Plasma GRP-like immunoreactivity in healthy and diseased subjects

Gastrin releasing peptide(GRP)-like immunoreactivity in human plasma was measured using radioimmunoassay of neuromedin C (NMC) in 83 healthy and 58 diseased subjects. In the healthy group, the mean value of fasting GRP-like immunoreactivity was 2.1±1.4 (mean±SD) pmol/L. There was a slight positive correlation between the GRP-like immunoreactivity values and aging. Postprandial serial measurements demonstrated that GRP-like immunoreacitivity showed no response to a significant elevation of serum gastrin concentration. The group with chronic renal failure on hemodialysis gave the highest value, 7.1+2.1 pmol/L (p<0.01). There were no statistical differences between the healthy controls and groups with peptic ulcer, liver cirrhosis, diabetes mellitus or carcinomas, although some cancer patients had a marked increase in GRP-like immunoreactivity value.     

Circadian and seasonal variation in human preovulatory follicular fluid melatonin concentration

The concentrations of melatonin in 112 preovulatory follicular fluid (FF) samples obtained from 60 women undergoing in vitro fertilization and 27 patients at laparotomy during a spontaneous cycle were measured by RIA and compared with those in peripheral serum. The circadian and seasonal variations in FF melatonin were also analyzed. The FF melatonin concentrations in stimulated (mean +/- SEM, 61.9 +/- 6.4 pmol/L) and spontaneous cycles (98.1 +/- 8.9 pmol/L) were significantly higher (P less than 0.005) than those in peripheral serum (25.4 +/- 1.2 and 38.6 +/- 1.8 pmol/L, respectively), and in the stimulated cycles there was a positive correlation between them. The FF melatonin concentration in the morning (58.9 +/- 3.8 pmol/L) was significantly higher (P less than 0.005) than that in the daytime (23.2 +/- 0.8 pmol/L), but the morning concentrations did not differ between the light and the dark seasons of the year, whereas the daytime values were higher (P less than 0.005) during the dark season (27.1 +/- 2.1 pmol/L) than during the light season (21.1 +/- 2.1 pmol/L). The FF melatonin concentration did not correlate with follicular volume, and FF and serum melatonin concentrations showed no significant correlation with the serum concentrations of estradiol, progesterone, testosterone, or PRL. There were also no differences between FF melatonin concentrations in aspirates with or without an ovum. In summary, significant circadian and circannual variations in high FF melatonin concentrations were found, which suggest that melatonin could potentially interfere with the regulation of reproduction in humans at the follicular level.     

Plasma endothelin in chronic heart failure.

BACKGROUND. Endothelins are recently characterized vasoconstrictor peptides. As chronic heart failure (CHF) is characterized by peripheral arteriolar and renal vasoconstriction, we have measured venous plasma endothelin-like immunoreactivity ("endothelin") in patients with this syndrome. METHODS AND RESULTS. Compared with age- and sex-matched healthy volunteers (mean +/- SEM plasma endothelin concentration 6.4 +/- 0.3 pmol/l, n = 16), patients with severe CHF had elevated peripheral venous endothelin concentrations (12.4 +/- 0.6 pmol/l, n = 47, p less than 0.01). Plasma endothelin did not increase with exercise in normal subjects or in patients. Plasma endothelin concentration (mean, 13.4 +/- 0.9 pmol/l) did not correlate with plasma atrial natriuretic factor concentration (mean, 88.9 +/- 11.9 pg/ml) in patients with CHF (n = 21). There was also no correlation between plasma endothelin and serum urea or between endothelin and serum creatinine in patients with CHF (n = 34). There was, however, significant renal extraction of endothelin (aorta, 11.1 +/- 0.8 pmol/l; renal vein, 8.8 +/- 0.6 pmol/ml; p = 0.02) in patients with CHF (n = 13). CONCLUSIONS. Evidence suggests that circulatory endothelin concentrations in the range 5-40 pmol/l are vasoactive. Consequently, the endothelin concentrations found in patients with CHF may be of pathophysiological significance.     

