Persistence of beta-endorphin in human cerebrospinal fluid after hypophysectomy

beta-Endorphin immunoactivity was measured in the plasma and cerebrospinal fluid (CSF) of 13 patients with metastatic cancer 1 day before and 5 days after complete transsphenoidal hypophysectomy. Preoperatively, mean beta-endorphin-like immunoactivity in plasma was 18.2 +/- 3.5 pg/ml (SEM) and in CSF 32.3 +/- 6.3 pg/ml. No correlation was noted between the concentration of beta-endorphin in plasma and CSF. Postoperatively, plasma beta-endorphin was undetectable (less than 7 pg/ml) in 12 patients and was low (9.6 pg/ml) in 1 patient. In CSF, however, beta-endorphin was detectable in 10 of the 13 patients postoperatively, with a mean of 14.0 +/- 2.2 pg/ml. Chromatography on Sephadex G-50 of CSF extracts pooled from 3 patients after hypophysectomy showed that the majority of beta-endorphin immunoactivity eluted in the same position as synthetic human beta-endorphin. We conclude that beta-endorphin becomes undetectable in plasma after hypophysectomy in patients receiving exogenous glucocorticoid replacement but remains detectable in significant amounts in CSF. It appears, therefore, that a considerable portion of the beta-endorphin in CSF is of nonpituitary origin, most likely resulting from synthesis and secretion of this peptide by brain directly into the CSF.     

Plasma beta-endorphin and beta-lipotropin in the human fetus at delivery: correlation with arterial pH and pO2.

Beta-endorphin-like immunoactivity was measured in the umbilical cord plasma of 45 term human fetuses. Mean concentration was 91 +/- 16 (SEM) pg/ml,an the normal adult level of 30.7 +/- 2.7 pg/ml. This immunoactivity was further characterized in 10 cases by Sephadex G-50 chromatography to separate beta-endorphin from beta-lipotropin (beta-LPH). Mean beta-endorphin and beta-LPH concentrations were 57 +/- 12.8 and 455 +/- 101 pg/ml, respectively. Both were higher (P less than 0.01) than the mean beta-endorphin and beta-LPH concentrations reported in the adult. The mean molar beta-endorphin to beta-LPH ratio was 0.35 in the fetus and 0.36 in the adult. In 17 fetuses whose umbilical arterial and venous concentrations were measured separately, mean beta-endorphin-like immunoactivity was higher in the artery than in the vein. A highly significant negative correlation (r = -0.831; P less than 0.001) was present between umbilical arteiral pH and beta-endorphin-like immunoactivity. A negative correlation (r = -0.611; P less than 0.005) with arterial pO2 was also noted. We conclude that high levels of beta-endorphin-like immunoactivity, composed of both beta-endorphin and beta-LPH, circulate in the human fetus at term, and that hypoxia and secondary acidosis may be major stimuli to the release of these peptides.     

Dopaminergic regulation of alpha-melanocyte-stimulating hormone and N-acetyl-beta-endorphin secretion in the fetal lamb

alpha MSH is present in high concentrations in the intermediate lobe of the fetal pituitary and has been implicated as a regulator of fetal adrenal steroidogenesis and fetal growth. However, there are few data regarding alpha MSH levels in fetal plasma or the control of fetal alpha MSH secretion. We measured alpha MSH immunoactivity in the plasma of chronically catheterized fetal lambs (gestational age, 116-138 days), newborn lambs, and adult sheep both in the baseline state and after dopamine receptor blockade with metoclopramide. The effect of metoclopramide on the release of another proopiomelanocortin-derived peptide, N-acetyl-beta-endorphin (N-acetyl-beta EP), which is synthesized together with alpha MSH in the intermediate lobe, was also studied. Baseline fetal plasma alpha MSH was significantly greater than maternal alpha MSH [35.6 +/- 2.2 (+/- SEM) vs. 10.0 +/- 1.0 pg/ml]. In eight studies in five fetal lambs, alpha MSH rose to a peak level of 121 +/- 23 pg/ml 15 min after metoclopramide administration to the fetus. Simultaneous maternal alpha MSH levels did not change, suggesting that the alpha MSH in fetal plasma was of fetal pituitary origin. Gel filtration of pooled fetal plasma extracts revealed that the alpha MSH immunoactivity eluted in the same position as the alpha MSH standard. Metoclopramide caused the secretion of nearly equimolar amounts of alpha MSH and N-acetyl-beta EP into fetal plasma. In four fetal lambs, basal N-acetyl-beta EP levels of 156 +/- 34 pg/ml rose to 305 +/- 65 pg/ml 15 min after metoclopramide treatment. Metoclopramide also stimulated plasma alpha MSH in newborn and adult sheep. In six newborn lambs, alpha MSH rose from 45.2 +/- 13 to 211 +/- 38 pg/ml 15 min after metoclopramide treatment, whereas in four adult sheep, a basal alpha MSH level of 11.1 +/- 2.2 pg/ml rose to 20.1 +/- 2.7 pg/ml 15 min after metoclopramide. In addition, metoclopramide stimulated fetal and neonatal PRL secretion, but had no effect on plasma vasopressin concentrations or acid-base and blood gas values. These studies indicate that immunoreactive alpha MSH and N-acetyl-beta EP are secreted into ovine fetal plasma and that the secretion of these peptides in the fetus appears to be under tonic dopamine inhibition, as is the case in the adult sheep and newborn lamb.     

