A MULTIPLE TIMEPOINT STUDY OF N-TERMINAL PRO-OPIOMELANOCORTIN IN DEPRESSION USING A TWO-SITE RECOGNITION IMMUNORADIOMETRIC ASSAY

N-pro-opiomelanocortin (N-POMC) is secreted from the same precursor as ACTH and beta-endorphin. Elevated plasma ACTH and beta-endorphin/beta-lipotrophin concentrations have been reported in depression, however there have been no previous studies of N-POMC. Twenty-five patients with major depression and 18 control subjects were studied at five timepoints to examine diurnal rhythm and the effect of a dexamethasone suppression test. N-POMC was measured using a newly developed two-site recognition immunoradiometric assay (IRMA). This demonstrated advantages of sensitivity, specificity and simplicity compared with existing radioimmunoassays. N-POMC exhibited a pattern of diurnal rhythm and suppression in response to dexamethasone as described for other POMC derived peptides. Depressed subjects had higher levels of N-POMC at 0900 h post-dexamethasone than did control subjects. In conclusion, the results of this study are consistent with a hypothesis of cosecretion of POMC-derived peptides. N-POMC has a similar pattern of abnormal concentrations to ACTH and beta-endorphin/beta-lipotrophin in depression. This constitutes probable evidence of POMC-derived peptide resistance to glucocorticoid feedback in this condition.     

Correlation between beta-endorphin plasma levels and anginal symptoms in patients with coronary artery disease

To verify whether beta-endorphin plasma levels influence the presence of anginal symptoms, 74 consecutive male patients were studied. All patients had previously documented coronary artery disease and reproducible exercise-induced myocardial ischemia. Thirty-five patients (Group I) had a history of angina and reported anginal symptoms during exercise stress testing; 39 patients (Group II) were asymptomatic and had documented silent myocardial ischemia during exercise. Baseline beta-endorphin plasma levels were measured in blood samples taken before exercise stress testing and analyzed by beta-endorphin-I125-RIA Kit-NEN (a radioimmunoassay method). The mean baseline beta-endorphin plasma level was 22.5 +/- 19 pg/ml in patients with anginal symptoms compared with 43.7 +/- 28 pg/ml in asymptomatic patients (p less than 0.001). Baseline blood pressure and heart rate-systolic pressure (rate-pressure) product at baseline and at ischemia threshold (1 mm ST segment depression) were similar in the two groups. Group II patients had a longer exercise duration (p less than 0.01), more pronounced ST segment depression (p less than 0.001) and a higher peak rate-pressure product (p less than 0.01). The extent of coronary artery disease, ejection fraction and left ventricular end-diastolic pressure were similar in the two groups. These data suggest that higher baseline beta-endorphin plasma levels may play a role in the decreased sensitivity to pain in patients with silent myocardial ischemia. In addition, different beta-endorphin levels can be associated with a different sensitivity to pain.     

Persistence of altered metabolic responses to beta-endorphin after normalization of body weight in human obesity

The responses of plasma glucose, insulin, C-peptide and glucagon to an infusion of human beta-endorphin (0.5 mg/h) were studied in 10 formerly obese subjects who had lost 35 kg by dieting (body mass index less than 25) and compared with those of 10 normal-weight control (body mass index less than 25) and 10 obese (body mass index greater than 30) subjects. The fasting plasma concentrations of beta-endorphin were significantly higher in both the obese and the post-obese group than in the control group. In both obese and post-obese subjects, the infusion of beta-endorphin caused significant increases in peripheral plasma glucose, insulin, C-peptide and glucagon concentrations. In the control group, matched for age, sex and weight with the formerly obese group, there was no appreciable change in plasma insulin and C-peptide concentrations during the infusion of beta-endorphin, but the rise in plasma glucose was more sustained. Thus, 1. the increased plasma beta-endorphin concentrations found in human obesity are not corrected by normalization of body weight; and 2. formerly obese, normal-weight subjects behave as obese subjects in their metabolic and hormonal responses to beta-endorphin infusion. The alteration of the opioid system in human obesity may play some role in the predisposition to weight gain.     

