Longest survival with primary intracranial malignant melanoma: A case report and literature review.

BACKGROUND: Primary intracranial malignant melanoma (PIMM) is rare, and its prognosis is very poor. It is not clear what systematic treatment strategy can achieve long-term survival. This case study attempted to identify the optimal strategy for long-term survival outcomes by reviewing the PIMM patient with the longest survival following comprehensive treatment and by reviewing the related literature. CASE SUMMARY: The patient is a 47-year-old Chinese man who suffered from dizziness and gait disturbance. He underwent surgery for right cerebellum melanoma and was subsequently diagnosed by pathology in June 2000. After the surgery, the patient received three cycles of chemotherapy but relapsed locally within 4 mo. Following the second surgery for total tumor resection, the patient received an injection of Newcastle disease virus-modified tumor vaccine, interferon, and ß-elemene treatment. The patient was tumor-free with a normal life for 21 years before the onset of the recurrence of melanoma without any symptoms in July 2021. A third gross-total resection with adjuvant radiotherapy and temozolomide therapy was performed. Brain magnetic resonance imaging showed no residual tumor or recurrence 3 mo after the 3rd operation, and the patient recovered well without neurological dysfunction until the last follow-up in June 2022, which was 22 years following the initial treatment. CONCLUSION: It is important for patients with PIMM to receive comprehensive treatment to enable the application of the most appropriate treatment strategies. Long-term survival is not impossible in patients with these malignancies.

Effects of adrenomedullin on the expression of inflammatory cytokines and chemokines in oviducts from women with tubal ectopic pregnancy: an in-vitro experimental study.

BACKGROUND: The occurrence of tubal ectopic pregnancy (tEP) is related to the inflammation of the oviduct. Recently, Adrenomedullin (ADM) was found highly expression in human oviduct. The current study is to investigate whether ADM have a modulatory action on inflammatory cytokines and chemokines in oviductal tissue from women with tubal ectopic pregnancy (tEP). METHODS: Oviductal isthmus samples were collected from women with tEP undergoing salpingectomy, and women undergoing hysterectomy for benign gynaecological conditions. The mRNA and protein levels of inflammatory cytokines/chemokines were assayed by PCR (n = 6 for tEP, n = 5 for controls) and protein microarray methods (n = 5 for both tEP and controls) respectively. RESULTS: Some of the inflammatory cytokines/chemokines were upregulated by ADM in oviducts from tEP patients at both mRNA and protein levels. Incubation of oviduct from tEP patients with ADM for 24 h down-regulated some of these cytokines/chemokines. CONCLUSION: Our results suggest an additional mechanism whereby ADM insufficiency may increase the susceptibility to tEP through diminished anti-inflammatory activity. The actual impact of the relationship between ADM and inflammatory process on tubal implantation needs further exploration.

Adrenomedullin increases the short-circuit current in the mouse seminal vesicle: actions on chloride secretion.

Adrenomedullin (ADM) may regulate seminal vesicle fluid secretion, and this may affect sperm quality. In this study, we investigated the effect of ADM on chloride secretion in the mouse seminal vesicle. The presence of ADM in mouse seminal vesicle was confirmed using immunostaining, and the molecular species was determined using gel filtration chromatography coupled with enzyme-linked assay for ADM. The effects of ADM on chloride secretion were studied by short-circuit current technique in a whole-mount preparation of mouse seminal vesicle in an Ussing chamber. The effects of specific ADM and calcitonin gene-related peptide (CGRP) receptor antagonists were investigated. Whether the ADM effect depended on the cAMP- and/or calcium-activated chloride channel was also studied using specific chloride channel blockers. The results showed that ADM was present in seminal vesicle epithelial cells. The major molecular species was precursor in the mouse seminal vesicle. ADM increased short-circuit current through the calcium-activated chloride channel in mouse seminal vesicle, and CGRP receptor was involved. We conclude that ADM may regulate chloride and fluid secretion from the seminal vesicle, which may affect the composition of the seminal plasma bathing the sperm and, hence, fertility.