High levels of corticotropin-releasing hormone immunoactivity in maternal and fetal plasma during pregnancy

Corticotropin-releasing hormone immunoactivity (CRHi) was measured in the plasma of 31 pregnant women and 6 nonpregnant women as well as in the umbilical cord plasma of 40 term fetuses. CRHi was not detectable (less than 44 pg/ml) in the plasma of 6 nonpregnant women or in 6 women in the first trimester of pregnancy. Mean plasma CRHi rose progressively to 58 +/- 18 and 270 +/- 68 pg/ml during the second and third trimesters, respectively, and again became undetectable within 24 h after delivery. Mean CRHi in 40 umbilical cord plasma samples was 136 +/- 16 pg/ml. Gel filtration of both fetal and maternal plasma showed that the majority of the CRHi eluted in the same position as synthetic human CRH. There was no significant correlation between CRHi and either beta-endorphin or ACTH in umbilical cord plasma, suggesting that this CRHi may not be primarily responsible for the release of beta-endorphin and ACTH into fetal plasma at delivery. A close correlation (r = 0.82) was found between simultaneously obtained maternal and umbilical cord plasma CRHi in 10 maternal-fetal pairs, supporting a common source for this peptide in maternal and fetal circulation. A placental source for fetal and maternal CRHi was suggested by the finding of a higher CRHi concentration in the umbilical vein than in the umbilical artery and by the disappearance of this peptide from maternal plasma after delivery. We conclude that a large amount of CRHi is secreted by the placenta into both the maternal and fetal circulation during pregnancy and suggest that this may be an important modulator of the maternal and fetal hypothalamic-pituitary-adrenal axis during gestation.     

Identification of beta-endorphins in the pituitary gland and blood plasma of the common carp (Cyprinus carpio)

Carp beta-endorphin is posttranslationally modified by N-terminal acetylation and C-terminal cleavage. These processes determine the biological activity of the beta-endorphins. Forms of beta-endorphin were identified in the pars intermedia and the pars distalis of the pituitary gland of the common carp (Cyprinus carpio), as well as the forms released in vitro and into the blood. After separation and quantitation by high performance liquid chromatography (HPLC) coupled with radioimmunoassay, the beta-endorphin immunoreactive products were identified by electrospray ionisation mass spectrometry and peptide sequencing. The release of beta-endorphins by the pituitary gland was studied after stimulation with corticotrophin-releasing factor (CRF) in vitro. In the pars intermedia, eight N-acetylated truncated forms were identified. Full length N-acetyl beta-endorphin(1-33) coeluted with N-acetyl beta-endorphin(1-29) and these forms together amounted to over 50% of total immunoreactivity. These products were partially processed to N-acetyl betaendorphin(1-15) (30.8% of total immunoreactivity) and N-acetyl beta-endorphin(1-10) (3.1%) via two different cleavage pathways. The acetylated carp homologues of mammalian alpha- and gamma-endorphin were also found. N-acetyl beta-endorphin(1-15) and (1-29) and/or (1-33) were the major products to be released in vitro, and were the only acetylated beta-endorphins found in blood plasma, although never together. CRF stimulated the release of opioid beta-endorphin from the pars distalis. This non-acetylated beta-endorphin represents the full length peptide and is the most abundant form in plasma.     