Role of endogenous arginine vasopressin in potentiating corticotropin-releasing hormone-stimulated corticotropin secretion in man

Exogenously administered vasopressin (VP) augments ACTH secretion stimulated by CRH. This study was performed to elucidate the role of endogenous VP in potentiating CRH-induced ACTH secretion in man. Synthetic human CRH (100 micrograms) was injected iv into seven normal men after they had been water loaded (20 mL/kg; 60 and 30 min before CRH injection; WL-CRH test) and water deprived (water restriction for 18 h before CRH injection; WD-CRH test). Blood samples were obtained before and 5, 15, 30, 60, 90, and 120 min after CRH injection at 0900 h for determination of plasma ACTH, cortisol, arginine vasopressin (AVP), CRH, and catecholamine levels and osmolality. Urine was obtained immediately before and 120 min after CRH injection for determination of osmolality. The mean plasma AVP levels were significantly higher during the WD-CRH test [1.8 +/- 0.4 (+/- SE) to 1.9 +/- 0.4 pmol/L] than during the WL-CRH test (0.6 +/- 0.1 to 0.9 +/- 0.1 pmol/L). The mean plasma ACTH and cortisol levels rose significantly from basal (4.5 +/- 0.6 pmol/L and 320 +/- 20 nmol/L, respectively) to peak values of 14.0 +/- 2.1 pmol/L at 30 min and 700 +/- 50 nmol/L at 60 min, respectively, during the WD-CRH test. During the WL-CRH test, mean basal plasma ACTH and cortisol levels were 3.5 +/- 0.7 pmol/L and 420 +/- 50 nmol/L, respectively, and reached peak values of 7.7 +/- 1.1 pmol/L at 60 min and 550 +/- 40 nmol/L at 30 min, respectively. Both the mean peak levels and integrated ACTH and cortisol responses were significantly higher during the WD-CRH than during the WL-CRH test. There was no significant difference between the plasma CRH and catecholamine concentrations in both tests. These results suggest that endogenous AVP potentiates CRH-stimulated ACTH secretion and, thus, plays a physiologically significant role in regulating CRH-stimulated ACTH and cortisol secretion in man.     

Hypothyroidism has no impact on insulin sensitivity assessed with HOMA-IR in totally thyroidectomized patients

The influence of thyroid hormones on insulin and glucose metabolism is controversial. We examined the impact of hypothyroidism on insulin sensitivity in 22 hypothyroid patients (15 females and 7 males, mean age 51.0 +/- 12.36 yrs). All subjects had a history of total thyroidectomy and radioiodine ablation for differentiated thyroid cancer. Each subject ceased levothyroxine treatment six weeks prior to admission. The controls were 17 healthy individuals, 6 women and 11 men, mean age 55.12 +/- 14.17 years. TSH, free thyroxine, and the HOMA index of insulin sensitivity, as well as HOMA B (%) and HOMA S (%) were assessed. Insulin sensitivity was compared between the groups, and the correlation between FT4 and TSH and insulin sensitivity was calculated. RESULTS: The mean FT4 was 4.6 +/- 4.64 pmol/L in the examined group vs. 16.2 +/- 1.8 pmol/L in controls, p<005; TSH 72.11 +/- 36.73 pmol/L vs. 1.24 +/- 1.07 pmol/L, p<0.005; plasma glucose 4.68 +/- 0.47 mmol/L vs. 5.04 +/- 0.62mmol/L, p=0.0436; plasma insulin 8.07 +/- 9.39 microU/mL vs. 7.24 +/- 4.06 microU/mL, p=0.7877; HOMA index 1.79 +/- 2.53 vs. 1.69 +/- 1.09, p=0.5148; HOMA B (%) 102.46 +/- 41.59 vs. 85.95 +/- 26.87, p=0.1926, and HOMA S (%) 150.46 +/- 95.90 vs. 153.80 +/- 108.85, p= 0.6710, in subjects and controls, respectively. The levels of insulin sensitivity did not differ significantly between the two groups. FT4 and TSH did not influence the insulin sensitivity in either group, the correlation was insignificant, respectively p=0.5426 and p=0.8175 in the examined group, and p=0.172 and p=0.4509 in the controls. CONCLUSION: Hypothyroidism has no impact on insulin sensitivity in the examined group.     

