Genetic polymorphisms of the beta 2-adrenergic receptor in nocturnal and nonnocturnal asthma. Evidence that Gly16 correlates with the nocturnal phenotype.

Nocturnal asthma represents a unique subset of patients with asthma who experience worsening symptoms and airflow obstruction at night. The basis for this phenotype of asthma is not known, but beta 2-adrenergic receptors (beta 2AR) are known to downregulate overnight in nocturnal asthmatics but not normal subjects or nonnocturnal asthmatics. We have recently delineated three polymorphic loci within the coding block of the beta 2AR which alter amino acids at positions 16, 27, and 164 and impart specific biochemical and pharmacologic phenotypes to the receptor. In site-directed mutagenesis/recombinant expression studies we have found that glycine at position 16 (Gly16) imparts an accelerated agonist-promoted downregulation of beta 2AR as compared to arginine at this position (Arg16). We hypothesized that Gly16 might be overrepresented in nocturnal asthmatics and thus determined the beta 2AR genotypes of two well-defined asthmatic cohorts: 23 nocturnal asthmatics with 34 +/- 2% nocturnal depression of peak expiratory flow rates, and 22 nonnocturnal asthmatics with virtually no such depression (2.3 +/- 0.8%). The frequency of the Gly16 allele was 80.4% in the nocturnal group as compared to 52.2% in the nonnocturnal group, while the Arg16 allele was present in 19.6 and 47.8%, respectively. This overrepresentation of the Gly16 allele in nocturnal asthma was significant at P = 0.007 with an odds ratio of having nocturnal asthma and the Gly16 polymorphism being 3.8. Comparisons of the two cohorts as to homozygosity for Gly16, homozygosity for Arg16, or heterozygosity were also consistent with segregation of Gly16 with nocturnal asthma. There was no difference in the frequency of polymorphisms at loci 27 (Gln27 or Glu27) and 164 (Thr164 or Ile164) between the two groups. Thus the Gly16 polymorphism of the beta 2AR, which imparts an enhanced downregulation of receptor number, is overrepresented in nocturnal asthma and appears to be an important genetic factor in the expression of this asthmatic phenotype.     

Plasma histamine, epinephrine, cortisol, and leukocyte beta-adrenergic receptors in nocturnal asthma.

Plasma histamine, cortisol, epinephrine, cyclic adenosine monophosphate (cAMP), and leukocyte beta-adrenergic receptors were measured in asthmatic patients with (n = 7) and without (n = 10) nocturnal asthma at 4 PM and 4 AM and compared with those of normal subjects (n = 10). A twofold higher plasma histamine concentration was observed at 4 AM compared with 4 PM in all groups, with no change in plasma cortisol, epinephrine, and cAMP concentrations. At 4 AM compared with 4 PM, only patients with nocturnal asthma had a significant 33% decrease (p less than 0.05) in mononuclear and polymorphonuclear leukocyte beta-adrenergic receptor density, with no difference in binding affinity in all three groups. Polymorphonuclear leukocytes from patients with nocturnal asthma had significantly impaired response to isoproterenol at 4 AM (17% +/- 7.3% SEM increase in cAMP; p less than 0.05) compared with those of patients without nocturnal asthma (69.4% +/- 13.7%) and normal (80.2% +/- 21.3%) subjects. A significant change in beta-adrenergic receptor density and function occurs at night in patients with nocturnal asthma.     

Circadian variation in vascular tone and endothelial cell function in normal males