Correlation between plasma levels of ACTH and beta-endorphin in the first seven days of postnatal life

Plasma adrenocorticotropic hormone (ACTH) and beta-endorphin (beta-EP) concentrations were measured by radioimmunoassay in 122 newborns, born vaginally after spontaneous labor between the 38th and the 41st week of pregnancy. Blood samples were taken from umbilical cord in 10 newborns and from antecubital vein in the remaining 112 newborns, divided into 8 groups aged from 12 h to 7 days. The mean (+/- SE) ACTH concentrations in cord plasma were 81.87 +/- 10.16 pg/ml and decreased significantly (p less than 0.01) at the 24th h of life (49.09 +/- 6.93 pg/ml). Afterwards mean ACTH plasma concentrations fluctuated around the latter values. The mean (+/- SE) B-EP concentrations in cord plasma were 21.96 +/- 3.12 pmol/l and decreased significantly at the 24th h of life (13.43 +/- 2.08 pmol/l; p less than 0.01). From the 24th h to the 7th day the mean plasma concentrations of beta-EP were not significantly different. ACTH and beta-EP plasma levels were positively correlated (p less than 0.001) at delivery and during the first seven days of life.     

Induction of the intermediate lobe pro-opiomelanocortin system with chronic swim stress and beta-adrenergic modulation of this induction

Swimming at 25-30 degrees C for 30 min stimulates release of beta-endorphin from both the anterior and intermediate lobe of the pituitary in rats. Measurement of N-acetyl beta-endorphin-immunoreactivity (IR), which is specific for intermediate lobe secretion, indicates a 2- to 3-fold increase in N-acetyl beta-endorphin IR in plasma following this challenge. When swim is repeated on a daily basis, there is an increase in the amount of N-acetyl beta-endorphin IR released with repeated swim over time. As well as increased response to the swim challenge, these animals demonstrate an increase in the resting plasma levels of N-acetyl beta-endorphin IR and an increase in the intermediate lobe content of N-acetyl beta-endorphin IR. Molecular sieving of plasma from rats which were swum repeatedly demonstrates that this N-acetyl beta-endorphin IR consists of both larger molecular weight N-acetyl beta-endorphin IR, e.g. N-acetyl beta-endorphin1-31 and C-terminally shortened forms, e.g. N-acetyl beta-endorphin1-27. Administration of propranolol (3 mg/kg), a beta-adrenergic antagonist, 30 min before the onset of swim is able to block the intermediate lobe release of N-acetyl beta-endorphin IR with acute swim challenge. However, repeated administration of propranolol in conjunction with repeated swim is not able to block the swim stress-induced increase in plasma N-acetyl beta-endorphin IR or the increase in N-acetyl beta-endorphin IR content of the intermediate lobe. This is not due to decreased sensitivity to propranolol with repeated administration since in rats given chronic propranolol treatment an acute dose of propranolol is still able to block swim stress-induced release of N-acetyl beta-endorphin IR. Similarly, it is not due to a decreased efficacy of this dose of propranolol in rats which were swum chronically.     

Endogenous opioids and ventilatory responses to hypoxia in normal humans

We studied the putative role of endorphins in modulating hypoxic ventilatory responsiveness. In 12 healthy men, minute ventilation (VE)and mouth occlusion pressure (P0.1) responses to progressive isocapnic hypoxia were determined before and after the intravenous administration of the opioid antagonist naloxone (10 mg) or placebo. Plasma levels of beta-endorphin were measured before and after hypoxia. Naloxone did not affect the slopes or x-intercepts of the relationships between either VE or P0.1 and arterial O2 saturation. There was no correlation between the baseline plasma level of beta-endorphin and any measure of responsiveness to hypoxia. Plasma beta-endorphin levels were not affected by either short-term hypoxia or naloxone alone; however, when hypoxia followed naloxone administration, mean +/- SD beta-endorphin increased from 8.0 +/- 8.9 pg/ml to 20.2 +/- 16.6 pg/ml (p less than 0.005). We concluded that endogenous opioids do not have an important modulating influence on hypoxic ventilatory responsiveness in adult human volunteers.     

