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PubMed1989

Radioimmunoassay of circulating alpha-interferon with reference to aging and osteoporosis.

Circulating immunoreactive alpha-interferon in elderly individuals was 0.139 +/- 0.042 ng/ml in males and 0.111 +/- 0.033 ng/ml in females at ages 70-79, and 0.120 +/- 0.045 ng/ml in males and 0.105 +/- 0.039 ng/ml in females at ages 80-89. These values were significantly lower than those in young adults (p less than 0.01), but higher compared with the values found in disease states including rheumatoid arthritis (p less than 0.0025). There was no correlation between circulating alpha-interferon and bone mass indices, such as bone mineral content or quantitative computed tomography values, in these elderly individuals. Circulating alpha-interferon was, however, significantly increased in senile osteoporotic patients after 2 months of treatment with 1 alpha-hydroxyvitamin D3 or calcitonin, whereas it was unaltered in patients receiving ipriflavone or in nonosteoporotic individuals without medication. These findings indicate that circulating alpha-interferon, which is highest in young adults, declines with aging. It appears that circulating alpha-interferon is maintained at a certain steady-state level in healthy elderly individuals. Although there was no apparent relationship between bone mass indices and circulating alpha-interferon, it is possible that bone and cellular metabolism related to vitamin D3 may be contributing factors for the maintenance of circulating alpha-interferon.

Aged↗
PubMed2004

Smoking cessation rapidly increases circulating progenitor cells in peripheral blood in chronic smokers.

OBJECTIVE: Circulating endothelial progenitor cells (EPCs) contribute to postnatal angiogenesis. The number of circulating EPCs has an inverse correlation with coronary risk scores. However, the effect of smoking on the number of circulating EPCs is not well-known. METHODS AND RESULTS: We examined the effects of chronic smoking and of smoking cessation on EPC levels. Circulating EPCs were quantified by flow cytometry as CD45lowCD34+CD133+ (progenitor cells [PCs]) or CD45lowCD34+CD133+VEGFR2+ (EPCs) in 14 nonsmokers and in 15 smokers. All smokers quit smoking. Eight quit smoking with nicotine patch and 7 without nicotine patch. PC/EPC levels were inversely correlated with the number of cigarettes smoked. Circulating PCs/EPCs increased rapidly after cessation (P<0.0001) and decreased again after resumption of smoking to the level similar to that before cessation (P=0.0031). The magnitude of increase in EPCs was greater in light smokers than in heavy smokers. CONCLUSIONS: The number of circulating PCs/EPCs was reduced in chronic smokers. Smoking cessation led to a rapid restoration of PC/EPC levels. The recovery of EPC levels was greater in light smokers than in heavy smokers. The decreased number of circulating EPCs would make smokers susceptible to cardiovascular disease, and even short-time cessation of smoking may be an effective means to reduce cardiovascular risk.

AC133 Antigen↗
PubMedDate not supplied

Both circulating and clot-bound plasminogen activator inhibitor-1 inhibit endogenous fibrinolysis in the rat.