Adrenomedullin and diabetes.

Adrenomedullin (ADM) is a peptide hormone widely expressed in different tissues, especially in the vasculature. Apart from its vasodilatatory and hypotensive effect, it plays multiple roles in the regulation of hormonal secretion, glucose metabolism and inflammatory response. ADM regulates insulin balance and may participate in the development of diabetes. The plasma level of ADM is increased in people with diabetes, while in healthy individuals the plasma ADM concentration remains low. Plasma ADM levels are further increased in patients with diabetic complications. In type 1 diabetes, plasma ADM level is correlated with renal failure and retinopathy, while in type 2 diabetes its level is linked with a wider range of complications. The elevation of ADM level in diabetes may be due to hyperinsulinemia, oxidative stress and endothelial injury. At the same time, a rise in plasma ADM level can trigger the onset of diabetes. Strategies to reduce ADM level should be explored so as to reduce diabetic complications.

Intermedin attenuates LPS-induced inflammation in the rat testis.

First reported as a vasoactive peptide in the cardiovascular system, intermedin (IMD), also known as adrenomedullin 2 (ADM2), is a hormone with multiple potent roles, including its antioxidant action on the pulmonary, central nervous, cardiovascular and renal systems. Though IMD may play certain roles in trophoblast cell invasion, early embryonic development and cumulus cell-oocyte interaction, the role of IMD in the male reproductive system has yet to be investigated. This paper reports our findings on the gene expression of IMD, its receptor components and its protein localization in the testes. In a rat model, bacterial lippolysaccharide (LPS) induced atypical orchitis, and LPS treatment upregulated the expression of IMD and one of its receptor component proteins, i.e. receptor activity modifying protein 2 (RAMP2). IMD decreased both plasma and testicular levels of reactive oxygen species (ROS) production, attenuated the increase in the gene expression of the proinflammatory cytokines tumor necrosis factor alpha (TNFα), interleukin 6 (IL6) and interleukin 1 beta (IL1ß), rescued spermatogenesis, and prevented the decrease in plasma testosterone levels caused by LPS. The restorative effect of IMD on steroidogenesis was also observed in hydrogen peroxide-treated rat primary Leydig cells culture. Our results indicate IMD plays an important protective role in spermatogenesis and steroidogenesis, suggesting therapeutic potential for IMD in pathological conditions such as orchitis.

Decreases in adrenomedullin expression and ciliary beat frequency in the nasal epithelium in tubal pregnancy.

OBJECTIVE: To study adrenomedullin (ADM) expression and its relation to ciliary beat frequency (CBF) in the nasal mucociliated epithelium in tubal ectopic pregnancy (tEP). DESIGN: Experimental study. SETTING: University teaching hospital. PATIENT(S): Women with tEP and normal intrauterine pregnancy matched for age and gestational age were recruited. Healthy nonpregnant women were also recruited as nonpregnant controls. INTERVENTION(S): Nasal epithelial brushing. MAIN OUTCOME MEASURE(S): Adrenomedullin expression in nasal epithelium (measured by real-time reverse transcription-polymerase chain reaction, plasma ADM concentration (measured by ELISA), and CBF (measured by photometric method). RESULT(S): We have demonstrated a similar decrease in ADM expression and CBF in the nasal mucociliated epithelium, as well as in plasma ADM concentration, in women with tEP compared with normal pregnant women. Adrenomedullin up-regulates nasal CBF via the ADM receptor, as in the oviduct. There is significant correlation between nasal and oviductal CBF. CONCLUSION(S): Nasal epithelium ADM and CBF, as well as plasma ADM, are possible predictors of women at risk of tEP.

Intermedin in rat uterus: changes in gene expression and peptide levels across the estrous cycle and its effects on uterine contraction.