High levels of beta-endorphin in hypophyseal portal blood

beta-Endorphin was measured by RIA in the hypophyseal portal blood of six pig tailed monkeys after pituitary stalk section. The mean beta-endorphin concentration was 4,770 pg/ml (range, 2,900-10,500 pg/ml). This was more than 100 times greater than the mean simultaneous peripheral venous concentration, which was less than or equal to 45 pg/ml. After gel filtration of the portal plasma extracts, the majority of beta-endorphin immunoactivity eluted as a single peak coincident with synthetic beta-endorphin standard. The demonstration of high levels of beta-endorphin in the hypophyseal portal blood suggests that endogenous opioids of hypothalamic origin are secreted into the portal blood and may directly affect the pituitary.     

PLASMA IMMUNOREACTIVE β-ENDORPHIN IS ELEVATED IN URAEMIA

Plasma immunoreactive-(IR) beta-endorphin (beta-EP) and beta-lipotrophin (beta-LPH) levels were measured in 15 adult uraemic patients on chronic haemodialysis. The presence of immunoreactivity eluting in the position of beta-EP was demonstrated following submission of pooled extracts of uraemic plasma to gel permeation chromatography on Sephadex G-50. To separate beta-EP from beta-LPH, pre-dialysis plasma extracts from six individual patients, and three pools of three patients each, were submitted to sequential immune-affinity chromatography and levels were measured by radioimmunoassay. In all cases, plasma IR beta-EP concentrations were markedly increased compared with normal subjects (m +/- SEM fmol/ml; 64.4 +/- 13.7 vs. 2.3 +/- 0.2). IR beta-LPH concentrations were also increased (m +/- SEM fmol/ml; 55.7 +/- 13.2 vs. normal 6.1 +/- 0.8). In addition, post-dialysis concentrations of plasma IR beta-EP and beta-LPH were lower than pre-dialysis levels (n = 4).     

The processing of beta-endorphin and alpha-melanotrophin in the pars intermedia of Xenopus laevis is influenced by background adaptation.

beta-Endorphin- and alpha-melanotrophin (alpha-MSH)-related peptides were extracted from the pars intermedia of Xenopus laevis maintained for 2, 4 or 6 weeks on a white background and for the same periods on a black background. The peptides were resolved under dissociating conditions by gel exclusion chromatography on Sephadex G-50 and they were detected by radioimmunoassay with antibodies to beta-endorphin, alpha,N-acetyl beta-endorphin and alpha-MSH. The beta-endorphin-related peptides separated into two fractions of different molecular size. Further purification of the peptides in each fraction was by ion exchange chromatography on SP-Sephadex C-25 and by high-pressure liquid chromatography. The alpha-MSH-related peptides were resolved by gel exclusion and ion exchange chromatography. The purified beta-endorphin- and alpha-MSH-immunoreactive peptides were identified by comparison of their chromatographic properties with the corresponding peptides from porcine pituitary or by comparison with synthetic peptides. The major form of beta-endorphin in the pars intermedia of the frog adapted to a white background was identified as alpha,N-acetyl beta-endorphin (1-8); it was accompanied by a small quantity of acetylated peptides with molecular size similar to beta-endorphin. In contrast, the pars intermedia of the frogs adapted to a black background contained approximately equal amounts of alpha,N-acetyl beta-endorphin (1-8) and the larger forms of beta-endorphin. The higher molecular weight forms were identified as the alpha,N-acetyl derivatives of beta-endorphin (1-26), (1-27) and (1-31); however after 6 weeks of white adaptation the sole remaining peptide in this group was the 26-residue peptide. An additional beta-endorphin immunoreactive peptide, provisionally identified as beta-endorphin (10-26), was present in both black- and white-adapted animals; the amounts of this peptide increased during white adaptation. Major differences in the processing of alpha-MSH were also observed. In the frogs adapted to a black background des-acetyl alpha-MSH greatly predominated over the acetyl form whereas after 6- weeks adaptation to a white background the acetylated peptide proved to be the principal component. The results demonstrate that the proteolytic processing of beta-endorphin and the acetylation of alpha-MSH in Xenopus laevis are influenced by background adaptation. The formation of beta-endorphin (1-8) appears to reflect the action of an endopeptidase that acts at the single arginine residue present at position 9.(ABSTRACT TRUNCATED AT 400 WORDS)     

Estradiol regulation of proopiomelanocortin gene expression and peptide content in the hypothalamus.

