we investigated the effect of SBP and estradiol in cells treated with protein kinase A inhibitor peptide (6-22) amide, a specific inhibitor of the cAMP target protein kinase A. The blockade of PKA had no effect on estradiol action on cell growth but masked completely the effect of SBP because MCF-7 increased growth sustained by estradiol was fully detectable also in the presence of SBP. We also observed that MCF-7 cells treated with increasing doses of 8Br-cAMP, cAMP analog and PKA activator, showed a progressive reduction of their growth. 8Br-cAMP was also able to inhibit estradiol promotion of MCF-7 cell growth. The inhibitory effect of 8Br-cAMP on estradiol-induced proliferation was already detectable at analog concentration of 100 nM, which has been reported to be the level reached by cAMP in MCF-7 cells treated with SBP and estradiol. In conclusion, the present study strongly confirms our previous observation that SBP inhibits the estradiol induction of MCF-7 cell growth, appropriately suggesting that this SBP action, a consequence of the interaction with the receptor, is likely to be mediated by cAMP and PKA. In addition, the study implies a significant role of cAMP in the control of breast cancer cell growth.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed2002

Estradiol and interleukin-1beta exert a synergistic stimulatory effect on the expression of the chemokine regulated upon activation, normal T cell expressed, and secreted in endometriotic cells.

Endometriosis, commonly associated with intraperitoneal inflammation, is estrogen dependent. Possible links between the immunoinflammatory and endocrine changes observed in endometriotic women have been poorly understood. In this study, we report that estradiol (E(2)) and IL-1beta exert a synergistic stimulatory action on RANTES (regulated upon activation, normal T cell expressed, and secreted) expression by endometriotic cells. Treatment of endometriotic cells with IL-1beta had a dose-dependent effect on RANTES protein secretion and mRNA steady state levels, whereas cell treatment with E(2) or progesterone had no detectable effect. Interestingly, treatment of endometriotic cells with E(2) before stimulation with IL-1beta resulted in a further increase in RANTES protein secretion and mRNA steady state levels, compared with IL-1beta alone, whereas treatment with progesterone did not significantly affect cell responsiveness to IL-1beta. Assessment of RANTES mRNA half-life revealed that cell pretreatment with E(2) enhanced RANTES mRNA stability and increased gene transcription as shown by run-on analysis. Immunohistochemical analysis of RANTES in endometriotic tissue showed immunostaining to be predominant in the stroma with no noticeable differences in tissues from the proliferative and secretory phase of the menstrual cycle. This appears to be consistent with the cell culture data and indicates that RANTES expression in endometriotic tissue is not subject to cyclic variation. These findings reveal a new regulatory mechanism by which IL-1beta produced by activated macrophages can in synergy with ovarian and locally produced E(2) lead to enhanced macrophage and T-lymphocyte recruitment, thereby exacerbating the local immunoinflammatory process. Furthermore, the findings provide a further evidence for a close relationship between the endocrine and immunological changes observed in endometriosis.

Adolescent↗
PubMed2003

Intensive insulin therapy exerts antiinflammatory effects in critically ill patients and counteracts the adverse effect of low mannose-binding lectin levels.

Adverse outcome of critical illness is often caused by systemic inflammation and sepsis. A recent study showed that mortality is significantly reduced by maintenance of normoglycemia using intensive insulin therapy. We examined whether the beneficial effects of intensive insulin therapy involve modulations of mannose-binding lectin (MBL) and C-reactive protein (CRP) levels. From a study of 1548 patients randomly assigned to either conventional treatment or intensive insulin therapy at an intensive care unit (ICU) we included all 451 patients who needed prolonged intensive care (>5 d). CRP and MBL concentrations were measured on admission, d 5, d 15, and the last day in the ICU. In all patients, serum MBL concentrations increased with time in the ICU (P < 0.0001). This acute phase response was suppressed by intensive insulin therapy at all time points studied (P < 0.02). Selectively in patients receiving conventional therapy, MBL concentrations at baseline were almost 3 times higher in survivors than in nonsurvivors (P = 0.04). Baseline CRP concentrations were elevated, but decreased with time in ICU (P < 0.0001). The decrease in CRP was significantly more pronounced in the intensive insulin-treated patients compared with the conventionally treated patients (P </= 0.02) at all time points. Multivariate logistic regression analysis, corrected for all other determinants of outcome, revealed that the antiinflammatory action on CRP, but not on MBL, largely explained the beneficial effects of intensive insulin therapy on morbidity and mortality. In conclusion, intensive insulin therapy exerts a powerful antiinflammatory effect during critical illness which at least partially explains improvement in morbidity and mortality. Possible adverse effects of low baseline MBL are overcome by intensive insulin therapy.

Anti-Inflammatory Agents↗
PubMed2003

Ghrelin main action on the regulation of growth hormone release is exerted at hypothalamic level.