The effects of both clot-bound and circulating plasminogen activator inhibitor-1 (PAI-1) on endogenous fibrinolysis were investigated in a rat model of pulmonary embolism. Iodine-125 fibrin(ogen)-labeled blood-clot homogenates were delivered through the left jugular vein to the lung microvasculature, and the subsequent extent of the clot lysis was monitored by measuring the release of 125I-fibrin degradation products (FDPs) into the blood. Clots that had incorporated activated PAI-1 ex vivo were subsequently protected from dissolution in vivo in a dose-responsive manner (half-maximal concentration [IC50] = 4.3 micrograms/ml). PAI-1-containing clots also resisted lysis, as measured by the release of the specific FDP D-dimer. Plasma levels of plasminogen activator (PA) and PAI activity were unaltered by administration of PAI-1-containing clots, and the clot-protective effects of clot-bound PAI-1 were reversed by exogenous tissue-type plasminogen activator administration. Clot lysis was also inhibited in a dose-responsive manner (IC50 = 58 micrograms/kg) by intravenous bolus delivery of activated PAI-1 to the circulation. The clot-protective effects of circulating PAI-1 were correlated with dose-dependent increases in plasma PAI-1 antigen and activity levels and decreases in plasma PA levels (IC50 = 37 micrograms/ml). There was no evidence of any accumulation of circulating PAI-1 in the lungs. Latent PAI-1, whether delivered with or delivered after the clot homogenates, did not affect the clot-lytic process. Activated and latent PAI-1 was cleared from the circulation in a monophasic manner, with a half-life of approximately 32 and 7 minutes, respectively. The results indicate that both clot-bound and circulating PAI-1 are potent inhibitors of fibrinolysis in vivo. Clot-bound PAI-1 may inhibit PAs in the immediate vicinity of the clots, whereas circulating PAI-1 may act systemically by controlling overall levels of PAs present in the blood.

Animals↗
PubMed1995

Differential regulation of circulating Mg2+ in the rat by beta 1- and beta 2-adrenergic receptor stimulation.

Extracellular Mg2+ homeostasis was studied in vivo in the anesthetized rat. Animals were infused with isoproterenol (ISO) for 10 minutes, and serum Mg2+ was measured after the infusion and then 10 and 20 minutes later. A dose-dependent increase in circulating Mg2+ was observed in animals infused with ISO at a rate of 0.1 microgram.kg-1.min-1 or higher. The time course of the effect demonstrated that circulating Mg2+ continued to increase 20 minutes after the end of the ISO infusion. A predicted maximal increase in serum Mg2+ concentration of 19.3% was derived with a predicted EC50 of 0.08 microgram.kg-1.min-1. The maximal percent increase corresponded to a net increase of 6.7 mumol/300 g body wt. Because infusion of ISO resulted in changes in hemodynamic parameters, most notably a drop in blood pressure, a group of animals was infused with nitroprusside to mimic the hypotensive response via a nonadrenergic mechanism. Under these conditions, there was a transient increase in circulating Mg2+ that was largely inhibited by propranolol, indicating that hypotension per se was not responsible for the mobilization of Mg2+. Infusion of salbutamol, but not prenalterol, also induced an increase in circulating Mg2+. Pretreatment with butoxamine, ICI-118551, or propranolol prevented the ISO-induced increase in serum Mg2+. Pretreatment with atenolol minimally affected the ISO-induced changes in circulating Mg2+. Pretreatment with CGP-20271A actually enhanced the ISO-induced increase in circulating Mg2+. This evidence demonstrates the existence of a pool of Mg2+ that is mobilized into the circulation in response to selective beta 2-adrenergic stimulation.

Adrenergic beta-Antagonists↗
PubMed2001

Circulating monocyte-platelet aggregates are a more sensitive marker of in vivo platelet activation than platelet surface P-selectin: studies in baboons, human coronary intervention, and human acute myocardial infarction.

BACKGROUND: Platelet surface P-selectin is considered the "gold standard" marker of platelet activation. Degranulated, P-selectin-positive platelets, however, aggregate with leukocytes in vitro and rapidly lose surface P-selectin in vivo. METHODS AND RESULTS: Flow cytometric tracking of autologous, biotinylated platelets in baboons enabled us to directly demonstrate for the first time in vivo that (1) infused degranulated platelets very rapidly form circulating aggregates with monocytes and neutrophils, and (2) 30 minutes after infusion of the degranulated platelets, the percentage of circulating monocytes aggregated with infused platelets persist at high levels, whereas the percentage of circulating neutrophils aggregated with infused platelets and the platelet surface P-selectin of nonaggregated infused platelets return to baseline. We therefore performed 2 clinical studies in patients with acute coronary syndromes. First, after percutaneous coronary intervention (n=10), there was an increased number of circulating monocyte-platelet (and to a lesser extent, neutrophil-platelet) aggregates but not P-selectin-positive platelets. Second, of 93 patients presenting to an Emergency Department with chest pain, patients with acute myocardial infarction (AMI) (n=9) had more circulating monocyte-platelet aggregates (34.2+/-10.3% [mean+/-SEM]) than patients with no AMI (n=84, 19.3+/-1.4%, P<0.05) and normal control subjects (n=10, 11.5+/-0.8%, P<0.001). Circulating P-selectin-positive platelets, however, were not increased in chest pain patients with or without AMI. CONCLUSIONS: As demonstrated by 3 independent means (in vivo tracking of activated platelets in baboons, human coronary intervention, and human AMI), circulating monocyte-platelet aggregates are a more sensitive marker of in vivo platelet activation than platelet surface P-selectin.