Blunted adrenocorticotropin but normal beta-endorphin release after human corticotropin-releasing hormone administration in depression

Since the discovery of CRH in 1981, several investigators have reported abnormalities of the hypothalamic-pituitary-adrenal (HPA) system in response to direct stimulation of the corticotroph cells in patients with psychiatric disorders. To further explore HPA system integrity in major depressive disorders, 13 drug-free patients and normal subjects matched for age, sex, ovarian status, and body weight received 100 micrograms synthetic human CRH as an iv bolus dose. Compared to that in the normal subjects, in the depressed patients a significant attenuation of the net ACTH release after CRH administration (772 +/- 597 vs. 263 +/- 286 pmol/min.L; P less than 0.02) was observed, while beta-endorphin and cortisol responses did not differ significantly between the groups. The magnitudes of ACTH and cortisol release were negatively correlated in the patient group only (r = -0.67; P less than 0.01). Thus, the blunted ACTH response to CRH in depression might be related to hypercortisolemia, while the implications of the apparent dissociation of ACTH and beta-endorphin after CRH administration still remain unclear. Our data support the hypothesis that the hyperactivity of the HPA system in depression most likely is a consequence of CRH hypersecretion, the origin of which may be explained by abnormal central glucocorticoid receptor or neurotransmitter regulation.     

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.     

Differences in the responses of the pituitary beta-endorphin and cardiovascular system to ethanol and stress as a function of family history

BACKGROUND: Genetic and environmental factors, such as stress, are important for the initiation and maintenance of heavy drinking, whereas beta-endorphin may be important in controlling alcohol consumption. These studies investigated the response of pituitary beta-endorphin to stress and the effect of alcohol on the stress response in subjects at low (LR) and high (HR) risk of alcoholism, as determined from their family history. METHODS: Twenty LR and 20 HR subjects were exposed to stress 30 min after ingestion of either a placebo or an alcohol drink. Plasma beta-endorphin was measured before and for 4 hr after the drink. Changes in the concentration of plasma beta-endorphin after ingestion of the placebo or alcohol drink alone served as controls to compare the stress-induced changes. Pulse and diastolic and systolic blood pressure were also measured. RESULTS: HR subjects presented higher baseline values of pulse and systolic blood pressure and lower plasma beta-endorphin than LR subjects. Stress induced a small increase in cardiovascular activity, whereas alcohol induced a stronger stimulation. Alcohol before stress did not prevent the stress-induced increase in cardiovascular activity. Stress, but not alcohol, increased the plasma beta-endorphin concentration. LR subjects presented a higher stress-induced increase in plasma beta-endorphin and a faster recovery than HR subjects. Alcohol before stress attenuated the stress-induced increase in plasma beta-endorphin in both LR and HR subjects. This attenuation was stronger in LR subjects. CONCLUSIONS: Thus, there are differences in the response of beta-endorphin to stress and the effect of ethanol on stress responses as a function of a family history of alcoholism.     

Beta-endorphin and islet hormone release in type-2 diabetes mellitus the effects of normoglycemia, enkephalin, naloxone and somatostatin

The present study was aimed at characterizing the effects of beta-endorphin on plasma glucose, insulin and glucagon plasma levels in subjects with type-2 diabetes mellitus. Infusion of 0.5 mg/h human beta-endorphin produced significant and simultaneous increments in both insulin and glucagon concentrations and decreased plasma glucose levels (-18 +/- 4 mg/dl, 60 min level, p less than 0.01). When the same diabetics were rendered euglycemic by an insulin infusion (1 mU/kg/min), beta-endorphin did not produce the expected decrease in plasma glucose concentrations nor raise plasma insulin levels; only the response of glucagon was preserved. Normal subjects were rendered hyperglycemic by an intravenous glucose infusion to match the plasma glucose levels of diabetic subjects. In this condition, beta-endorphin produced a significant increase of insulin concentrations, whereas glucagon remained suppressed. The intravenous administration of the long-acting met-enkephalin analogue DAMME (0.25 mg) blunted the hormonal responses to the subsequent beta-endorphin infusion in diabetic patients, although the inhibition was short-lived (30-40 min). Naloxone (5 mg), an opiate antagonist, did not produce any significant change in the insulin and glucagon responses to beta-endorphin, while somatostatin (0.25 mg/h) completely abolished the hormonal responses to the opioid.(ABSTRACT TRUNCATED AT 250 WORDS)     