BACKGROUND: The present study demonstrates the expression of intermedin (IMD) and its receptor components in the uterus of the female rat during the estrous cycle and its effect on uterine contraction. METHODS: The gene expression level of intermedin and its receptor components and the peptide level of intermedin were studied by real-time RT-PCR and enzyme immunoassay (EIA) respectively. The separation of precursor and mature IMD was studied by gel filtration chromatography and EIA. The localization of IMD in the uterus was investigated by immunohistochemistry. The effect of IMD on in vitro uterine contraction was studied by organ bath technique. RESULTS: Uterine mRNAs of Imd and its receptor components and IMD levels displayed cyclic changes across the estrous cycle. Imd mRNA level was the highest at proestrus while the IMD level was the highest at diestrus. IMD was found in the luminal and glandular epithelia and IMD treatment significantly reduced the amplitude and frequency of uterine contraction but not the basal tone. Both calcitonin gene-related peptide (CGRP) receptor antagonist hCGRP8-37 and adrenomedullin (ADM) receptor antagonist hADM22-52 partially abolished the inhibitory effect of IMD on uterine contraction while the specific IMD receptor antagonist hIMD17-47 completely blocked the actions. The enzyme inhibitors of NO (L-NAME) and PI3K (Wortmannin) pathways diminished the IMD effects on uterine contraction while the cAMP/PKA blocker, KT5720, had no effect, indicating an involvement of NO and PI3K/Akt but not PKA. CONCLUSIONS: IMD and the gene expression of its receptor components are differentially regulated in the uterus during the estrous cycle and IMD inhibits uterine contraction by decreasing the amplitude and frequency.

Possible functions of adrenomedullin from the seminal fluid in the female reproductive tract of the rat.

Adrenomedullin (ADM) is found in male accessory sex glands and is part of the seminal secretion. It plays an important role in protecting the sperm in the female reproductive tract. In this study, we investigated the roles of ADM in inflammation and oxidative stress in the endometrium and in leukocyte and macrophage infiltration in the endometrial stroma. The expression of the ADM gene in the ventral prostate, coagulating gland, and seminal vesicle was determined by real time PCR. The peptide levels in the tissue and secretion were measured using an EIA Kit. The highest ADM mRNA and peptide levels were found in the ventral prostate. Most of the ADM in the seminal vesicle was stored in the tissue while little was secreted. The expression of the IL-1ß gene and the secretion of TNFα and IL-6 in uterine tissue decreased significantly after treatment with ADM for 4 hours. Using an immunostaining method, the levels of leukocyte and macrophage infiltration were found to be lower at 24 hours post coitus than 1.5 hours post coitus. The infusion of ADM receptor antagonist reduced the infiltration of leukocyte and macrophages in the endometrial stroma at 24 hours post coitus. As to the anti-oxidative effect of ADM in the female tract, the reactive oxygen species (ROS) level in isolated endometrial epithelial cells was significantly decreased after treatment with ADM or seminal fluid. Our findings demonstrated that ADM in the seminal secretion may modify the inflammatory responses, play an anti-oxidative role, and increase leukocyte and macrophage infiltration in the uterus.

Adrenomedullin inhibits norepinephrine-induced contraction of rat seminal vesicle.

OBJECTIVE: To investigate the effect of adrenomedullin (ADM) on seminal vesicle smooth muscle contractions in the rat and the specific receptor involved. Whether it was dependent on the nitric oxidant pathway was also investigated. METHODS: The seminal vesicles from Sprague-Dawley rats aged 8-10 weeks were incubated in Kreb's solution. Using an organ bath technique, the contraction of the seminal vesicle in response to norepinephrine (NE) and ADM was recorded, in the presence or absence of an ADM receptor blocker (hADM22-52), a calcitonin-gene-related peptide (CGRP) receptor blocker (hCGRP8-37), and L-NG-nitroarginine methyl ester, an endothelial nitric oxide synthase inhibitor. The basal tone, amplitude, and frequency of contraction were measured after incubation with the drugs. RESULTS: The results showed that the contraction induced by NE was effectively inhibited by ADM. The basal tone, amplitude, and frequency all decreased. The ADM effects on the NE-induced increases in basal tone and amplitude were completely blocked by hCGRP8-37, the CGRP receptor antagonist, but were not abolished by L-NG-nitroarginine methyl ester. CONCLUSION: The findings have demonstrated that in the seminal vesicle the inhibitory effect of ADM on NE-induced contraction was mediated by the CGRP receptor but not by nitric oxide production.