Previous studies have shown that the hypothalamic concentrations of beta-endorphin (beta-EP) and other proopiomelanocortin (POMC)-derived peptides change in the female rat following castration and gonadal steroid replacement. In this study we have measured POMC mRNA by solution hybridization assay in the medial basal hypothalamus (MBH) of ovariectomized rats treated with a regimen of estradiol (E2) that we have previously shown alters brain beta-EP peptide content. In addition the effect of progesterone (P) was also studied. In the first experiment the concentration of beta-EP and alpha-melanocyte-stimulating hormone (alpha-MSH) in the MBH of castrated rats decreased significantly after 3 weeks of E2 treatment compared to castrated unreplaced rats: beta-EP decreased from 6.00 +/- 0.46 to 4.32 +/- 0.38 ng/mg protein and alpha-MSH decreased from 3.00 +/- 0.23 to 2.35 +/- 0.15 ng/mg protein (p less than 0.05). A similar decrease in peptide content was noted in the anterior hypothalamus/preoptic area. A parallel reduction in the concentration of POMC mRNA was measured in the MBH of the E2-replaced animals: 1.17 +/- 0.14 vs. 0.72 +/- 0.08 pg/microgram RNA (p less than 0.02). In a second study castrated rats were studied after 2 weeks of E2 or E2 plus P treatment. After 2 weeks, POMC peptide levels did not change significantly in the MBH of either the E2- or E2 plus P-treated rats. POMC mRNA, however, was significantly reduced from 1.10 +/- 0.10 pg/micrograms RNA in the unreplaced rats to 0.58 +/- 0.05 and 0.61 +/- 0.06 pg/microgram RNA after E2 or E2 plus P, respectively (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)     

The relation of vasoactive intestinal peptide and acute hypoxia

In order to observe the effect of acute hypoxia on release of vasoactive intestinal peptide (VIP), the plasma VIP content was determined in anesthetized dogs by a specific radioimmunoassay technique during acute hypoxia. Blood gases and hemodynamics were monitored simultaneously. After inhalation of 10% oxygen. the plasma VIP levels elevated along with decrease in PaO2 and increase in pulmonary artery pressure. The plasma concentration of VIP in the portal vein increased significantly from 106 +/- 21 pg/ml before hypoxia to 173 +/- 36 pg/ml 15 minutes after the onset of hypoxia (P less than 0.01). The difference of arterio-venous VIP content increased from -3 +/- 6 pg/ml before hypoxia to +9 +/- 7 pg/ml after inhalation of 10% oxygen for 30 minutes. The results suggested that VIP was released from the gastrointestinal tract as well as from the lung in case of hypoxia and pulmonary hypertension. It is considered that the release of VIP may be an adaptive and compensatory response, promoting vasodilation and perfusion in vital organs.     

Specific radioimmunoassay of human beta-endorphin in unextracted plasma.

With an antiserum against human beta-endorphin (beta-EP) crossreacting less than 2% with human beta-lipotropin (beta-LPH) by weight we have developed a radioimmunoassay that can detect 1 pg beta-EP in diluted raw plasma. In a.m. fasting plasma of 14 normal subjects beta-EP ranged from less than 5 to 45 pg/ml. beta-EP was elevated in untreated, but normal in successfully treated Cushing's disease; undetectable in a patient with adrenal adenoma; extremely high in Nelson's syndrome; and elevated in a patient with bronchogenic carcinoma before, but undetectable after tumor resection. In subjects with intact hypothalamic-pituitary-adrenal axis, beta-EP was undetectable after dexamethasone and increased after metyrapone administration and insulin-induced hypoglycemia. beta-EP concentration was considerably lower in serum than in simultaneously collected plasma, but increased in serum left unfrozen for several hours after clot removal. Thus, beta-EP behaves like a hormone responding to the same stimuli as ACTH and beta-LPH and blood appears to contain enzymes both generating and destroying immunoreactive beta-EP.     

Substantial rise of plasma beta-endorphin levels after insulin-induced hypoglycemia in human subjects.