Acute Disease↗
PubMed1980

Clearance of thrombin from circulation in rabbits by high-affinity binding sites on endothelium. Possible role in the inactivation of thrombin by antithrombin III.

The clearance of (125)I-thrombin and diisopropylphosphoryl-(125)I-thrombin (DIP-thrombin) from the circulation in rabbits was studied. When given either intraarterially or intravenously, DIP-thrombin, which is active-site blocked, was approximately 90% cleared from the circulation by 1 min, the time of earliest sampling, indicating a large first-pass effect. DIP-thrombin given intravenously is found predominantly in the lungs, whereas DIP-thrombin injected into the aortic arch is distributed diffusely in approximate proportion to the blood supply. Renal artery, femoral artery, ear artery, left atrium, and portal vein infusions demonstrate that kidney, muscle, ear, heart, and liver, respectively, can remove DIP-thrombin from the circulation. These data imply that the clearance of DIP-thrombin is not a function of a specific organ but of the vascular bed per se. The clearance of DIP-thrombin was reversible since injection of 0.5 mg of unlabeled DIP-thrombin 10 min after the injection of a tracer dose of DIP-(125)I-thrombin resulted in the rapid reappearance of the DIP-(125)I-thrombin into the circulation. In addition, the clearance of DIP-thrombin was saturable, i.e., clearance of DIP-(125)I-thrombin was inhibited by unlabeled DIP-thrombin in a dose-dependent fashion. In vivo Scatchard analysis of the saturation of the clearance process demonstrated that DIP-thrombin can be removed by binding to high-affinity binding sites, since dissociation constants (K(D)) of 10 and 13 nM were obtained for human and bovine DIP-thrombin, respectively. In contrast to DIP-thrombin, approximately 75% of the radioactivity associated with active thrombin remained in the circulation at 1 min. By 10 min 55% of (125)I-thrombin had been removed from the circulation, and essentially all of the radioactivity can be accounted for in the liver. Sodium dodecyl sulfate-polyacrylamide gel radioelectrophoresis of plasma samples taken after injection of (125)I-thrombin demonstrated that all of the active thrombin was converted to covalent thrombin-antithrombin III complex by the time of initial sampling (30 s). The in vitro conversion of (125)I-thrombin to thrombin-antithrombin III complex was considerably slower (50+/-5% conversion at 30 s). The simultaneous injection of excess unlabeled DIP-thrombin inhibited the rate of formation of (125)I-thrombin-antithrombin III complex formation in vivo (but not in vitro), which suggests that the binding of active thrombin to the high affinity binding sites is required for the rapid inactivation of thrombin in vivo. We propose that (a) thrombin in the circulation binds to active site-independent high-affinity binding sites on the endothelial cell surface; (b) the inactivation of thrombin by antithrombin III is faster in vivo than in vitro because the high-affinity binding sites, present in a high concentration in the microcirculation, catalyze the reaction; (c) thrombin-antithrombin III complexes are selectively removed by the liver.

Animals↗
PubMed2002

Mechanical properties of rat bone marrow and circulating neutrophils and their responses to inflammatory mediators.