Preimplantation antagonism of adrenomedullin action compromises fetoplacental development and reduces litter size.

Concentrations of adrenomedullin (ADM) in circulation, the uterus, and corpora lutea (CL) increase during pregnancy. We previously reported a temporal-spatial pattern of ADM level and gene expression of Adm and its receptor components, from early pregnancy through midpregnancy to late pregnancy in rats. Two earlier reports using an in vivo model of ADM antagonism demonstrated the important roles of ADM in the post-implantation period. Treatment with ADM receptor blocker hADM22-52 starting from gestation Day 8 or Day 14 resulted in fetal-placental growth restriction and reduction in litter size. In this study, the endogenous ADM actions were abolished in the preimplantation period by infusing the antagonist for the ADM receptor (hADM22-52) with the osmotic (Alzet) pump from Days 1-4 of pregnancy. We inferred that ADM, acting through the ADM receptor, had critical roles during preimplantation, as brief inhibition of ADM action by hADM22-52 during this period reduced litter size by restricting placental growth and increasing fetal resorption in midpregnancy.

Adrenomedullin: exciting new horizons.

Adrenomedullin is a peptide initially isolated from pheochromocytoma. It has a wide distribution and has multiple actions in many systems including the cardiovascular, renal, endocrine, reproductive, immune, nervous and musculoskeletal systems. This is reflected in the patents. These cover the use of adrenomedullin in diagnosis and as a biomarker for prognosis, especially in cardiovascular diseases and diabetes. It has also been proposed as a therapeutic agent, as a method to promote regeneration and repair, such as in ischaemic conditions and bone fractures. Conversely, its antagonists or antibodies binding it are claimed to have potential use in blocking angiogenesis in cancers.

Adrenomedullin in rat follicles and corpora lutea: expression, functions and interaction with endothelin-1.

BACKGROUND: Adrenomedullin (ADM), a novel vasorelaxant peptide, was found in human/rat ovaries. The present study investigated the interaction of ADM and endothelin-1 (ET-1) in follicles and newly formed corpora lutea (CL) and the actions of ADM on progesterone production in CL during pregnancy. METHODS: The peptide and gene expression level of adrenomedullin in small antral follicles, large antral follicles and CL was studied by real-time RT-PCR and EIA. The effect of ADM treatment on oestradiol production in 5-day follicular culture and on progesterone production from CL of different pregnant stages was measured by EIA. The interaction of ADM and ET-1 in follicles and CL at their gene expression level was studied by real-time RT-PCR. RESULTS: In the rat ovary, the gene expression of Adm increased during development from small antral follicles to large antral follicles and CL. In vitro treatment of preantral follicular culture for 5 days with ADM increased oestradiol production but did not affect follicular growth or ovulation rate. The regulation of progesterone production by ADM in CL in culture was pregnancy-stage dependent, inhibitory at early and late pregnancy but stimulatory at mid-pregnancy, which might contribute to the high progesterone production rate of the CL at mid-pregnancy. Moreover, the interaction between ADM and ET-1 at both the production and functional levels indicates that these two vasoactive peptides may form an important local, fine-tuning regulatory system together with LH and prolactin for progesterone production in rat CL. CONCLUSIONS: As the CL is the major source of progesterone production even after the formation of placenta in rats, ADM may be an important regulator in progesterone production to meet the requirement of pregnancy.

Coexpression of adrenomedullin and its receptor component proteins in the reproductive system of the rat during gestation.