Primary role of glucagon release in the effect of beta-endorphin on glucose homeostasis in normal man

The present study aimed at evaluating the effect of human beta-endorphin on pancreatic hormone levels and on glucose metabolism in normal subjects. Infusion of 143 nmol/h beta-endorphin in 7 subjects caused a significant rise in plasma glucose concentrations (+ 1.7 +/- 0.3 mmol/l) which was preceded by a significant increase in peripheral plasma glucagon levels (+ 44 +/- 13 ng/l). No changes occurred in the plasma concentrations of insulin and catecholamines (adrenaline and noradrenaline). The influence of beta-endorphin per se on glucose homeostasis was studied in 7 other subjects using the euglycaemic clamp technique in which the endocrine pancreatic function was fixed at its basal level with somatostatin together with replacement of basal insulin and glucagon by the exogenous infusion of these hormones. In this new metabolic conditions, beta-endorphin failed to have significant influences on the various parameters of tracer-estimated glucose metabolism (production, utilization, and clearance) and on the plasma levels of the gluconeogenic precursors (glycerol and alanine). Moreover, the levels of pancreatic and counterregulatory hormones (cortisol and catecholamines) were not different between beta-endorphin and control studies. We conclude that the naturally occurring opioid peptide beta-endorphin produced an hyperglycaemic effect in man which appears to be mediated by glucagon. The opioid seems to have no direct effect on glucose metabolism. These results suggest that the metabolic effects of beta-endorphin in normal man are secondary to its impact on pancreatic hormone secretion and not a consequence of a direct modulation of glucose metabolism.     

β-Endorphin and adrenocortical function in obesity

OBJECTIVE: To test the hypothesis that the hyperendorphinaemia in obesity originates from outside the pituitary. DESIGN: Intravenous administration of corticotrophin-releasing hormone (CRH) after overnight suppression with 2 mg of dexamethasone in normal-weight controls and in obese subjects before and after weight reduction. PATIENTS: Eleven obese females, age (mean +/- SEM) 30 +/- 2.1 years, body mass index (BMI) 41.2 +/- 1.9 kg/m2. Eight normal-weight females served as controls, age 26 +/- 2.1 years, BMI 21.4 +/- 0.5 kg/m2. Five obese subjects were also studied after weight loss of 18.4 +/- 1.0% of original weight. MEASUREMENTS: Plasma beta-endorphin, ACTH and cortisol. Cortisol production rate in 24-hour urine. Basal (without dexamethasone suppression) plasma beta-endorphin levels. RESULTS: Basal (without dexamethasone suppression) beta-endorphin levels were 7.7 +/- 0.8 pmol/l in the obese and 3.8 +/- 0.5 pmol/l in the control subjects (P less than 0.005). The degree of suppression of beta-endorphin after dexamethasone was similar in the obese (23.2 +/- 3.7%) and in the control subjects (28.2 +/- 0.12%). Administration of CRH following dexamethasone suppression resulted in a small but significant increase of plasma beta-endorphin in both obese (from 1.55 +/- 0.12 to 2.32 +/- 0.28 pmol/l) and control subjects (from 0.98 +/- 0.24 to 1.69 +/- 0.33 pmol/l). The groups did not differ regarding this response, nor regarding the release of ACTH and cortisol after CRH. Cortisol production rate was higher (P less than 0.001) in the obese (68.7 +/- 3.3 mumol/24 h) than in the controls (40.0 +/- 3.0 mumol/24 h). No correlation between cortisol production rate and basal beta-endorphin levels was found. Weight loss appeared to have no influence on cortisol production rate, basal beta-endorphin levels, or on the responses to dexamethasone or CRH. CONCLUSIONS: Plasma beta-endorphin in obese subjects can be affected by manipulations of the hypothalamic-pituitary-adrenocortical axis; the hypothesis that the hyperendorphinaemia of obesity originates from outside the pituitary cannot be confirmed.     