The existence of circadian rhythms in the time of onset of acute cardiovascular events has been described previously. This report describes the circadian variation in endothelial cell products, such as nitric oxide (NO) and endothelin-1 (ET-1) levels, and endothelium-dependent and -independent vasodilation in normal males. Plasma ET-1 and NO were measured every 4 h in nine subjects (20-41 years old) over a 24 h period. Endothelium-dependent and -independent vascular responses were measured in the forearm skin every 4 h using laser Doppler imaging after iontophoresis of increasing doses of acetylcholine (ACh) and sodium nitroprusside respectively. A statistically significant circadian variation was demonstrated for the mean ACh response (P=0.0001, ANOVA). The peak response [in arbitrary perfusion units (AU)] occurred at 16.00 hours (8.90+/-1.91 AU) and the lowest response at 08.00 hours (4.57+/-0.66 AU). A significant circadian variation was also seen for the highest dose of sodium nitroprusside (P=0.036, ANOVA), the peak occurred at 16.00 hours (3.97+/-1.80 AU), and the lowest at 04.00 hours (2.62+/-0.58 AU) and 08.00 hours (2.58+/-1.16 AU). There was a significant circadian variation in the ET-1 levels (P=0.04) with two peaks, one at 20.00 hours (0.80+/-0.28 pg/ml) and the other at 08.00 hours (0.84+/-0.15 pg/ml). The lowest value occurred at 16.00 hours (0.61+/-0.24 pg/ml). There was also a borderline trend for a circadian variation in NO levels (P=0.06), with higher levels at 20.00 hours (15.53+/-8.42 micromol/l), and low levels at 04.00 hours (10.87+/-4.70 micromol/l) and 08.00 hours (9.82+/-3.15 micromol/l). ACh responses were significantly correlated with ET-1 (r=-0.3, P=0.02) and NO (r=0.30, P=0.02) levels. Our findings suggest that endothelial activity has a circadian variation with attenuation in the morning. These circadian variations in endothelial activity might play an important role in the occurrence of acute cardiovascular events at this time, which are precipitated through the interplay between ET-1, NO and vascular function.     

Recurrent nocturnal asthma after bronchoprovocation with Western Red Cedar sawdust: association with acute increase in non-allergic bronchial responsiveness

Recurrent nocturnal asthma following a single exposure to Western Red Cedar sawdust was documented by measurements of peak flow rates in two sensitized subjects. The nocturnal asthma followed a dual asthmatic response in the first subject and a late (non-immediate) asthmatic response in the second. Both subjects developed a 10-fold reduction in the dose of histamine required to decrease the FEV1 by 20%. This cedar-induced increase in non-specific bronchial reactivity was maximal at the time of the recurrent nocturnal asthma, and persisted after nocturnal asthma had ceased and after FEV1 had returned to normal. We hypothesize that the enhanced non-specific bronchial reactivity which occurs following late asthmatic responses to bronchial challenge is the cause of recurrent nocturnal asthma following single exposure to a sensitizing agent.     

Variations of airway responsiveness to methacholine and exercise in asthmatic and normal subjects over a 12-month period

This study looked at seasonal fluctuations of airway responsiveness (AR) to methacholine and exercise in ten mild asthmatic and seven normal subjects. Each subject had a monthly methacholine inhalation test. An exercise challenge with measurement of expiratory flows was performed initially in the fall (F), then in winter (W), and in summer (S). Throughout the study, the subjects were asked to record on a diary card twice daily peak flow rates and respiratory symptoms, one week a month. Airway responsiveness to exercise and methacholine remained generally stable throughout the year, although an increase in respiratory symptoms occurred during fall and winter. The overall AR to methacholine was not significantly different during the different seasons (F, W, S and Spring) with the methacholine concentration producing a 20% fall in FEV1, PC20 (mg/ml) values, respectively, of 1.7 +/- 1.2 mg/ml, 1.8 +/- 1.1, 2.1 +/- 1.2, and 2.0 +/- 1.9 for asthmatics and 79.0 +/- 1.2 mg/ml, 66.8 +/- 1.0, 87.3 +/- 1.0, and 73.1 +/- 1.0 for normals. However, short term variations in AR were associated to exposure to antigens and cold weather. Mean daily peak expiratory flows remained generally stable through the seasons. On the three exercise tests, the VO2 max and the mean % fall in FEV1 after maximal exercise showed large variations; these, however, were not significantly different (mean fall: 16.2% (F), 16.6% (W), and 14.7% (S) in asthmatics). In conclusion, although it may increase transiently, overall airway responsiveness to methacholine and exercise remains generally stable in asthmatic and normal subjects throughout the year.     