BACKGROUND: Adrenomedullin (ADM), a novel vasorelaxant peptide, was found in human/rat ovaries and uteri. Plasma ADM level increases in pregnant women and pregnant rats. METHODS: The gene expression levels of Adm and its receptor components - Crlr, Ramp1, Ramp2 and Ramp3, the ADM peptide concentration and localization in the rat female reproductive system during gestation were studied by real-time RT-PCR, EIA and immunohistochemical techniques. RESULTS: The mRNAs of Adm and its receptor component and ADM were differentially distributed between implantation sites and inter-implantation sites of the pregnant uterus. The day on which vaginal sperm were found was taken to be pregnancy day 1. The Adm mRNA levels in the implantation sites of the uteri in mid- (day 12) and late pregnancy (day 17) were more than 10-fold higher than those in nonpregnancy, pre-implantation (day 3) or early (day 7) pregnancy. ADM was localized in the endometrial stroma with increased immunoreactivity from nonpregnancy to pregnancy. The ADM level and the mRNA levels of Adm, Crlr, Ramp2 and Ramp3 in the corpus luteum all increased in late pregnancy compared with early pregnancy. The gene expression of Adm and it receptor components and intense immunostaining of ADM were also found in the oviduct during pregnancy. CONCLUSIONS: The gene expressions levels of Adm and its receptor components - Crlr, Ramp1, Ramp2 and Ramp3, and ADM peptide concentration exhibited a spatio-temporal pattern in the rat female reproductive system during gestation and this suggests that ADM may play important roles in gestation.

Expression of adrenomedullin in human oviduct, its regulation by the hormonal cycle and contact with spermatozoa, and its effect on ciliary beat frequency of the oviductal epithelium.

CONTEXT: Adrenomedullin (ADM) has been found expressed in the mouse oviduct and might play a role in reproduction. OBJECTIVE: The objective of the study was to demonstrate the expression of ADM in the human oviduct, investigate its regulation by steroidal hormones and spermatozoa contact, and study its effect on ciliary beat frequency (CBF) in the human oviduct. DESIGN, SETTING, PATIENTS, AND INTERVENTIONS: Oviducts from women undergoing hysterectomy for benign diseases in a university hospital were collected. The oviducts were treated with estradiol and/or progesterone to simulate different phases of the ovarian cycle. ADM expression was studied at the peptide and mRNA levels by immunohistochemistry and RT-PCR, respectively. CBF was measured after treatment with graded concentrations of ADM and its antagonists. Cells from OE-E6/E7, an immortalized oviductal cell line, as well as oviductal tissue were cocultured with and without direct contact with capacitated human spermatozoa to compare oviductal cell ADM expression levels. CBF was also analyzed in oviductal tissue after spermatozoa-oviduct coincubation. RESULTS: ADM expression was the highest in the isthmic region and in a hormonal environment simulating the early luteal phase. CBF was increased by ADM in a dose-dependent manner, which was blocked by ADM and calcitonin-gene-related peptide receptor antagonists. Direct contact with spermatozoa in coculture resulted in higher ADM expression in OE-E6/E7 cell line and oviductal tissue and higher CBF in oviductal epithelium. CONCLUSIONS: ADM expression in the human oviduct is hormone dependent and is up-regulated by sperm contact. ADM stimulates ciliary motility of the human oviduct.

Coexpression of adrenomedullin and its receptors in the reproductive system of the rat: effects on steroid secretion in rat ovary.

The present study demonstrates the expression of adrenomedullin (ADM) in the reproductive system of the female rat and its effect on the secretion of estradiol and progesterone. Ovarian ADM and Adm mRNA levels were decreased at estrus, whereas oviductal Adm mRNA levels were low at proestrus. Both tissues were shown to coexpress mRNAs encoding the calcitonin receptor-like receptor and receptor activity-modifying protein 1 (Ramp1), Ramp2, and Ramp3. Gel filtration chromatography of ovarian extracts showed two peaks, with the predominant one eluting at the position of authentic rat ADM (1-50) at estrus and at the position of ADM precursor at diestrus. Positive ADM immunostaining was localized in the granulosa and theca cells of the follicle and corpora lutea of the ovary. Adrenomedullin inhibited FSH-induced estradiol secretion in 2-day-old follicles and also suppressed eCG-stimulated progesterone release in corpora lutea. The inhibitory effect of ADM on the follicles and the corpora lutea was abolished by calcitonin gene-related peptide (8-37) and ADM (22-52), respectively. The presence of ADM and the gene expression of ADM and its receptor components in the female reproductive system suggest a paracrine effect of ADM on ovarian steroidogenesis.