Twenty-four-hour beta-endorphin secretory pattern in the elderly

A chronobiological study was carried out in seven elderly male subjects (78-84 years) to evaluate the 24-h beta-endorphin secretory pattern. Seven young adult males (28-37 years) made up the control group. Blood samples were drawn every four hours from 08.00 to 20.00 h and every two hours from 24.00 to 06.00 h. ACTH and cortisol levels were also determined in the same plasma samples. Mean 24-h beta-endorphin values in the elderly (32.6 +/- 1.1 ng/l) and in the young adult male subjects (29.5 +/- 1.4 ng/l) did not differ statistically, but the circadian rhythm was absent in the elderly subjects. In the elderly, plasma ACTH and cortisol concentrations showed a circadian rhythm similar to that observed in the adult subjects. However, in the elderly patients, in contrast to that in the adult subjects, the multilinear regression analysis did not show any statistically significant correlation between the beta-endorphin, ACTH and cortisol 24-h plasma concentrations.     

Cardiocirculatory effects of physiological doses of beta-endorphin

Beta-endorphin has been implicated in the cardiovascular depression that occurs in shock. While pharmacologic doses of beta-endorphin cause hypotension, physiologic doses of beta-endorphin have not been studied. In this study, six dogs (group I) were given IV beta-endorphin (peak concentrations previously determined in canine shock, 3,200 pg/ml); 5 minutes prior to beta-endorphin infusion, four dogs (group II) were given naloxone, 2 mg/kg bolus, and continuous infusion, 2 mg/kg/hr. In group I, beta-endorphin decreased stroke volume (from 0.99 +/- .12 to 0.57 +/- .08 ml/kg), dP/dt (from 3,167 +/- 140 to 2,875 +/- 412 mmHg X sec), and coronary blood flow (from 2.5 +/- .47 to .68 +/- .11 ml/min/gm), while heart rate rose significantly. Naloxone pretreatment maintained dP/dt, stroke volume, and coronary blood flow with no change in heart rate or mean arterial pressure. This study confirms that beta-endorphin depresses contractility and coronary blood flow in normovolemic nonstressed dogs, suggesting that beta-endorphin is in part responsible for cardiovascular depression in shock.     

Physiological elevations of plasma beta-endorphin alter glucose metabolism in obese, but not normal-weight, subjects.

The present study was undertaken to evaluate the metabolic and hormonal responses to physiologic elevations of plasma beta-endorphin concentrations in both normal-weight and obese healthy subjects. The infusion of synthetic human beta-endorphin (4.5 ng/kg/min) produced the following: (1) in normal-weight subjects, no significant change of plasma glucose and pancreatic hormones (insulin, C-peptide, and glucagon), a significant plasma free fatty acids (FFA) increase, and a suppression of glycerol plasma levels; (2) in obese subjects, significant increases of glucose, insulin, C-peptide, and glucagon, a progressive decline of circulating FFA, and no change in glycerol plasma levels. In obese subjects, the intravenous administration of naloxone, given as a bolus (5 mg injected in 5 minutes) before the start of beta-endorphin infusion, reduced the plasma glucose response to the opioid by approximately half, annulled the pancreatic hormonal responses, and also reduced the FFA, but not glycerol, response. In normal-weight subjects, naloxone pretreatment did not induce any change of the flat glucose and hormonal responses to beta-endorphin, but reversed its effects on circulating FFA and glycerol. These data suggest that physiological elevations of plasma beta-endorphin concentrations produce metabolic and hormonal effects in obese subjects significantly different from those occurring in normal-weight subjects; these effects are partially naloxone-sensitive, suggesting the mediation of endogenous opioid receptors.     