Neutrophils are continuously released from the bone marrow (BM), and this release is accelerated during inflammation. This study compared the mechanical properties of mature neutrophils within the BM and the circulating blood, as well as the role of microtubule rearrangement in the release of neutrophils from the BM in rats. Neutrophils isolated from the BM were stiffer than neutrophils in the circulating blood, using magnetic twisting cytometry. BM neutrophils also contained more F-actin within the submembrane region than circulating neutrophils when examined using confocal microscopy, suggesting that mature quiescent neutrophils within the BM are stiffer than circulating neutrophils because of increased formation of F-actin beneath the plasma membrane. Complement protein 5 fragments or formylmethionyl-leucylphenylalanine (fMLP) induced a stiffening response within 2 minutes that was greater in circulating than in BM neutrophils. This stiffening required F-actin formation within the submembrane region but not microtubule rearrangement in both circulating and BM neutrophils. fMLP-induced shape changes were more pronounced in circulating than in BM neutrophils, which showed fewer and smaller pseudopods and fewer membrane irregularities. In vivo, fMLP induced neutropenia, sequestration of neutrophils within the pulmonary capillaries, and release of neutrophils from the BM. Studies using colchicine demonstrated that rearrangement of microtubules was not required for any of these processes but was required for normal trafficking of neutrophils through the pulmonary capillaries.

Actins↗
PubMed2006

Circulating cells with osteogenic potential.

While osteoclast lineage cells are clearly present in the peripheral circulation, whether there is a comparable pool of circulating osteoblast lineage cells has remained controversial. Using assays requiring adherence to plastic (as originally described by Friedenstein and colleagues for bone marrow stromal cells over four decades ago), several studies have shown that plastic adherent cells with osteogenic potential are, indeed, present in the circulation of a number of species, but at extremely low concentrations. Work from a number of independent groups over the past decade has also identified a population of nonadherent bone marrow cells with osteogenic potential. Since these nonadherent cells may be much more likely to access the peripheral circulation than plastic adherent cells, we tested for the presence of circulating osteoblast lineage cells in humans using flow cytometry to identify cells in the peripheral blood expressing bone-related proteins. Our findings indicate that these cells are present in the circulation in significant numbers, are markedly increased in the peripheral blood of adolescent boys going through the growth spurt, and may also increase following fractures. These circulating osteogenic cells express bone-related proteins, can mineralize in vitro, and form bone in vivo. The identification of these osteogenic cells in peripheral blood opens up new questions regarding the possible role of these cells in bone remodeling, in fracture repair, and possibly in vascular calcification.

Animals↗
PubMed1985

Circulating DF3 and CA125 antigen levels in serum from patients with epithelial ovarian carcinoma.

The murine monoclonal antibody (MAb), designated DF3, reacts with a 300-kilodalton (kd) mammary epithelial antigen. A sequential double-determinant enzyme-linked immunoassay (EIA) has been developed to monitor circulating DF3 antigen. Previous studies have demonstrated that the use of the DF3 EIA provides a new and potentially useful marker to follow the clinical course of patients with metastatic breast cancer. In the present study, we have monitored circulating DF3 antigen in the serum of patients with epithelial ovarian carcinomas and non-ovarian gynecologic malignancies. Twenty-one of 45 patients (47%) with ovarian carcinoma had elevated DF3 antigen levels (greater than or equal to 30 U/mL). In contrast, three of 20 patients (15%) with non-ovarian gynecologic malignancies, and only four of 59 control women (7%) had elevation of circulating DF3 antigen. The difference between DF3 antigen values from patients with ovarian cancer and from controls was significant (P less than .001). The elevation of circulating DF3 antigen in ovarian cancer patients has also been confirmed by transblot assays. MAb DF3 reactivity occurred predominately with circulating antigens of molecular weights (mol wt) ranging from 300 to 450 kd. Furthermore, DF3 antigen levels have been shown to correlate with progression of disease in six patients with ovarian cancer and after resection of disease in two others. The half-life of circulating DF3 antigen was approximately 45 to 60 days. The results also demonstrate that DF3 antigen is distinct from CA125, a glycoprotein associated with coelomic epithelium and developmental amnion. The use of both the DF3 EIA and the immunoradiometric assay previously described to detect circulating CA125 suggests that determining levels of both markers may enhance the sensitivity of monitoring the course of ovarian cancer. Furthermore, the use of both assays may be useful in distinguishing ovarian cancer from other malignancies.