Adrenomedullin in the rat testis. I: Its production, actions on testosterone secretion, regulation by human chorionic gonadotropin, and its interaction with endothelin 1 in the leydig cell.

Based on the finding of gene expression of adrenomedullin (Adm) and its receptor components in the rat testis, a paracrine effect of ADM on testicular steroidogenesis has been suggested by our group. The present study demonstrates the gene expression of Adm and the effect of ADM on testosterone production in the Leydig cell. The regulation of ADM by hCG and its interaction with endothelin 1 (EDN1) in the rat Leydig cells are also observed. Primary culture of Leydig cells produced Adm mRNA and secreted 275+/-19 pg immunoreactive ADM per 10(6) cells in 24 h. In addition, the Leydig cell was shown to coexpress mRNAs encoding for the calcitonin receptor-like receptor (CALCRL) and receptor activity-modifying protein (RAMP1, RAMP2, and RAMP3). These may account for the specific binding of ADM to the Leydig cells. Administration of ADM to Leydig cells resulted in an inhibition of hCG- and EDN1-stimulated testosterone production. Correlated with this, ADM reduced EDN1 production, whereas its production was increased by EDN1. Furthermore, the production of ADM and the mRNA levels of Calcrl and Ramp2 were suppressed by hCG. Our results suggest that ADM has an autocrine effect on Leydig cell steroidogenesis, possibly by interacting with EDN1 and under the control of gonadotropin. We propose that there is an ADM/EDN1 local regulatory mechanism that may be important in modulating the control of testicular functions by gonadotropins.

Adrenomedullin in the rat testis. II: Its production, actions on inhibin secretion, regulation by follicle-stimulating hormone, and its interaction with endothelin 1 in the Sertoli cell.

The present study demonstrates the expression of adrenomedullin (ADM) in the rat Sertoli cells and its effect on inhibin production. The regulation of ADM by FSH and its interaction with endothelin 1 (EDN1) in the rat Sertoli cells have also been established. Primary culture of Sertoli cells secreted 414+/-27 pg immunoreactive ADM per 10(6) cells in 24 h and expressed Adm mRNA. In addition, the Sertoli cell was shown to co-express mRNAs encoding for the calcitonin receptor-like receptor (CALCRL) and receptor activity-modifying proteins (RAMPs) 1-3. These may account for the specific binding of ADM to the Sertoli cells. Administration of ADM to Sertoli cells resulted in an enhancement of basal and FSH-stimulated inhibin B production. On the other hand, the production of ADM and the mRNA levels of Calcrl and Ramp2 in the Sertoli cells were suppressed by FSH. The results suggest that ADM, via its control in the secretion of inhibin B, may play a role in regulating spermatogenesis as well as the hypothalamus-pituitary-gonad feedback system. In addition, like in the Leydig cell, ADM and EDN1 were found to regulate the production of each other in opposite directions in the Sertoli cells, suggesting the presence of yet another local regulatory mechanism in the rat testis that may be important in modulating testicular functions regulated by gonadotropins.

Differential regulation of adrenomedullin gene expression in the fundic and pyloric regions of the rat stomach during acute and chronic starvation.

Adrenomedullin (AM) has been shown to be present in the stomach but the role of gastric AM is obscure. To investigate the effects of starvation on AM in the stomach, we studied the changes in gene expression of preproadrenomedullin (preproAM) and AM receptors by reverse transcription-polymerase chain reaction (RT-PCR), and tissue AM concentrations by radioimmunoassay (RIA) in the fundus and pylorus of the stomach of rats subjected to either acute (1-day) or chronic (4-day) starvation. An up-regulation of preproAM gene expression was observed in the fundus after acute starvation, and in the pylorus after chronic starvation. Immunoreactive AM (ir-AM) levels were increased in both fundus and pylorus after chronic starvation. In addition, marked reductions in the gene expression of fundic calcitonin receptor-like receptor (CRLR) and receptor activity-modifying protein (RAMP) 3 as well as the pyloric CRLR and RAMP2 were observed in the chronically starved rats. The present study suggests that the gene expression of preproadrenomedullin mRNA is differentially regulated by starvation in the different parts of the stomach.