Impaired beta-endorphin response to human corticotropin-releasing hormone in obese children

In order to evaluate the secretion of beta-endorphin in obese children and adolescents, we measured plasma beta-endorphin, ACTH and cortisol levels before and following administration of CRH (1 microgram/kg). Fourteen normal weight and 22 obese subjects (weight excess ranging from 30 to 98%) were studied. Plasma hormone levels were measured by radioimmunoassay directly in plasma (cortisol, ACTH) and after silicic acid extraction and Sephadex G-75 column chromatography (beta-endorphin). Basal beta-endorphin levels in obese children were significantly higher than in controls (14.7 +/- 1.8 vs 6.0 +/- 0.6 pmol/l; mean +/- SEM). No differences were found in basal ACTH and cortisol levels. CRH administration significantly increased beta-endorphin, ACTH and cortisol levels in normal subjects and ACTH and cortisol levels in obese subjects. Plasma beta-endorphin levels in obese children and adolescents did not show any significant increment. These data confirm the higher than normal beta-endorphin plasma levels in obese subjects in childhood and demonstrate that CRH is unable to increase beta-endorphin levels, suggesting an impairment of the hypothalamo-pituitary control mechanisms or an extra-anterior pituitary source.     

beta-Endorphin stimulates plasma renin and aldosterone release in normal human subjects

To determine the effect of beta-endorphin on the renin-angiotensin-aldosterone system, human synthetic beta-endorphin (0.3, 1.0, and 3.0 micrograms/kg X min) was infused iv in normal subjects. Each dose was administered for 30 min, and a control infusion of 5% dextrose and water was given on another day. Ten subjects were studied recumbent and in balance while ingesting a 10-meq Na+ diet. Plasma renin activity (PRA), plasma aldosterone (PA), and plasma cortisol (F) were measured basally and every 30 min for 210 min. The increments in PRA and PA above basal significantly (P less than 0.05) increased (3.1 +/- 1.2 ng/ml X h and 12.2 +/- 5.3 ng/dl, respectively; P less than 0.05) at the end of the beta-endorphin infusion. beta-Endorphin also significantly (P less than 0.01) suppressed F levels. Since in the low salt study, beta-endorphin suppressed F release while stimulating renin secretion, an additional five subjects were pretreated with dexamethasone (0.5 mg every 6 h) and were studied in balance while ingesting a 200-meq Na+ diet to suppress the renin-angiotensin system. Significant (P less than 0.025) increments in PRA (2.1 +/- 0.7 ng/ml X h) and PA (4.1 +/- 1.7 ng/dl) levels above basal were again found during the sequential dose infusion of beta-endorphin (0.3, 1.0, and 3.0 micrograms/kg X min). However, PA elevations were sustained for at least 120 min after the beta-endorphin infusion was stopped despite a drop in PRA 90 min earlier. In additional studies, an attempt was made to define the minimal effective dose of beta-endorphin by 60-min infusions (0.03, 0.1, and 0.3 micrograms/kg X min) in subjects on a 200-meq Na+ diet who were dexamethasone pretreated. The PRA and PA levels rose significantly (P less than 0.05) above basal at the 0.3 micrograms/kg X min dose, but not at the 0.03 or 0.1 micrograms/kg X min dosage levels. There were no changes in blood pressure or potassium during either the 10 or 200-meq Na+ studies. Thus, beta-endorphin stimulates aldosterone release in vivo. However, the underlying mechanisms are complex, since renin levels also increased. The data suggest that the early aldosterone rise may be secondary to an increase in renin release, but renin cannot account for the sustained postinfusion elevations of aldosterone.     

Infusion of beta-endorphin has no suppressive effect on the releasing hormone-stimulated pituitary-adrenal-axis of normal human subjects