Ghrelin, a recently isolated hormone, seems to participate in the physiological regulation of GH secretion. Exogenously administered ghrelin stimulates GH discharge in all species so far tested including man, but whether this action is exerted at pituitary or alternatively at hypothalamic level is not known at present. To understand the point of ghrelin action a group of patients with organic lesion mainly in the hypothalamic area and matched controls were studied. Patients showed a severe GH deficiency after hypothalamic stimulation (ITT), but partial response after GHRH administration. Cases and controls were tested on three separate days by either ghrelin; GHRH; and ghrelin plus GHRH; always at 1 micro g/Kg iv. The mean GH peak after stimulation in the patients were: 0.4 +/- 0.1 micro g/L by ITT; 3.1 +/- 0.5 micro g/L after GHRH; 2.0 +/- 0.8 micro g/L after ghrelin; and 9.6 +/- 2.9 micro g/L after the combination of GHRH plus ghrelin. In the controls GHRH induced a GH peak of 21.2 +/- 7.5 micro g/L, and 75.1 +/- 16.0 micro g/L after ghrelin with a peak after GHRH + ghrelin of 103.5 +/- 26.4 micro g/L. These data indicate that when hypothalamic structures are not operative ghrelin, either alone or in combination with GHRH, is not able to significantly release GH. In addition to postulating a hypothalamic point of action for the ghrelin-induced GH secretion, these results suggests that ghrelin will not have significant clinical utility in patients with GH deficiency due to organic lesion.

Adult↗
PubMed1981

Physiological concentrations of growth hormone exert insulin-like and insulin antagonistic effects on both hepatic and extrahepatic tissues in man.

To determine whether increments in circulating GH concentrations within the physiological range would exert insulin-like as well as insulin-antagonistic actions in man and, if so, whether both actions would occur in hepatic and extrahepatic tissues, normal volunteers (n = 6) were infused with human GH (hGH; 100 ng/kg . min) for 6 h along with somatostatin (100 micrograms/h) to suppress insulin, glucagon, and hGH secretion and also with sufficient insulin (100 microU/kg . min) to maintain a constant plasma insulin level. During the final 2 h, glucose (2 mg/kg . min) was infused. In control studies, saline was infused instead of hGH. Infusion of hGH increased plasma hGH to 35 ng/ml. Plasma glucose decreased to 60 +/- 2 mg/dl compared to 67 +/- 1 mg/dl observed in control studies (P less than 0.05); this greater hypoglycemia was due to both greater suppression of hepatic glucose production (P less than 0.05) and greater augmentation of glucose clearance (P less than 0.05). These insulin-like effects of hGH were no longer evident after 2 h. Subsequently, when glucose was infused, plasma glucose increased to 133 +/- 4 mg/dl compared to the 104 +/- 6 mg/dl observed in control studies (P less than 0.01). This greater hyperglycemia was due to both impaired suppression of hepatic glucose production (P less than 0.001) and decreased glucose clearance (P less than 0.01). These results indicate that physiological increments in plasma hGH cause both insulin-like and insulin-antagonistic effects in man and that these actions occur in hepatic as well as extrahepatic tissues. The insulin-like actions of hGH are transient.

Adult↗
PubMed1986

Atropine blockade of growth hormone (GH)-releasing hormone-induced GH secretion in man is not exerted at pituitary level.

The role of acetylcholine (Ach) in the regulation of human GH secretion was assessed using atropine, which selectively blocks cholinergic muscarinic receptors. Paired tests were performed in seven normal subjects using GH-releasing hormone (GHRH) 1-44 (1 microgram/kg iv), with and without atropine pretreatment (1 mg im). The GHRH 1-44-induced GH secretory peak [20.7 +/- 4.5 (SEM) ng/ml] was completely blocked by atropine administration (2.3 +/- 0.6 ng/ml) (P less than 0.01). To determine whether this atropine blockade was at the pituitary level, a series of in vitro studies were conducted using monolayer cultures of cells from bovine anterior pituitary glands. GHRH 1-44 (10(-8) M) stimulated bovine GH release (11.1 +/- 1.5 micrograms/ml) as compared to control values (5.1 +/- 0.4 microgram/ml) (P less than 0.01). This response was not altered by 10(-6) M atropine (14.9 +/- 0.9 microgram/ml). Similar results were obtained with GHRH, 10(-9) M, with or without atropine, 10(-7) M. Addition of 10(-6) M Ach to the incubation medium significantly increased bovine GH release (12.7 +/- 1.2 microgram/ml) and the effect of 10(-6) M Ach and 10(-8) M GHRH was additive (20.9 +/- 2.1 micrograms/ml) (P less than 0.01). Similar results were obtained with Ach, 10(-5) M, and GHRH, 10(-9) M. Atropine or eserine alone did not alter basal GH secretion, and atropine blocked Ach-stimulating activity. In conclusion, atropine blockade of GHRH-induced GH secretion appears to be exerted at a site other than pituitary.

Acetylcholine↗