Cholecystokinin does not stimulate prosomatostatin-derived peptides in man

In man, plasma cholecystokinin (CCK) and somatostatin-28 (S-28) levels increase after ingestion of a mixed meal. Both peptides originate from the gastrointestinal tract. In supra- and periphysiological doses, CCK stimulates the release of somatostatin-14 from in vitro pancreatic islets and gastric cells and increases circulating somatostatin-like immunoreactivity in dogs, leading to the conjecture that CCK regulates somatostatin-like immunoreactivity secretion. Nonetheless, whether CCK is responsible in part for the meal-induced rise in S-28 in man has not been established. Therefore, the present study was designed to determine if CCK, at both physiological and supraphysiological concentrations, increases the circulating levels of prosomatostatin (proS)-derived peptides in humans. On 3 separate days, five healthy men ate a mixed liquid meal or received iv infusions of CCK at rates of 18 or 38 pmol/kg.h. Plasma levels of pro-S-derived peptides, including pro-S, S-14, S-13, S-28, and CCK, were measured. Basal CCK levels averaged 0.9 +/- 0.1 pmol/L and increased after the meal to a peak level of 5.4 +/- 1.5 pmol/L and averaged 3.1 +/- 1.2 pmol/L over 90 min. The mean basal levels of pro-S, S-14, and S-13, measured collectively, was 6.1 +/- 0.4 pmol/L eq S14 and was unaltered by food intake. The S-28 level was 6.7 +/- 0.6 pmol/L and rose to a zenith of 13.1 +/- 3.3 pmol/L by 90 min. Infusion of CCK at 18 and 38 pmol/kg.h produced steady state plasma CCK levels of 4.1 +/- 1.1 and 9.9 +/- 1.5 pmol/L, respectively. Basal levels of pro-S-derived peptides were unaltered during the infusion of either the low or high dose of CCK. We conclude that CCK by itself is not a physiological signal to the release of pro-S-derived peptides in man.     

Serum and amniotic fluid melatonin during human labor

The serum and amniotic fluid concentrations of melatonin (MT) were measured by RIA during human labor in different conditions related to the type of delivery and the time of the day of delivery. Serum MT concentrations displayed a normal diurnal rhythm, resembling that of nongravid women; the mean concentration [163.8 +/- 149.6 (+/- SD) pmol/L] at night was significantly (P less than 0.001) higher than that during the day (31.4 +/- 16.3 pmol/L). The amniotic fluid MT concentration, which showed a significant positive correlation to the serum MT concentration (r = 0.625; P less than 0.01), also showed an obvious diurnal rhythm; the mean MT concentration was significantly (P less than 0.01) higher during the night [99.3 +/- 59.3 (+/- SD) pmol/L] than during the day (58.9 +/- 33.5 pmol/L). Reverse phase high pressure liquid chromatography confirmed that the amniotic fluid MT immunoreactivity eluated as synthetic MT. During the night the mean amniotic fluid MT concentration [99.3 +/- 59.3 (+/- SD) pmol/L] was significantly (P less than 0.01) lower than that in serum (178.9 +/- 189.6 pmol/L). The progress of delivery, estimated by cervical dilatation, did not affect serum MT concentrations. Induction of delivery by amniotomy and/or oxytocin, and operative delivery by cesarean section had no effect on serum MT concentrations. Human MT secretion does not seem to be influenced by the physical stress of labor or endocrine changes associated with parturition. The single factor regulating MT secretion during human delivery appears to be the time of day.     

Arginine vasopressin and oxytocin responses to insulin-induced hypoglycemia in type 1 (insulin-dependent) diabetes

In normal humans, arginine vasopressin and oxytocin are released acutely from the posterior pituitary gland in response to hypoglycemia, and their release may assist counterregulation. The responses of these hormones to insulin-induced hypoglycemia were measured in 16 insulin-dependent diabetic patients with no autonomic neuropathy (8 patients who had been diabetic less than 5 yr and 8 patients who had been diabetic greater than 15 yr) and in 6 normal subjects. The time of the onset of hypoglycemia and the mean blood glucose nadirs were similar in all groups, but the blood glucose recovery was delayed in the diabetic patients. In the normal subjects plasma arginine vasopressin rose from a mean basal value of 0.4 +/- 0.2 (+/- SE) pmol/L to a maximum of 1.3 +/- 0.6 pmol/L, and plasma oxytocin rose from 0.7 +/- 0.1 pmol/L to a maximum of 1.2 +/- 0.2 pmol/L 30 min after the onset of hypoglycemia. The plasma arginine vasopressin and oxytocin concentrations after hypoglycemia were significantly higher in both of the diabetic groups compared with those in the normal group. Arginine vasopressin and oxytocin rose in all control subjects after hypoglycemia. The individual hormonal profiles in the diabetic patients were variable, with an exaggerated rise of oxytocin in some diabetic patients and no rise in others. The arginine vasopressin responses were exaggerated in all of the diabetic patients. There was no correlation between the hormonal responses and the duration of diabetes. The exaggerated plasma arginine vasopressin and oxytocin responses to hypoglycemia in diabetic patients may indicate the failure of a normal inhibitory mechanism which modulates hormonal secretion or a compensatory response to impaired glucose recovery.     