The determination of blood histamine in asthmatic patients with a simple and sensitive method

The histamine level of whole blood and plasma in asthmatic patients was estimated by means of a simple, sensitive and specific method, which was developed to measure low histamine levels. This method consists of the following procedures; the partial purification of histamine with a small P-cellulose column; its further purification with high performance liquid chromatography (HPLC); and fluorometric detection with precolumn o-phthaldehyde (OPT) reaction. The present assay could detect as little as 0.5 ng of histamine concentration. Blood histamine levels in patient with asthmatic attack, 57 +/- 34 ng/ml (mean +/- S.D. N = 14), were significantly different from those in symptom-free period, 37 +/- 15 ng/ml (N = 15) as well as those in normal subjects, 36 +/- 17 ng/ml (N = 12). However, there were no significant differences among plasma histamine levels in normal subjects, 1.6 +/- 1.7 ng/ml (N = 12) and, in asthmatic patients during attacks, 1.6 +/- 1.8 ng/ml (N = 14) and symptom-free periods, 1.6 +/- 1.7 ng/ml (N = 15). These results indicate that plasma histamine concentration does not increase during asthmatic attacks, even though there was significant increase of blood histamine concentration.     

Comparative effects of verapamil and isradipine on steady-state digoxin kinetics

The effects on the steady-state digoxin pharmacokinetics of verapamil (240 mg/day) and a new dihydropyridine calcium channel blocker, isradipine (15 mg/day), were compared. Nineteen healthy white men, aged 23 to 40 years, ingested 0.25 mg digoxin tablets every 12 hours for two consecutive periods of 2 weeks. Each subject also received one of the calcium channel blockers during one of these periods, with agent and sequence randomized. Analyst-blind RIA serum digoxin determinations demonstrated that the nine subjects who received isradipine, 5 mg t.i.d., had a small increment in peak digoxin level from 2.3 +/- 0.6 to 2.9 +/- 0.7 ng/ml (p less than 0.05) but no significant change in steady-state level or AUC over 12 hours. By contrast, the 10 subjects who received verapamil, 80 mg t.i.d., showed significant increases in steady-state (0.9 +/- 0.1 to 1.3 +/- 0.2 ng/ml; p less than 0.001) and peak serum digoxin concentrations (2.5 +/- 0.7 to 3.6 +/- 0.8 ng/ml; p less than 0.001) and in AUC (15.7 +/- 1.7 to 23.6 +/- 2.9 ng . hr/ml; p less than 0.001). Neither calcium channel blocker reduced renal digoxin clearance. Verapamil increases digoxin levels without affecting renal clearance. Isradipine has no clinically important interaction with digoxin.     

Impaired growth hormone secretion in the adult population: relation to age and adiposity.

Growth hormone (GH) release was studied in adults of normal stature, ages 21-86 yr. The subjects were 85-115% of ideal body weight, between the 5th and 95th percentiles in height, and free of active or progressive disease. 9 to 12 individuals in each decade from thirds to ninth were evaluated. The following criteria of GH status were measured: serum GH concentration, analyzed by radioimmunoassay at half-hour intervals for 4 h after onset of sleep, and at 1-h intervals from 8 a.m. to 4 p.m. in 52 subjects; daily retention of N, P, and K in response to 0.168 U human (h)GH/kg body wt3/4/day in 18 subjects; and plasma somatomedin C (SmC) level before and during exogenous hGH treatment in 18 subjects. All 10 individuals, 20-29 yr old, released substantial amounts of endogenous GH during both day and night (average peak serum GH obtained during day and night was 7.3 and 20.3 ng/ml, respectively); average plasma SmC was 1.43 U/ml (95% tolerance limits, 0.64-2.22 U/ml). There was no significant effect of exogenous hGH on elemental balances or on plasma SmC. In contrast, 6 of 12 individuals 60-79 yr old showed the following evidences of impaired GH release; peak waking and sleeping serum GH less than 4 ng/ml; plasma SmC less than 0.38 U/ml; a significant retention in N, P, and K; and a significant rise in plasma SmC, in response to exogenous hGH. Plasma SmC, serum GH during sleep, serum GH during the day, retentions of N, P, and K in response to exogenous hGH, and rise in plasma SmC in response to hGH were all intercorrelated (P less than 0.05). Plasma SmC less than 0.38 U/ml corresponded to peak nocturnal serum GH less than 4 ng/ml. The prevalence of plasma SmC less than 0.38 U/ml increased progressively from age 20 to 90: third decade, 0%; fourth, 11%; fifth, 20%; sixth, 22%; seventh, 42%; eight, 55%; and ninth, 55%. Within each decade, plasma SmC was inversely related to adiposity.     