The existence of a short-loop feedback inhibition of pituitary ACTH release by administration of beta-endorphin was postulated. However, data on the effect of peripherally administered beta-endorphin in humans are highly controversial. We infused human synthetic beta-endorphin at a constant rate of 1 microgram.kg-1.min-1 or normal saline to 7 normal volunteers for 90 min. Thirty min after starting the beta-endorphin or placebo infusion, releasing hormones were injected as a bolus iv (oCRH and GHRH 1 microgram/kg, GnRH 100 micrograms, TRH 200 micrograms) and blood was drawn for measurements of beta-endorphin immunoreactivity, all other pituitary hormones, and cortisol. Infusion of beta-endorphin resulted in high beta-endorphin plasma levels with a rapid decrease after the infusion was stopped. During the control infusion, beta-endorphin plasma levels rose in response to CRH. Plasma ACTH and serum cortisol levels in response to the releasing hormone were not different in subjects infused with beta-endorphin or placebo. The PRL response to TRH was significantly higher after beta-endorphin than after placebo (area under the stimulation curve 1209 +/- 183 vs 834 +/- 104 micrograms.l-1.h). There was no difference in the response of all other hormones measured. Our data on ACTH and cortisol secretion do not support the concept of a short-loop negative feedback of beta-endorphin acting at the site of the pituitary.     

Increase of plasma levels of beta-endorphin during maximum bicycle ergometry effort in sedentary and trained subjects

Plasmatic levels of beta-endorphin during maximal graded bicycle stress test were measured by RIA on extracted plasma in 10 well-trained (A group) and in 8 untrained subjects (C group). Blood samples were obtained at rest, at peak work load and at the third, 10th and 90th min of recovery. For every stress test the following were evaluated: exercise time, maximum work load, total work load, maximum double product and mean K (an index of velocity of heart rate recovery during the first three minutes after the exercise). Both groups A and C showed a significant rise in beta-endorphin activity at the third minute of recovery; the increase was significantly greater in trained rather than in sedentary subjects (p less than 0.01). Beta-endorphin release was closely related to mean K; no relationship was found between exercise time, maximum work load, total work load, maximum double product and beta-endorphin rise. Our data shows that a release of beta-endorphin occurs during the initial phase of recovery after a maximal stress test; beta-endorphin rise is greater in trained subjects and correlates with the speed of heart rate recovery, but has no relationship with the duration and the grade of the effort. Whether beta-endorphin increase plays a role in the rapid decrease of adrenergic tone which occurs after exercise or represents a secondary phenomenon remains to be determined.     

Circadian rhythms of beta-endorphin in the aged

A circadian rhythm for beta-endorphin was observed by means of the cosinor method in aged subjects. The rhythm mesor is a little lower but its amplitude is more extended than in young subjects. The confidence intervals of the acrophases of the two groups are superimposable with a timing in the morning.     

Altered metabolic and hormonal responses to epinephrine and beta-endorphin in human obesity

Catecholamines and endogenous opioid peptides are released in response to stress. Exogenous infusions of epinephrine and beta-endorphin (both in doses of 15, 50, and 80 ng/kg.min sequentially, each dose lasting 30 min) were used to mimic short term stress in both normal weight (body mass index, less than 25 kg/m2) and obese (body mass index, greater than 30 kg/m2) subjects. Fasting plasma insulin, C-peptide, and beta-endorphin concentrations were significantly higher in the obese than in the normal subjects (P less than 0.01-0.005). In lean subjects epinephrine produced significant increases in plasma glucose levels, but no appreciable changes in plasma insulin, C-peptide, or glucagon. Infusion of beta-endorphin in the same subjects caused plasma glucose and glucagon to rise, but insulin and C-peptide levels did not change. The simultaneous infusion of epinephrine and beta-endorphin produced a glycemic response which, although greater, was not significantly different than the sum of the responses to the individual hormone infusions. However, the two hormones had a synergistic interaction on plasma glucagon levels [total glucagon response, 2275 +/- 370 pg/min.mL (ng/min.L); sum of single effects, 750 +/- 152 (+/- SE) pg/min.mL (ng/min.L); P less than 0.01]. The plasma epinephrine [207 +/- 21, 607 +/- 70, and 1205 +/- 134 pg/mL (1130 +/- 115, 3640 +/- 382, and 6577 +/- 691 pmol/L] and beta-endorphin [875 +/- 88, 1250 +/- 137, and 1562 +/- 165 pg/mL (250 +/- 25, 358 +/- 39, and 447 +/- 47 pmol/L] concentrations attained during the infusions of each single hormone were not different from those recorded during the combined hormonal infusion. In obese subjects epinephrine raised plasma glucose levels and caused dose-related increments of plasma glucagon concentrations. Plasma insulin and C-peptide concentrations remained low and rebounded at the end of the infusions. In the same subjects, beta-endorphin produced elevations of plasma glucose, insulin, C-peptide, and glucagon. When the combined hormonal infusion was given to obese subjects, the plasma epinephrine and beta-endorphin concentrations rose to values not significantly different from those in normal weight subjects. However, there was a dramatic increase in plasma glucose exceeding 200 mg/dL (11.1 mmol/L), which remained elevated 30 min after the infusion. The glucagon response was not greater than the sum of the single effects.(ABSTRACT TRUNCATED AT 400 WORDS)     