The presence, characterisation and synthesis of neuromedin B in the human pituitary gland.

Neuromedin B is a 10-amino-acid mammalian peptide of the bombesin family. We have used a specific radioimmunoassay and Northern blot hybridisation to investigate the possible synthesis of neuromedin-B-like immunoreactivity in the human pituitary gland. The concentration of immunoreactive neuromedin B in whole human pituitary was 15.2 +/- 4.2 pmol/g wet weight in males and 12.8 +/- 2.7 pmol/g wet weight in females (mean +/- SEM, n = 10). In pituitary tumour extracts, neuromedin B immunoreactivity was 9.1 +/- 1.7 pmol/g wet weight (mean +/- SEM, n = 14) in inactive tumours, 18.4 +/- 6.9 pmol/g wet weight (mean +/- SEM, n = 4) in somatotrophs and 10.4 +/- 2.7 pmol/g wet weight (mean +/- SEM, n = 2) in prolactinomas, with no apparent significant difference between the groups. Gel permeation chromatography of pituitary extracts revealed two immunoreactive peaks, the major one of which corresponded in position to that of neuromedin B-32 and a later minor peak to the position of the neuromedin B-10 standard. On fast protein liquid chromatography, neuromedin-B-like immunoreactivity again eluted in two peaks, a minor peak corresponding to the synthetic neuromedin B standard, and a major more hydrophobic peak which was the big neuromedin B form. Northern blot analysis of poly(A)+RNA from human pituitaries revealed the presence of a hybridising band of between 750 and 850 base pairs. These results suggest that neuromedin B is synthesised in the human pituitary gland where it may be of importance in the regulation of pituitary function. Furthermore, the adenomatous condition is not associated with abnormal levels of this peptide.     

Atrial natriuretic peptide and the development of congestive heart failure in the oldest old: a seven-year prospective study

BACKGROUND: Atrial natriuretic peptide (ANP) levels are elevated in symptomatic heart failure and correlate with invasively measured left heart pressures. OBJECTIVE: To examine the association between plasma ANP level and the subsequent development of congestive heart failure (CHF) in older subjects with no history of CHF. DESIGN: A 7-year, prospective, blinded, cohort study. SETTING: A life care facility in Boston, Massachusetts. PARTICIPANTS: Two hundred fifty-six frail older subjects (mean age 88 +/- 7) with no history of CHF at study entry. MAIN OUTCOME MEASURE: Clinical episodes of CHF with confirmatory chest roentgenogram findings. Cox proportional hazard analyses were performed to examine the relationship between ANP levels and the development of CHF while controlling for 19 clinical, physical, and laboratory parameters. A Kaplan-Meier estimator (log-rank test) was used to determine if the development of CHF differed by tertile of ANP. RESULTS: During the follow-up period, 32% of the cohort developed CHF. The mean ANP level in the CHF group was 95 pmol/L +/- 11 pmol/L versus 60 pmol/L +/- 5 pmol/L in the no CHF group (two tailed t test P = .005). On multivariate analysis, a high ANP level was found to be associated significantly (P = .01) with the development of CHF. CONCLUSIONS: There is a statistically significant association between ANP level and the subsequent development of CHF in frail older individuals with no history of CHF.     

Maternal pinealectomy abolishes the diurnal rhythm in plasma melatonin concentrations in the fetal sheep and pregnant ewe during late gestation

We have investigated the effect of pinealectomy of ewes in pregnancy on the presence of the diurnal rhythm in fetal and maternal plasma concentrations of melatonin. Six ewes were pinealectomized between 104 and 118 days of gestation. Fetal and maternal blood samples were collected during 24-h periods between 125 and 140 days of gestation in the pinealectomized ewes and in an intact control (n = 4). There was a significant diurnal rhythm in both fetal and maternal plasma concentrations of melatonin in the control group. In this group, the fetal and maternal plasma melatonin concentrations were significantly higher in the dark (128.4 +/- 6.2 and 192.2 +/- 10.7 pmol/l respectively) than in the light (46.2 +/- 4.2 and 25.8 +/- 2.1 pmol/l respectively). However there was no diurnal rhythm in either the fetal or maternal plasma melatonin concentrations in the pinealectomized group between 125 and 140 days of gestation. In contrast to the control animals, there was also no light-dark difference in the fetal or maternal plasma melatonin concentrations in four pinealectomized animals sampled frequently in the 3-7 days preceding delivery (mean length of gestation 146.5 days). However, in the pinealectomized sheep there was a gradual increase in the combined light-dark fetal plasma melatonin concentrations during late gestation from 27.9 +/- 2.8 pmol/l (at 15-20 days before delivery) to 95.2 +/- 14.1 pmol/l on the day of delivery. We have therefore demonstrated that the maternal pineal is the major source of the diurnal rhythm in maternal and fetal plasma melatonin concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)     