Reduction of serum theophylline levels by terbutaline in children with asthma

We studied the effect of oral terbutaline on serum theophylline levels in 12 children with asthma. Sustained-release theophylline (10 mg/kg twice a day) was given with placebo or terbutaline (0.075 mg/kg three times a day) in a chronic, randomized, double-blind, crossover design. The trough serum theophylline concentration fell from 13.8 +/- 4.0 to 10.8 +/- 3.6 micrograms/ml and the peak expiratory flow rate increased from 285 +/- 30 to 310 +/- 29 L/min after terbutaline. Further investigation is needed to clarify the mechanism of action by which terbutaline decreases serum theophylline levels.     

Effect of a standard breakfast on digoxin absorption in normal subjects

The influence of food on absorption of digoxin was studied in 6 healthy volunteers who received 1.0 mg digoxin as 4 tablets of Lanoxin either after an overnight fast, immediately after a standard breakfast, or 90 min after a standard breakfast. There was no significant difference between the three regimens in terms of area under the plasma concentration-time curve for 79 hr or in the 10-day cumulative urinary excretion. The mean peak plasma concentration was higher (p less than 0.05) when digoxin was given fasting (4.2 +/- 0.46 ng/ml) than immediately after food (2.8 +/- 0.24 ng/ml). The mean peak plasma concentration when digoxin was administered 90 min after food (3.3 +/- 0.30 ng/ml) was intermediate but not significantly different from either of the other mean peak concentrations. The results demonstrate that ingestion of food decreases rate but not extent of absorption of concurrently administered digoxin.     

Peak flow and peak cough flow in the evaluation of expiratory muscle weakness and bulbar impairment in patients with neuromuscular disease

OBJECTIVE: To study the expiratory muscle force and the ability to cough estimated by the peak expiratory flow and peak cough flow in patients with Duchenne muscular dystrophy and amyotrophic lateral sclerosis. DESIGN: A total of 27 patients with amyotrophic lateral sclerosis and 52 patients with Duchenne muscular dystrophy were studied. From the group of 144 normal subjects of this laboratory, we selected 38 for comparison. RESULTS: The maximal inspiratory pressure in patients with Duchenne muscular dystrophy and amyotrophic lateral sclerosis was 64.5 +/- 24.7% and 37.8 +/- 21.8%, respectively, and maximal expiratory pressure was 64.2 +/- 32.5% and 37.7 +/- 21.6%, respectively. Patient groups showed a significant lower peak expiratory flow than normal subjects. Higher peak cough flow than peak expiratory flow was found in all groups. The peak cough flow-peak expiratory flow difference was 46 +/- 18% in normal subjects, 43 +/- 23% in patients with Duchenne muscular dystrophy, and 11 +/- 17% in patients with amyotrophic lateral sclerosis. The peak expiratory flow and peak cough flow were not different in bulbar onset amyotrophic lateral sclerosis. In patient groups, the dynamic and static behavior correlated positively. CONCLUSIONS: These results suggest that peak cough flow-peak expiratory flow is useful to monitor expiratory muscle weakness and bulbar involvement and to assess its evolution in these patients.     

Treatment of nocturnal asthma in children with a single dose of sustained-release theophylline taken after supper

In a placebo-controlled, double-blind cross-over study of 2 X 3 weeks' duration, twenty-four children with stable asthma who were wheezing during the night, were treated with a single dose of sustained-release theophylline (SRT) taken after supper. The mean serum theophylline levels 4 and 12 hr after dosing were 7.7 and 11.2 mg/l, respectively. Few side-effects were seen. The mean morning peak expiratory flow (PEF) was significantly higher during SRT treatment (244 +/- 11 1/min) than during placebo treatment (207 +/- 121/min) (P less than 0.001). The mean difference between morning and evening PEF was reduced from 20.7 to 8.6% by treatment with SRT (P less than 0.001). Theophylline significantly reduced the severity of attacks of bronchoconstriction during the night as judged by PEF measurement and use of extra bronchodilator treatment per attack. The response to inhaled terbutaline was increased during SRT treatment compared with that in the placebo period, however pre-treatment PEF did differ significantly between the two periods. The number of acute asthma attacks during the night, the number of symptom-free nights and the use of extra bronchodilators during the night were all significantly improved by SRT treatment (P less than 0.001). Seventeen children correctly identified the SRT period whilst six children showed no preference for either period. A single dose of SRT taken after supper is an effective treatment for nocturnal asthma in children.     