Adult↗
PubMed2001

Clinical implications of circulating angiogenic factors in cancer patients.

PURPOSE: Angiogenesis, a process fundamental to tumor growth, is regulated by angiogenic factors. This article reviews prognostic and other clinical implications of circulating angiogenic factors in cancer patients. METHODS: A MEDLINE search of literature was performed using the names of various angiogenic factors as the key words. Studies pertaining to circulating angiogenic factors in cancer patients were reviewed. Pertinent literature regarding tumor expression of common angiogenic factors and their prognostic relevance in human cancers were also examined. RESULTS: A substantial number of studies have demonstrated a strong association between elevated tumor expression of vascular endothelial growth factor (VEGF) and advanced disease or poor prognosis in various cancers. This supports the pivotal role of VEGF in regulating tumor angiogenesis. More recently, there is mounting evidence that the level of circulating VEGF in patients with different types of cancer may be predictive of tumor status and prognosis. Preliminary data also suggest that circulating VEGF may be useful in predicting and monitoring tumor response to anticancer therapies and in follow-up surveillance for tumor relapse. There are reports supporting the prognostic value of other circulating angiogenic factors such as basic fibroblast growth factor, platelet-derived endothelial cell growth factor, transforming growth factor-beta, and angiogenin, but their clinical significance is less conclusive because of limited data. CONCLUSION: Circulating VEGF seems to be a reliable surrogate marker of angiogenic activity and tumor progression in cancer patients. Evaluation of circulating angiogenic factors is a promising novel approach of prognostication in cancer patients that has the advantages of being convenient and noninvasive, and it may provide new prognostic information that is not afforded by conventional clinicopathologic prognostic indicators.

Angiogenesis Inducing Agents↗
PubMed1979

Developmental patterns of the testicular response to experimental modifications of circulating androgen levels in the fetal rabbit.

The circulating level of free androgens in fetal and newborn rabbits was reduced by active immunization of mothers against testosterone (T) or was increased by injecting dihydrotestosterone (DHT) into the mothers. After immunization, about 100% of the circulating T and DHT in fetuses was bound. After maternal injection of DHT, the circulating level of this hormone in fetuses was increased 2- to 120-fold. The effects of these treatments were evaluated by determining testicular levels of T, a physiological index of circulating gonadotropin. From 20--23 days of gestation, testicular T content was modified neither by circulating antibodies nor by an increase of blood DHT. The same overloads of circulating DHT, which were ineffective between 20--23 days, significantly reduced testicular T content between 25--29 days. Testicular T content was significantly increased in newborns from immunized mothers. These results suggest that the appearance of the negative feedback action of circulating androgens takes place relatively late, at 24 or 25 days, after differentiation of the genital tract.

Animals↗
PubMed1981

Differences between circulating and tissue thyroglobulin in rats.

The mechanism whereby thyroglobulin (TG) reaches the circulation can involve either the release of newly synthesized TG or the release of colloid-stored TG from the thyroid gland. To distinguish between these possibilities, we have compared the properties of circulating and glandular TG in normal and thyroidectomized thyroid tumor-bearing rats. Circulating TG had the properties of poorly iodinated molecules; it was more susceptible to dissociation into subunits and had a lower density, the latter determined by equilibrium centrifugation in concentrated RbCl. The density of circulating TG was the same as that of glandular TG from propylthiouracil-treated rats, suggesting that circulating TG was nearly or completely devoid of iodine. Circulating TG bound to Concanavalin A-Sepharose and had a normal MCR, indicating that mannose was present and galactose was not in terminal positions, both properties of glandular TG. Since previous studies suggest that these properties cannot arise from differential clearance of TG molecules in the periphery, these data suggest that the TG in the circulation may arise from the direct release of poorly iodinated newly synthesized TG from the thyroid.