Elevated plasma atrial natriuretic factor and vasopressin in high-altitude pulmonary edema

A diagnosis of acute high-altitude pulmonary edema was made in five male skiers (age, 35.0 +/- 1.8 years) by history and physical examination and was confirmed by a characteristic chest radiogram showing alveolar infiltrates associated with a normal cardiac silhouette. Five healthy age- and sex-matched subjects with similar physical activity at the same altitude served as controls. Plasma sodium was 135.0 +/- 1.5 mmol/L in the acutely ill patients compared with 144.0 +/- 3.3 mmol/L in the controls (P less than 0.025). Mean plasma atrial natriuretic factor immunoreactivity averaged 17.6 +/- 5.6 pmol/L in patients with high-altitude pulmonary edema compared with 6.8 +/- 0.7 pmol/L in the controls at the same altitude (P less than 0.05). Elevated atrial natriuretic factor levels normalized to 7.5 +/- 1.9 pmol/L (P less than 0.05) during recovery in Denver (altitude, 1600 meters) 24 hours later. Plasma arginine vasopressin levels were 1.8 +/- 0.37 pmol/L in patients with high-altitude pulmonary edema at diagnosis compared with 0.92 +/- 0.28 pmol/L in controls (P = 0.07). The inappropriately elevated arginine vasopressin levels decreased to 1.29 +/- 0.37 pmol/L during recovery (P less than 0.025), but the lowered plasma sodium concentration had not normalized by discharge within 24-hours of transfer to Denver and averaged 135.8 +/- 1.2 mmol/L. The pathophysiologic implications of these findings are discussed.     

Failure of L-arginine to induce hypotension in patients with a history of accelerated-malignant hypertension

A profound elevation of blood pressure on exercises or after withdrawal of antihypertensive drugs has been reported in patients with a history of accelerated-malignant hypertension. We tested the hypothesis that severe endothelial dysfunction is responsible for the profound hypertensive response in these patients. Responses of blood pressure, heart rate and plasma cyclic guanosine monophosphate to intravenously infused L-arginine, a precursor of nitric oxide, was investigated in hypertensive patients with (group A) or without any history of accelerated-malignant hypertension (group B) in order to evaluate endothelial function. Casual blood pressure or severity of hypertension was not different between group A and B. Infusion of L-arginine decreased mean blood pressure in group B (97.4 +/- 8.7 to 81.7 +/- 6.9 mm Hg), but not in group A (99.0 +/- 10.2 to 101.5 +/- 8.7 mm Hg). Plasma levels of cyclic guanosine monophosphate were increased after infusion of L-arginine in group B (5.4 +/- 2.0 to 7. 7 +/- 1.7 pmol/ml, P< 0.01), while no significant changes were observed in group A (5.4 +/- 2.1 to 5.9 +/- 2.1 pmol/ml). There was a significant correlation between decrease in mean blood pressure and increase in plasma levels of cyclic guanosine monophosphate (r = 0.83, P < 0.001). The results indicated that much more severe endothelial dysfunction is present in hypertensive patients with a history of accelerated-malignant hypertension as compared to those without the history. The difference in the endothelial function may account for the different pressor responses to exercises or other stimuli observed in hypertensive patients with and without a history of accelerated-malignant hypertension. Journal of Human Hypertension (2000) 14, 485-488     

Intravenous morphine reduces plasma endothelin 1 concentration through activation of neutral endopeptidase 24.11 in patients with myocardial infarction