Effect of nifedipine and theophylline in asthma

The effect of nifedipine, 10 mg po q.i.d. for 2 weeks, was studied in a randomized, double-blind, crossover trial in nine patients with asthma receiving theophylline. Nifedipine did not significantly affect the mean (+/- SD) morning peak expiratory flow rate (PEFR; 336 +/- 130 L/min for drug vs. 349 +/- 92 L/min for placebo), evening PEFR (393 +/- 69 L/min for drug vs. 367 +/- 66 L/min for placebo), symptom score (27.4% +/- 22.9% for drug vs. 33.8% +/- 26.4% for placebo), or the number of albuterol inhalations per day (5.8 +/- 3.5 for drug vs. 6.2 +/- 4.1 for placebo). Furthermore, there was no change in PEFR 30, 60, or 120 minutes after nifedipine dosing. Nifedipine did not significantly affect the steady-state serum theophylline trough levels (9.1 +/- 2.2 mg/ml for drug vs. 10.2 +/- 1.9 micrograms/ml for placebo) or the theophylline pharmacokinetic parameters, such as the elimination t1/2, peak serum concentration, time to peak, and AUC(0-24). We conclude that nifedipine has little, if any, effect on the clinical status, PEFR, or theophylline serum levels in patients with asthma who receive theophylline.     

Airway hyperresponsiveness in asthma: a problem of limited smooth muscle relaxation with inspiration.

We hypothesized that hyperresponsiveness in asthma is caused by an impairment in the ability of inspiration to stretch airway smooth muscle. If the hypothesis was correct, we reasoned that the sensitivity to inhaled methacholine in normal and asthmatic subjects should be the same if the challenge was carried out under conditions where deep inspirations were prohibited. 10 asthmatic and 10 normal subjects received increasing concentrations of inhaled methacholine under conditions where forced expirations from a normal end-tidal inspiration were performed. When no deep inspirations were allowed, the response to methacholine was similar in the normal and asthmatic subjects, compatible with the hypothesis we propose. Completely contrary to our expectations, however, was the marked responsivity to methacholine that remained in the normal subjects after deep breaths were initiated. 6 of the 10 normal subjects had > 20% reduction in forced expiratory volume in one second (FEV 1) at doses of methacholine < 8 mg/ml, whereas there was < 15% reduction with 75 mg/ml during routine challenge. The ability of normal subjects to develop asthmatic responses when the modulating effects of increases in lung volume was voluntarily suppressed suggests that an intrinsic impairment of the ability of inspiration to stretch airway smooth muscle is a major feature of asthma.     

Diurnal variations in the plasma concentrations of mevalonic acid in patients with abetalipoproteinaemia

Abstract Previous studies have demonstrated that changes in the rates of cholesterol biosynthesis can be evaluated by the determination of plasma concentrations of sterol intermediates, including mevalonic acid and lathosterol and that, in normal human subjects, a diurnal rhythm exists in which the highest concentrations of sterol intermediates are observed at night. The factors responsible for this diurnal rhythm in cholesterol synthesis are, however, unknown. To test the hypothesis that the nocturnal increase in cholesterol biosynthesis is attributable to a reduced rate of hepatic uptake of chylomicron remnants at night as compared to higher rates of uptake during the daytime in response to alimentary lipaemia, we have examined the diurnal rhythm of mevalonic acid in six normal volunteers and three patients with phenotypic abetalipoproteinaemia. The latter patients do not absorb appreciable amounts of dietary cholesterol and are unable to synthesize chylomicron particles. Plasma concentrations of mevalonic acid exhibited a diurnal rhythm in the normal subjects, and the highest plasma concentrations were observed between 24.00 hours/04.00 hours. A similar rhythm was observed in the plasma of patients with abetalipoproteinaemia. These results suggest that the nocturnal increase in cholesterol biosynthesis which occurs in humans is not attributable to reduced hepatic uptake of chylomicron remnants at night; further studies are needed to better define those factors which influence the periodicity of cholesterol biosynthesis in humans.     

Nocturnal rise of leptin in lean, obese, and non-insulin-dependent diabetes mellitus subjects.