Acute pressor and hormonal effects of beta-endorphin at high doses in healthy and hypertensive subjects: role of opioid receptor agonism

CONTEXT: The opioid system is involved in blood pressure regulation in both normal humans and patients with essential hypertension. OBJECTIVE: The objective of the study was to investigate the effects of a high-dose infusion of beta-endorphin, an opioid peptide, on blood pressure and on the hormonal profile in healthy subjects and in hypertensive patients and the mediation played by opioid receptor agonism. DESIGN, SETTING, AND PARTICIPANTS: According to a randomized double-blind design, 11 healthy subjects (controls) and 12 hypertensive inpatients (mean age, 38.9 and 40.4 yr, respectively) received 1-h iv infusion of beta-endorphin (250 mug/h) and, on another occasion, the same infusion protocol preceded by the opioid antagonist naloxone (8 mg). MAIN OUTCOME MEASURES: Hemodynamic and hormonal measurements were performed at established times during the infusion protocols. RESULTS: At baseline, circulating beta-endorphin, norepinephrine, and endothelin-1 in hypertensive patients were significantly (P < 0.05) higher than in controls. In controls, beta-endorphin reduced blood pressure (P < 0.01) and circulating norepinephrine (P < 0.02) and increased plasma atrial natriuretic factor (P < 0.003) and GH (P < 0.0001). In hypertensive patients, beta-endorphin decreased systemic vascular resistance (P < 0.0001), blood pressure (P < 0.0001), and plasma norepinephrine (P < 0.0001) and endothelin-1 (P < 0.0001) and raised circulating atrial natriuretic factor (P < 0.0001), GH (P < 0.0001), and IGF-I (P < 0.0001). These hemodynamic and hormonal responses to beta-endorphin in hypertensive patients were significantly (P < 0.0001) greater than in controls but were annulled in all individuals when naloxone preceded beta-endorphin infusion. CONCLUSIONS: High doses of beta-endorphin induce hypotensive and beneficial hormonal effects in humans, which are enhanced in essential hypertension and are mediated by opioid receptors.     

Plasma beta-endorphin levels in primary aldosteronism

Excessive production of an as yet unidentified aldosterone-stimulating factor may cause idiopathic hyperaldosteronism (IHA). This putative factor may be related to proopiomelanocortin-derived peptides, some of which have aldosterone-stimulating properties. The present study evaluated plasma beta-endorphin, ACTH, cortisol, and aldosterone levels in patients with IHA (n = 10), aldosterone-producing adenomas (n = 4), essential hypertension (n = 11), and normal subjects (n = 10). Plasma and urinary hormone measurements were obtained at timed intervals during an isocaloric, fixed electrolyte intake (Na+, 128 meq/day; K+, 80 meq/day) in a metabolic unit. Plasma for beta-endorphin assay was preincubated with sepharose-bound anti-beta-lipotropin to remove beta-lipotropin that cross-reacted with the beta-endorphin RIA. Mean +/- SE plasma beta-endorphin levels at 0800 h were elevated in IHA patients (47 +/- 13 fmol/ml) compared to those in aldosterone-producing adenoma (25 +/- 9), essential hypertension (16 +/- 1), and normal control (20 +/- 2; P less than 0.05) subjects. Plasma ACTH, plasma cortisol, and urinary cortisol levels were not different in these four groups. These data support the hypothesis that excess production of either beta-endorphin or related proopiomelanocortin-derived peptides may function as aldosterone secretogogue(s) in IHA.