Animals↗
PubMed1987

The disappearance from the circulation of chylomicrons obtained from control and diabetic rats.

Previous studies have demonstrated that cholesterol synthesis is increased in the small intestine of diabetic animals and that there is an increased transport of this newly synthesized cholesterol from the small intestine into the circulation. Chylomicrons play an important role in the transport of cholesterol from the small intestine into the circulation, and the present study compared the rates of disappearance from the circulation and the fate of chylomicron cholesterol obtained from control and diabetic animals when administered to either intact control or diabetic rats. Thoracic duct lymph was collected from normal and diabetic rats after the administration of [14C]cholesterol and [3H]vitamin A1. The labeled chylomicrons were isolated by centrifugation and then administered to either control or diabetic rats. The major observation of this study is that chylomicron-associated sterols obtained from diabetic animals were cleared from the circulation in a normal manner. If one compares the rate of disappearance of either [3H]vitamin A1 or [14C] cholesterol-labeled normal chylomicrons administered to control animals with that of labeled diabetic chylomicrons administered to diabetic animals, the half-times in the circulation are almost identical (control: [3H]vitamin A1 t 1/2, 3.6 min; [14C]cholesterol t 1/2, 5.7 min; diabetic: [3H]vitamin A1 t 1/2, 3.5 min; [14C]cholesterol t 1/2, 4.4 min). In both experimental situations the rapid disappearance of [14C]cholesterol was associated with the appearance of [14C]cholesterol in the liver. Very little [14C]cholesterol was present in tissues other than liver, indicating that the rapid removal of labeled chylomicron remnants from the circulation was accounted for by hepatic uptake. These results demonstrate that in diabetic animals chylomicron-associated sterols are cleared from the circulation normally and that the bulk of intestinally derived cholesterol carried in the chylomicron lipoprotein fraction is rapidly delivered to the liver, where it could potentially influence lipoprotein metabolism.

Animals↗
PubMed1975

Sequential patterns of circulating luteinizing hormone and follicle-stimulating hormone in female sheep from early postnatal life through the first estrous cycles.

Patterns of circulating LH and FSH were examined during several 6-h periods in developing female sheep from 3 weeks of age through the first estrous cycles (30--40 weeks of age) and early pregnancy. With the onset of pulsatile LH secretion, beginning 11 weeks after birth, circulating LH increased to levels 2- to 5-fold greater than those observed in the adult. Thereafter, high and variable levels of circulating LH persisted through young adulthood when ovarian cyclicity including ovulation became manifest. Although prior to the initial estrus changes in frequency of LH release (number of LH discharges/6-h period) appeared to occur randomly from week to week, after first estrus, changes in frequency became predictable. During the early (day 1) and late (day 15) luteal phases of the first estrous cycles, when circulating progesterone was low (less than 0.6 ng/ml), the frequency of LH release was increased (5--7 discharges/6 h) while during the mid-luteal phase (day 7--12), when circulating progesterone was high (2--4 ng/ml), the frequency was diminished (0--2 discharges/6 h). Massive and sustained discharges of LH which resembled preovulatory surges were observed only shortly before first estrus. In contrast to the pulsatile release pattern of LH, concentrations of circulating FSH within the 6-h periods were relatively constant and within the range found in the adult. These findings lead to the following conclusions: a) changes in negative feedback control are not directly responsible for the onset of ovarian cyclicity in the sheep as indicated by the lack of differences in mean concentrations of circulating LH and FSH before and after first ovulation; b) the onset of the surge mode of gonadotropin secretion occurs only shortly before first ovulation; and c) progesterone may play an inhibitory role in regulating tonic LH secretion during the first estrous cycles.