We studied 24-h profiles of circulating leptin levels using a sensitive and specific RIA in lean controls and obese subjects with or without non-insulin-dependent diabetes mellitus (NIDDM) during normal routine activity. Serum leptin levels were significantly higher in obese (41.7 +/- 9.0 ng/ml; n = 11) and obese NIDDM (30.8 +/- 6.7; n = 9) subjects compared with those in lean controls (12.0 +/- 4.4, n = 6). In all the three groups, serum leptin levels were highest between midnight and early morning hours and lowest around noon to midafternoon. The nocturnal rise in leptin levels was significant when data were analyzed by ANOVA (lean: F = 3.17, P < 0.0001, n = 4; obese: F = 2.02, P < 0.005, n = 11; and obese NIDDM: F = 4.9, P < 0.0001, n = 5). The average circadian amplitude between acrophase and nadir was 75.6% in lean, 51.7%, in obese and 60.7% in obese NIDDM groups, respectively. No significant correlations (P > 0.05) were observed between circulating levels of leptin and either insulin or glucose levels in any of the 20 subjects studied for 24-h profiles. The nocturnal rise in leptin observed in the present study resembles those reported for prolactin, thyroid-stimulating hormone, and free fatty acids. We speculate that the nocturnal rise in leptin could have an effect in suppressing appetite during the night while sleeping.     

The effect of sustained-release theophylline in nocturnal asthma

Nocturnal symptoms are common and often disabling in asthmatic subjects. Furthermore, they often persist, in spite of appropriate dosages of inhaled beta 2-agonists and topical steroids. In such a clinical situation, theophylline preparations may have a therapeutic role. This double-blind, placebo-controlled, cross-over trial was designed to evaluate the effectiveness of a twice-daily Bioavail slow-release theophylline capsule in a group of out-patient asthmatics, with a history of nocturnal and/or early morning wheeze or chest tightness. Theophylline was initially prescribed and monitored in an 'open' phase to obtain the drug dosage required to achieve a serum level in the therapeutic range of 10-20 mg/l. In the ten patients who completed the study, serum theophylline levels were stable throughout. During active treatment there was an improvement in morning peak expiratory flow rate (PEFR), and a reduction in measurements of diurnal variation. In addition, the bronchodilator response to an inhaled beta 2-agonist was preserved. Bioavail theophylline has thus been shown to be an effective agent in the management of adults with nocturnal asthma.     

Flecainide excretion in human breast milk

Healthy human volunteers who intended not to breast feed were placed on a regimen of 100 mg oral flecainide every 12 hours for 5 1/2 days beginning 1 day after parturition. Milk and blood samples were collected during the dosing period and for 2 days after the last dose. Concentrations of flecainide in milk and plasma were assayed by HPLC. Apparent steady-state levels of flecainide in both milk and plasma were achieved in most cases by day 4 of the study. Highest daily average concentration of flecainide in milk ranged from 270 to 1529 ng/ml for the 11 subjects. Mean +/- SD milk to plasma flecainide ratios were 3.7 +/- 3.5, 3.2 +/- 2.3, 3.5 +/- 2.1, and 2.6 +/- 0.7 on study days 2, 3, 4, and 5, respectively. After the last dose of flecainide, peak milk levels of the drug occurred at 3 to 6 hours and then declined monoexponentially. The half-life for elimination of flecainide from milk was 14.7 +/- 3.5 hours and is very similar to the plasma elimination half-life of flecainide in healthy human subjects. The mean milk to plasma ratios for flecainide after the last dose were 2.3 +/- 1.0 and 2.9 +/- 1.1 at 24 and 48 hours after the dose, respectively. Based on the pharmacokinetics of flecainide in infants, the expected average steady-state plasma concentration of flecainide in a newborn infant consuming all of the milk production of its mother (approximately 700 ml/day) would not be expected to exceed about 62 ng/ml.(ABSTRACT TRUNCATED AT 250 WORDS)     

Counterregulation during spontaneous nocturnal hypoglycemia in prepubertal children with type 1 diabetes.