STUDY OBJECTIVE: Morphine has multiple cardiovascular effects, but its action on hydrolysis of endothelin 1 (ET-1) has not been investigated. METHODS: We measured plasma levels of ET-1, C-terminal degradation products of ET-1, and neutral endopeptidase 24.11 (NEP) in 68 patients with acute Q-wave myocardial infarction and 29 control subjects. All the patients underwent blood sampling at initial presentation and 10 minutes later. Thirty-six of those with Q-wave myocardial infarction intravenously received 3 mg of morphine immediately after the first sampling (group 1), and the other 32 received the same after the second sampling (group 2). Twenty-four of the control subjects (group 3) were randomized to the protocol of group 1, and the remaining 5 subjects (group 4) were randomized to the protocol of group 2. RESULTS: The plasma ET-1 levels were significantly higher in groups 1 and 2 than in groups 3 and 4 (control groups). In group 1, the ET-1 level decreased significantly at second blood samplings (2.5+/-0.4 pmol/L versus 1.7+/-0.6 pmol/L, P <.001), whereas there were no definite changes of ET-1 levels in group 2 (2.5+/-0.5 pmol/L versus 2.6+/-0.6 pmol/L, P =not significant). However, the C-terminal degradation products increased significantly at second blood samplings in group 1 (0.8+/-0.2 pmol/L versus 1.3+/-0.4 pmol/L, P <.001), whereas there were no definite changes in group 2 (0.9+/-0.3 pmol/L versus 0.9+/-0.4 pmol/L, P =not significant). There was no significant difference in baseline NEP activities between groups 1 and 2 (5.02+/-1.30 nmol/mg protein versus 5.06+/-1.48 nmol/mg protein, P =not significant). However, the NEP activities at second blood samplings declined significantly in group 1 (9.76+/-1.76 nmol/mg protein, P <.001 versus baseline), whereas no definite changes were observed in group 2 (5.09+/-1.62 nmol/mg protein, P =not significant versus baseline). CONCLUSION: Intravenous morphine may increase NEP activities to accentuate hydrolysis of ET-1.     

绝经后妇女血清降钙素基因相关肽、同型半胱氨酸水平与性激素及冠心病的关系

目的　了解绝经后女性冠心病 (CHD)患者血清降钙素基因相关肽 (CGRP)、同型半胱氨酸 (Hcy)与女性激素水平的关系。方法　用断面调查方法收集经冠状动脉造影确诊的绝经后女性CHD患者 75例、非CHD患者 6 9例及同期年轻女性 6 6例 ,测定血清CGRP、Hcy及性激素水平。 结果CHD组血清Hcy水平 (15 3± 6 5 ) μmol/L高于非CHD组 (10 2± 2 8) μmol/L ,P <0 0 1。CHD组血清CGRP水平 (10 3 6± 5 9 8)ng/L低于非CHD组 (16 4 6± 5 0 7)ng/L ,P <0 0 1。CHD组女性激素水平低于非CHD组 [雌二醇 :(6 7 9± 2 4 4 ) pmol/L比 (91 7± 2 3 0 ) pmol/L ,P <0 0 1;孕酮 :(0 89± 0 4 6 )nmol/L比 (1 11± 0 4 5 )nmol/L ,P <0 0 1]。CHD组患高血压、糖尿病的比例高于非CHD组。CHD组患者年龄高于非CHD组。多因素分析证实 ,Hcy的OR大于 1,并有显著差异 ;CGRP与女性激素的OR小于 1。用前进法观察Hcy、女性激素及CGRP的偏回归系数变化 ,证实Hcy是CHD的独立危险因素 ;CGRP及女性激素是CHD的独立保护因素。结论　Hcy是导致女性CHD的独立危险因素。CGRP是CHD的独立保护因素。女性激素对Hcy及CGRP水平无明显影响     

Increased plasma 21-deoxycorticosterone (21-DB) levels in late-onset adrenal 21-hydroxylase deficiency suggest a mild defect of the mineralocorticoid pathway

Plasma 21-deoxycorticosterone (21-DB) concentrations were measured before (basal) and 1 h after ACTH stimulation in a population of 34 normal subjects, 18 patients with the late-onset form of congenital adrenal hyperplasia (LO-CAH) due to 21-hydroxylase deficiency, and 19 LOCAH heterozygotes. For comparison, plasma 21-deoxycortisol (21-DOF) and 17-hydroxyprogesterone (17-OHP) were determined simultaneously in the same subjects. Plasma 21-DB concentrations as well as those of 21-DOF did not vary significantly as a function of age, sex, or phase of the menstrual cycle, in contrast to plasma 17-OHP. The mean plasma 21-DB concentrations in normal subjects (adult men, follicular and luteal phase women, and children) were 19.0 +/- 9.5 (+/- SD) pmol/L before and 73.2 +/- 31.0 after ACTH stimulation. In the LOCAH patient group, the mean post-ACTH plasma 21-DB concentration was 1736.0 +/- 1243.0 pmol/L, and all values were above the highest post-ACTH value (148.2 pmol/L) in the normal subjects. Similarly, in the LOCAH patients the post-ACTH plasma 21-DOF concentration was 33.7 +/- 20.3 nmol/L, and the post-ACTH plasma 17-OHP value was 134.0 +/- 70.6 nmol/L; all LOCAH patients had supranormal responses to ACTH. However, 38.9%, 11.2% and 16.7% of the basal plasma 21-DB, 21-DOF, and 17-OHP values in the LOCAH patients overlapped those in the normal subjects. There was a rather large overlap (63.2%) in post-ACTH plasma 21-DB levels between the LOCAH heterozygotes and the normal subjects; it was less than the overlap in plasma 17-OHP (74%) and more than the overlap in plasma 21-DOF values (5.2%) in these same 2 groups. There was moderate overlap (21%) in the post-ACTH plasma 21-DB levels between the LOCAH heterozygotes and LOCAH patients, but no overlap between these 2 groups for either 21-DOF or 17-OHP. The abnormally elevated post-ACTH plasma 21-DB levels found in all the LOCAH patients as well as in some LOCAH heterozygotes suggest the existence of minor 21-hydroxylase deficiency in the mineralocorticoid synthetic pathway in these patients in addition to the well known impairment in the glucocorticoid pathway demonstrated by the elevated post-ACTH 21-DOF and 17-OHP levels.     