Age Factors↗
PubMed2002

Circulating estradiol and osteoprotegerin as determinants of bone turnover and bone density in postmenopausal women.

Osteoprotegerin (OPG) is a recently identified cytokine that acts as a decoy receptor for the receptor activator of NF kappa B ligand. OPG has been shown to be an important inhibitor of osteoclast differentiation and activation in rodent models. Estrogen is known to suppress bone resorption, and the action of estrogen on bone may be mediated by OPG. The relationship between endogenous estrogen and circulating OPG levels and bone status in human populations is unclear. Thus, the aim of this study was to investigate the relationship between biochemical markers of bone turnover and bone density and circulating OPG and endogenous estradiol levels in a population-based cohort of postmenopausal women. Subjects were 180 women ages 55-91 yr (mean age, 67 yr). Serum estradiol was measured using an auto-analyzer. Serum concentrations of OPG were determined by ELISA. Markers of bone formation and resorption were measured by standard methods. Bone mineral density at total body, total hip, femoral neck, and lumbar spine was measured by dual energy x-ray absorptiometry. There was a significant inverse relationship between estradiol and all bone turnover markers (r-values from -0.46 to -0.23; P < 0.05). Serum estradiol was positively related to absolute bone density at all sites and to change in bone density at the hip and femoral neck by univariate analysis (r-values from 0.15-0.29; P < 0.05). We observed a weak inverse association between OPG and serum-based bone turnover markers (r-values -0.18 and -0.16; P < 0.05). There was a significant positive relationship between OPG and bone mineral density at total body, total hip, and femoral neck (r-values from 0.17-0.2; P < 0.05) by univariate analysis, which was lost after adjustment for age and body mass index. There was a significant weak positive relationship between circulating OPG and serum estradiol (r = 0.18; P < 0.02). We observed no significant relationships between OPG and bone turnover markers measured in urine. We conclude that the variation in circulating endogenous estradiol levels is an important factor contributing to levels of bone turnover and bone density at the menopause. Our observations also suggest that circulating levels of OPG may reflect OPG activity in bone and are related to circulating endogenous levels of estradiol. We have previously reported high levels of variability in urine markers of bone resorption, and we suggest that this could account for the absence of a significant association between these markers and circulating OPG.

Aged↗
PubMed1994

Effects of 17 beta-estradiol on circulating adhesion molecules.

The effects of 17 beta-estradiol (E2) on the serum levels of the circulating endothelial-leukocyte, intercellular, and vascular adhesion molecules [ELAM-1, ICAM-1 (CD54), and VCAM-1] were evaluated in healthy male volunteers after single im injection of 10 mg E2 valerate. In addition, a time course of the effects of E2 on circulating adhesion molecules (AMs), cortisol serum levels, differential blood counts, and surface expression of the lymphocyte function-associated antigen-1 (CD11a/CD18), CD3, CD4, CD19, and CD25 on leukocytes was studied in another group of volunteers. A 5% decrease in circulating ICAM-1 (P = 0.045 vs. placebo) was found when a single time point (96 h after E2 injection) was studied. However, this decrease was smaller than the intrasubject (day to day) variability observed, and there was no consistent and time-dependent effect of E2 on circulating AMs. Circulating neutrophils increased 2.3-fold over baseline after E2 treatment (P = 0.0008 vs. placebo). The mean coefficients of variation for the intrasubject (day to day) and intersubject variability of circulating AMs were between 5.4-7.5% and 20-29%, respectively. Our findings indicate that the effect of E2 on circulating AMs is not distinguishable from the intrasubject variability observed after placebo treatment. Thus, an effect of E2 on adhesion molecules is unlikely to contribute to the antiatherogenic-cardioprotective effect of E2. The pronounced E2-mediated increase in neutrophils deserves further studies to elucidate its (patho-)physiological implications.

Adult↗
PubMed1997

Circulating adrenomedullin does not regulate systemic blood pressure but increases plasma prolactin after intravenous infusion in humans: a pharmacokinetic study.