To elucidate whether insulin-induced hypoglycemia enhances the release of beta-endorphin in man, plasma extracts obtained from healthy subjects and patients with Graves' disease before and 45 min after insulin injection were subjected to gel chromatography, and the fractions obtained were measured by RIA for beta-endorphin. In four healthy subjects, basal plasma beta-endorphin levels were less than 3 to 3.1 pg/ml, and the levels rose substantially to 47.5 +/- 12.4 pg/ml (mean +/- SE) 45 min after insulin injection. Basal plasma beta-endorphin levels in three hyperthyroid patinets (less than 3 to 3.8 pg/ml) did not seem to be different from those in healthy subjects; however, the rise after insulin injection tended to be higher in cases of hyperthyroidism, with a peak value of 68.5 +/- 9.7 pg/ml. Plasma beta-lipotropin and ACTH levels also rose in parallel with beta-endorphin in response to insulin-induced hypoglycemia in both healthy subjects and hyperthyroid patients. It would thus appear that beta-endorphin, like ACTH or beta-lipotropin, is released in human subjects by hypoglycemic stress.     

Measurement of beta-endorphin in human plasma.

beta-endorphin has been identified in human plasma by means of gel filtration and a sensitive radioimmunoassay for human beta-endorphin (beta h-endorphin). Mean baseline plasma beta h-endorphin concentration in 5 individuals was 21 +/- 7.3 (SD) pg/ml (6.2 +/- 2.2 (SD) fmole/ml). Following metyrapone stimulation mean plasma concentration increased to 55.4 +/- 10.1 (SD) pg/ml (16.3 +/- 3.1 (SD) fmole/ml). The molar ratio of human beta-lipotropin (beta h-LPH) to beta h-endorphin was 2.2 in baseline plasma and 2.4 after metyrapone stimulation.     

THE EFFECT OF CHOLINERGIC BLOCKADE ON THE ACTH, β-ENDORPHIN AND CORTISOL RESPONSES TO INSULIN-INDUCED HYPOGLYCAEMIA

To assess the effect of cholinergic blockade on the ACTH, beta-endorphin and cortisol responses to insulin-induced hypoglycaemia, six healthy male volunteers each underwent two insulin tolerance tests in random order, separated by at least 1 week with and without atropine. ACTH levels were significantly greater at +45 min (mean +/- SEM, 223 +/- 21 pg/ml vs 148 +/- 15 pg/ml, P less than 0.01) and at +120 min (54 +/- 11 pg/ml vs 29 +/- 10 pg/ml, P less than 0.05). beta-endorphin levels were significantly greater at +30 min (170 +/- 45 pg/ml vs 96 +/- 32 pg/ml, P less than 0.05) and at +105 min (81 +/- 14 pg/ml vs 54 +/- 7 pg/ml, P less than 0.01). Cholinergic blockade had no effect on plasma glucose or cortisol concentrations. This study demonstrates that cholinergic blockade with atropine facilitates the ACTH and beta-endorphin responses to insulin-induced hypoglycaemia without altering the cortisol responses.     

Elevated plasma beta-endorphin levels in patients with congestive heart failure

Recent experimental studies show that the opioid system is important to the pathophysiology of cardiovascular impairment in congestive heart failure. Plasma beta-endorphin levels were measured in 37 patients with congestive heart failure and compared with those of 21 age- and gender-matched normal subjects. The relation of plasma beta-endorphin levels and cardiac function at rest and exercise capacity was assessed in 17 of the patients with dilated cardiomyopathy. Exercise capacity was determined by symptom-limited maximal treadmill exercise with expired gas analysis. Plasma beta-endorphin levels were elevated and correlated with the patients' New York Heart Association functional cardiac status (control: 14.0 +/- 4.4 pg/ml; class II: 17.9 +/- 3.6 pg/ml; class III: 28.3 +/- 8.8 pg/ml; class IV: 46.7 +/- 14.6 pg/ml, mean +/- SD). No relation was found between plasma beta-endorphin levels and left ventricular systolic performance as assessed by M-mode and Doppler echocardiography. Plasma beta-endorphin levels were negatively correlated with cardiac output determined by Doppler echocardiography and positively correlated with systemic vascular resistance (r = -0.733, r = 0.747, respectively, both p less than 0.001), but not correlated with calf blood flow as measured by a plethysmography. A good correlation was found between plasma beta-endorphin levels at rest and exercise capacity. The correlations with peak oxygen consumption, anaerobic threshold, and peak rate-pressure product were r = -0.721, -0.672, and -0.674, respectively (p less than 0.01). The data show that plasma beta-endorphin levels are elevated in patients with congestive heart failure and reflect, to some degree, the severity of the disease.     