Age-related changes in adrenomedullin expression and hypoxia-inducible factor-1 activity in the rat lung and their responses to hypoxia.

Male rats aged 3 months, 12 months and 20 months were subjected to breathing 8% oxygen for 6 hours. Lung preproadrenomedullin (AM) messenger RNA (mRNA) levels were measured by solution hybridization-RNase protection assay while AM was measured by radioimmunoassay. The binding of hypoxia-inducible factor-1alpha (HIF-1alpha) to DNA was determined by electrophoretic mobility shift. There was an age-related increase in basal levels of preproAM mRNA and AM and of the binding of hypoxia-inducible factor (HIF) to DNA. Upon hypoxic stimulation, HIF binding to DNA increased in the young and middle-aged rats, but not in the old rats. AM gene expression increased in response to hypoxia in rats of all ages, but the increase was much less in the old rats. AM peptide levels in the lung decreased with age in hypoxia. In a separate experiment, male rats aged 3 months and 20 months were subjected to hypoxia as described above. PreproAM, calcitonin receptor-like receptor (CRLR), receptor activity modifying protein (RAMP) mRNA, HIF-1 and peptidyl-glycine-amidating monooxygenase (PAM) mRNA levels were measured by reverse transcription-polymerase chain reaction. All except PAM showed a decrease in basal levels and a diminished response to hypoxia in the old rats. Polysome profiling demonstrated decreases in the percentages of translatable preproAM mRNA in response to hypoxia, with a greater decrease in the old than the young rats. It is concluded that an age-dependent decrease in the hypoxic response of the AM system in the lung was associated with high basal levels of HIF activity and AM expression in the old rats, and a lower proportion of translatable preproAM mRNA in the old rats in response to hypoxia. Thus, the HIF-AM pathway may be impaired in the aged lung, and other mechanisms may be present to maintain an AM response to hypoxia.

Adrenomedullin and its receptor components in adipose tissues: Differences between white and brown fats and the effects of adrenergic stimulation.

Male Sprague-Dawley rats were subcutaneously injected with 2.5mg/kg phenylephrine or 2.5mg/kg isoproterenol or both (2.5mg/kg for each drug) for 4 days, twice a day. Samples of scapular brown adipose tissue (BAT) and epididymal white adipose tissue (WAT) were collected for the measurement of adrenomedullin (AM) levels and the gene expression of preproAM, calcitonin receptor like receptor (CRLR) and its activity modifying proteins (RAMPs) by radioimmunoassay and RT-PCR. These values were compared with those in the rats that received 0.9% saline. The gene expression of AM and AM receptor components in BAT are much less than that in epididymal WAT. In BAT there were an increase in AM peptide level after a combined treatment of alpha(1) and beta adrenoceptor agonists and increases in preproAM mRNA levels for rats treated with alpha(1) and beta receptor agonists alone or in combination. Both CRLR and RAMP2 mRNA levels of alphabeta group were increased significantly. In WAT, AM peptide level, RAMP1 and RAMP2 mRNA expression levels were augmented in the alpha group while CRLR mRNA level was enhanced in the beta group. The levels of AM, its receptor and RAMPs are much less in BAT than in WAT but adrenergic stimulation has a greater effect on the AM and its receptor components in BAT than those in WAT. AM stimulates lipolysis and increases the level of uncoupling protein-1 (UCP-1) in BAT. It may therefore enhance thermogenesis by increasing the availability of free fatty acids substrate as well as the UCP-1 level on the mitochondrial membrane.