Adrenomedullin has been proposed to be a circulating hormone regulating systemic and pulmonary blood pressure. A potential therapeutic role in the management of pulmonary hypertension has been suggested based on animal studies, but the pharmacokinetics and pharmacodynamics in human subjects have not been studied. We have infused adrenomedullin into volunteers at 3.2 pmol/kg.min, which more than quadrupled (52 pmol/L) normal circulating concentrations. At this dose no change in heart rate or blood pressure was noted. When infused at 13.4 pmol/kg.min to achieve a concentration over 40 times normal circulating levels (448 pmol/L), there was a significant fall in diastolic blood pressure from 69 +/- 2 to 53 +/- 2 mm Hg and a significant increase in pulse rate from 57 +/- 3 to 95 +/- 4 beats/min. Circulating PRL concentrations rose from 197 +/- 46 to 372 +/- 64 IU/L (mean +/- SEM; P < 0.01). No effect was seen on ACTH, TSH, FSH, LH, or cortisol. When the infusion was discontinued, baseline pulse and blood pressure were reestablished after 20 min. Adrenomedullin has a MCR of 27.4 +/- 3.6 mL/kg.min, with a circulating half life of 22 +/- 1.6 min and an apparent volume of distribution of 880 +/- 150 mL/kg. Column chromatography of plasma taken during infusion and decay of adrenomedullin showed no evidence of the production of additional molecular forms. These results are consistent with a peptide that is markedly tissue bound. Plasma adrenomedullin concentrations were increased in patients with renal impairment (14.1 +/- 0.9 pmol/L) compared to those in healthy volunteers (8.1 +/- 0.7 pmol/L), with a good correlation (r = 0.86) between circulating adrenomedullin and plasma creatinine. The circulating concentration of adrenomedullin necessary to affect blood pressure greatly exceeds that observed in healthy volunteers and in patients with a range of pathological conditions. Thus, adrenomedullin may be a paracrine regulator of vascular smooth muscle in humans.

Adrenomedullin↗
PubMed1997

Circulating concentrations of dimeric inhibin A and B in the male rhesus monkey (Macaca mulatta).

The purpose of this study was to determine the relative concentrations of inhibin A and B in peripheral serum of the adult male rhesus monkey and to examine the testicular contribution to these circulating forms of inhibin. In addition, inhibin B concentrations were also determined in peripheral sera of neonatal and juvenile males and in spermatic vein blood of adults. Immunoradiometric assays specific for the measurement of inhibin A and B were used. These assays also provided an opportunity to reexamine the physiological significance of a replacement infusion of recombinant human (rh)-inhibin A previously employed to study the role of this hormone in regulating FSH secretion in the monkey. In intact adults, the mean (+/-SE) serum concentration of inhibin B was 1008 +/- 184 pg/mL. In contrast, circulating inhibin A concentrations were very low (< 46 pg/mL). Inhibin B was consistently detected in neonatal monkey serum (275 +/- 57 pg/mL), and concentrations of this inhibin dimer increased throughout postnatal development, reaching maximum values in adulthood. Circulating inhibin A concentrations in neonatal and juvenile monkeys were undetectable (< 7 pg/mL). Both forms of inhibin were generally undetectable in castrate sera. The ratio of inhibin B concentrations in testicular venous blood to those in the peripheral circulation was 1.4:1. These findings indicate that, in the male monkey, inhibin B is the principal form of circulating dimeric inhibin, and that this hormone is derived exclusively from the testis. The elevated levels of circulating inhibin B in the juvenile male monkey suggest that, during this phase of development, testicular inhibin B secretion is relatively gonadotropin independent. Additionally, we found that the concentration of circulating inhibin A in castrate animals that had earlier received an iv infusion of rh-inhibin A (832 ng/h/kg BW) was 9881 +/- 2135 pg/mL, indicating that this mode of inhibin replacement may not have been entirely physiological.

Animals↗