Plasma corticotropin-releasing factor concentrations in the baboon during pregnancy.

We have studied the secretion of placental CRF during pregnancy in the baboon, an animal model with many similarities to human pregnancy. Plasma CRF was measured in two groups of animals. In group 1, studies were performed in six anesthetized animals beginning 8 days postconception. In group 2, studies were performed in five unanesthetized chronically catheterized maternal and five fetal animals in the latter third of pregnancy. In the first study beginning early in pregnancy, CRF was undetectable in all animals on days 8 and 15 postconception. Plasma CRF became detectable in two animals on day 24 and in the remaining four on day 30. Plasma CRF rose significantly to a mean of 810 +/- 160 pg/ml at 37 days gestation (F = 4.20; P < 0.001). Mean maternal plasma CRF was 2452 +/- 1120 pg/ml on day 44 and remained elevated, with a great deal of variability between subjects, until the end of the study period (128 days of gestation). Samples in this group were obtained after ketamine sedation. The effect of ketamine on CRF was studied in three chronically catheterized animals. Samples were obtained before and 2, 4, 6, and 24 h after ketamine administration (40 mg, iv). The baseline CRF concentration was 1168 +/- 131 pg/ml and did not change significantly over the time period studied. In the second study in the chronically catheterized animals, maternal plasma CRF was 1990 +/- 680 pg/ml at 131-140 days gestation and remained elevated until near term at 170 days (term = 175-180 days). Within 24 h after birth, plasma CRF became undetectable (< 60 pg/ml). CRF was also measured in chronically catheterized fetal baboons. The mean CRF concentration was 614 +/- 224 pg/ml at 131-140 days and remained in this range until the end of the period studied (151-160 days gestation). To characterize the CRF immunoactivity in maternal baboon plasma, Sephadex chromatography was performed on an 8.4-ml plasma sample obtained at 160 days gestation. The majority of the CRF immunoactivity eluted in the same position as synthetic human CRF. We conclude that high levels of placental CRF are present in the systemic circulation of the maternal and fetal baboon during pregnancy. In contrast to human pregnancy, which is characterized by an exponential rise in maternal CRF concentrations in the final weeks before delivery, an exponential rise in maternal baboon CRF concentrations occurs early in pregnancy.     

Impairment of adrenergic-induced proopiomelanocortin-related peptide release in heroin addicts

The effects of iv stimulation with clonidine on plasma levels of beta-lipotropin (beta-LPH), beta-endorphin (beta-EP), cortisol, growth hormone (GH) and adrenocorticotrophic hormone (ACTH) were tested in a group of 10 healthy volunteers and in 8 heroin abusers. Hormones were measured either by direct radioimmunoassay (RIA) (GH, cortisol) or after plasma extraction and Sephadex G-75 column chromatography (beta-LPH and beta-EP) or by immunoradiometric assay (IRMA) (ACTH). Plasma levels of GH increased in a similar fashion in the two groups. In the controls, clonidine induced release of beta-LPH and beta-EP after 30 min (from 8.9 +/- 1.0 to 19.1 +/- 4.6 fmol/ml, P less than 0.01 and from 8.1 +/- 0.6 to 17.9 +/- 4.6, P less than 0.01) and of ACTH after 60 min (from 12.1 +/- 1.8 to 18.1 +/- 1.8, P less than 0.05) while in addicts beta-EP but not beta-LPH showed a significant increase (from 8.5 +/- 0.7 to 19.8 +/- 4.2, P less than 0.05), 90 min after the injection. In heroin addicts, plasma cortisol levels decreased continuously after clonidine stimulation while in controls they showed a biphasic pattern, decreasing until the 60th min (from 135.2 +/- 30.4 ng/ml to 74.0 +/- 13.3, P less than 0.05) and regaining basal levels 1 h later (122.0 +/- 24.8, P less than 0.05 vs 60th min value). These data demonstrate the existence in human beings of noradrenergic control of proopiomelanocortin (POMC)-related peptides and indicate that chronic opiate abuse greatly interferes with this control. Clonidine-induced release of plasma beta-EP may be of importance with regard to its therapeutic effects in detoxification.