Identification and plasma concentrations of the N-terminal fragment of proatrial natriuretic factor in man

A specific RIA was developed to measure plasma atrial natriuretic factor (ANF) N-terminal immunoreactivity in man. Antibodies raised in rabbits against a rat ANF N-terminal fragment [ANF-(11-37)] had 100% cross-reactivity with human ANF-(1-30) and purified plasma N-terminal ANF immunoreactivity. The ED80 and ED50 of standard curves prepared using [125I]human ANF-(1-30) and human ANF-(1-30) were 31.5 +/- 5.4 (+/- SD) and 132.5 +/- 20.4 fmol/tube, respectively. The plasma ANF N-terminal peptide concentrations were assayed directly, without extraction, since dilution of plasma and addition of standard to plasma yielded parallel dose-responses in the RIA and virtually 100% recovery of ANF-(1-30) added to plasma. Purification of ANF N-terminal immunoreactivity from 1.5 L human plasma by affinity chromatography and amino acid sequencing suggested that it was closely related to ANF-(1-98), although some degraded peptides were also detected. The mean basal plasma ANF N-terminal peptide level measured in 34 normal subjects was 420 +/- 157 (+/- SD) pmol/L. The values were higher in plasma from patients with congestive heart failure (grades III and IV; 7,041 +/- 6,136 pmol/L; n = 13) or chronic renal failure (10,079 +/- 4,942 pmol/L; n = 20). In 9 patients with chronic renal failure, hemodialysis resulted in a 30% (P less than 0.05) decrease in plasma ANF-(99-126) levels, from 34.7 +/- 12.3 (+/- SD) to 23.2 + 6.1 pmol/L, but no changes in plasma ANF N-terminal peptide concentrations. These data indicate that the N-terminal portion of pro-ANF is cosecreted with ANF-(99-126). Its higher plasma levels in the basal state and during chronic renal failure suggest a different process of elimination than that of ANF-(99-126), which may be partly mediated by the kidney.     

Serial cerebrospinal fluid corticotropin-releasing hormone concentrations in healthy and depressed humans.

CRH, a hypothalamic peptide that is the most potent ACTH secretagogue known, also appears to be produced in the cerebral cortex and spinal cord. Depressed patients have blunted responses to exogenous CRH and normal to high concentrations of CRH immunoreactivity in single morning samples of lumbar cerebrospinal fluid (CSF). Although these data suggest that depression may be associated with hypersecretion of CRH, it has also been postulated that central nervous system insufficiency of CRH might have a pathophysiological role in certain depressive syndromes. We continuously sampled lumbar CSF via indwelling subarachnoid catheters from 1100-1700 h and measured CRH at 10-min intervals in depressed patients and normal subjects. A standardized mixed liquid meal was administered at 1300 h. CSF CRH was strikingly reduced in depressed patients compared to normal subjects [4.2 +/- 1.1 pmol/L vs. 13 +/- 2.1 pmol/L (mean +/- SEM), respectively, P less than 0.01 by Wilcoxon test]. CSF CRH concentrations rose progressively during the experiment in both groups, suggesting a diurnal rhythm and, possibly, response to a test meal. CRH had a very brief half-life in CSF (less than 10 min), suggesting that the spinal cord is the origin of CRH in lumbar CSF. The rapid transients in CSF CRH concentration demonstrate that single samples provide very limited information. There were no intraindividual correlations between CSF CRH concentrations and those of either plasma ACTH or cortisol, both of which rose in response to eating. The present data show that impaired central nervous system secretion of CRH can exist during states of severe depression.     