OBJECTIVE: To examine counterregulatory responses during spontaneous nocturnal hypoglycemia in prepubertal children with type 1 diabetes. RESEARCH DESIGN AND METHODS: A total of 29 prepubertal patients with type 1 diabetes underwent two overnight profiles. Data were analyzed from 16 children (median [range] 8.7 [5.9-12.9] years of age) with a night of hypoglycemia and a nonhypoglycemic night. Children hypoglycemic (< 3.5 mmol/l) on night 1 were given 25% extra carbohydrate as uncooked cornstarch with their usual evening snack on night 2 to avoid hypoglycemia. Glucose, growth hormone, and cortisol were measured every 15 min, catecholamines every 30 min, and glucagon, pancreatic polypeptide, insulin, and ketones every 60 min. A group of 15 healthy control subjects, aged 9.5 (5.6-12.1) years, underwent one overnight profile. RESULTS: Median duration of hypoglycemia was 225 (30-630) min, and glucose nadir was 2.0 (1.2-3.3) mmol/l. Insulin levels were not different on the two nights (P = 0.9, analysis of variance), but children with diabetes had higher insulin levels than normal control subjects between 2300 and 0300, maximal at 0200 (mean +/- SEM 57.4 +/- 5.7 vs. 31.6 +/- 5.0 pmol/l, P = 0.002). Peak epinephrine was higher on the night of hypoglycemia (0.98 [0.52-2.09] nmol/l) versus nonhypoglycemia (0.32 [0.21-0.62] nmol/l), P = 0.001, but norepinephrine (1.29 [1.07-2.64] vs. 1.26 [1.04-1.88] nmol/l, P = 0.5), glucagon (93 [64.2-125.6] vs. 100.5 [54.6-158] ng/l, P = 0.6), pancreatic polypeptide (410.2 [191-643.2] vs. 270.8 [158.2-777.8] ng/l, P = 0.5), and cortisol (513 [300-679] vs. 475 [235-739] nmol/l, P = 0.6) were not different. Glucose threshold for epinephrine release was very low, 1.9 +/- 0.2 mmol/l. There was a short-lived rise in growth hormone from 75-105 min after onset of hypoglycemia, maximal at 90 min (7.8 +/- 1.2 vs. 3.5 +/- 0.9 ng/ml, P = 0.02). CONCLUSIONS: The prolonged nature of nocturnal hypoglycemic episodes may be explained in part by defective counterregulation. The risk of nocturnal hypoglycemia needs to be reduced before intensification of insulin therapy can be contemplated in this age-group.     

Diurnal variation of plasma atrial natriuretic peptide in normals and patients with enuresis nocturna.

The circadian variation of plasma atrial natriuretic peptide (ANP) in relation to urinary excretion of sodium (UNa) and potassium (UK) as well as clearance of creatinine (Ccrea) was assessed in 15 juvenile patients with enuresis nocturna and compared with 11 age-, sex-, and weight-matched normal subjects. Normal juveniles showed a highly significant diurnal variation (p less than 0.001) of plasma ANP with diurnal peak levels at midnight (0000 hours) and minimum levels at 0400 hours. Enuretic patients showed a similar diurnal rhythmicity with normal levels during day and night. In normals both UNa and UK showed significant diurnal rhythmicity with a marked reduction from daytime to night-time. Although the total diurnal excretions of UNa and UK were similar to normals, patients with enuresis showed abnormal diurnal variation in both UNa (p less than 0.05) and UK (p less than 0.01). The abnormal circadian rhythm of UNa and UK in enuretics seemed to be caused by abnormal tubular handling as similar abnormalities were found in the fractional excretions and as the circadian variation of Ccrea was normal. Especially during the first hours of sleep (2200 hours to 0000 hours), the patients showed polyuria (230 +/- 138 ml vs 116 +/- 58 ml, p less than 0.01), natriuresis (20.9 +/- 16.3 mmol l-1 vs 10.7 +/- 6.8 mmol l-1, p less than 0.01), and kaliuresis (7.3 +/- 6.3 mmol l-1 vs 3.7 +/- 2.3 mmol l-1, p less than 0.05), despite normal levels of plasma ANP. In conclusion, the study describes the diurnal variation of plasma ANP in relation to urinary excretion of sodium and potassium in a juvenile normal population. Patients with nocturnal enuresis show abnormal diurnal rhythmicity in the urinary excretion of sodium and potassium that is not correlated to the plasma levels of ANP.