The influence of caloric deprivation and food composition on TSH, thyroid hormones and nuclear binding of T3 in mononuclear blood cells in obese women

In vivo changes in thyroid-stimulating hormone (TSH), thyroxin (T4), triiodothyronine (T3) and nuclear binding of T3 (NBT3) in mononuclear blood cells were studied in obese women during seven days of caloric deprivation (maximum 1,100 kcal/d). In seven women given a high protein diet (80% protein, 7% carbohydrates, 7% fat) and in two women who fasted (group 1), total T3 (TT3) decreased from 1.66 +/- 0.43 nmol/L to 1.11 +/- 0.32 nmol/L (P less than .01), free T3 (FT3) decreased from 5.7 +/- 1.1 pmol/L to 4.3 +/- 1.6 pmol/L (P less than .01), and free T4 (FT4) increased from 17.8 +/- 2.3 pmol/L to 21.1 +/- 2.0 pmol/L (P less than .01). In five women given a carbohydrate diet (Dextrin-maltose 100%) (group 2), thyroid hormones were unchanged, TT3 was at start 1.66 +/- 0.24 nmol/L and after seven days 1.43 +/- 0.26 nmol/L (NS), FT3 changed from 6.4 +/- 1.8 pmol/L to 6.0 +/- 2.1 pmol/L (NS) and FT4 changed from 20.4 +/- 5.1 pmol/L to 20.6 +/- 3.1 pmol/L (NS). The caloric intake and the weight reduction was the same in the two groups. Basal TSH and TSH after thyrotropin-releasing hormone (TRH) (TSH+30min) declined in both groups. In group 1, basal TSH declined from 1.88 +/- 1.07 microU/mL (P less than .03), and TSH+30min declined from 12.44 +/- 7.49 microU/mL to 9.38 +/- 5.97 microU/mL (P less than .03). In group 2, basal TSH declined from 2.09 +/- 0.87 microU/mL to 1.66 +/- 0.92 microU/mL (P less than .03), and TSH+30min declined from 15.63 +/- 7.90 microU/mL to 11.93 +/- 7.20 microU/mL (NS).(ABSTRACT TRUNCATED AT 250 WORDS)     

Changes in endothelium-dependent vasodilatation and alpha-adrenergic responses in resistance vessels during the menstrual cycle in healthy women

During the menstrual cycle, changes in endothelium-dependent vasodilatation have been demonstrated in conduit vessels in vivo, but responses in resistance vessels have not been studied. The aim of this study was to examine endothelium-dependent vasodilatation, the effects of local nitric oxide synthesis, and alpha-adrenergic constriction in resistance vessels during the menstrual cycle in 15 healthy female volunteers (mean age, 28.07 +/- 2.1 yr). Forearm blood flow in response to intrabrachial infusion of bradykinin (10, 30, and 100 pmol/min; endothelium-dependent vasodilator), glyceryl trinitrate (4, 8, and 16 nmol/min; endothelium-independent vasodilator), noradrenaline (60, 120, and 240 pmol/min; alpha-adrenergic receptor agonist), and N(G)-monomethyl-L-arginine (1, 2, and 4 micromol/min; nitric oxide synthase inhibitor) was assessed by venous occlusion plethysmography. All subjects were studied in early menstrual phase (days 1--4) and midcycle (days 10-13). Vasodilator response to bradykinin, expressed as the within-subject mean difference in the area under the dose-response curve between phases, was significantly increased at midcycle compared with that in the early menstrual phase (486.5 +/- 165.0; P = 0.01), whereas there was no significant difference in response to glyceryl trinitrate (185.8 +/- 239.0; P = 0.45). The vasoconstrictor response to noradrenaline was significantly greater at midcycle (97.1 +/- 39.4; P = 0.027), but the response to N(G)-monomethyl-L-arginine was not significantly different (17.5 +/- 35.2; P = 0.63). Serum estradiol was approximately 3-fold higher at midcycle, with a mean difference of 252.3 +/- 56.0 pmol/L (P = 0.0005). Progesterone concentrations were not significantly different (-0.11 +/- 0.1 nmol/L; P = 0.28). Differences in endogenous estrogen levels between menstrual phases may underlie changes in bradykinin and noradrenaline responses. If exogenous estrogens have similar effects, the balance of these two opposing actions may determine whether estrogen replacement in postmenopausal women has beneficial or harmful effects on the vasculature.