Prolactin and beta-endorphin responses to hypoglycemia are reduced in well-controlled insulin-dependent diabetes mellitus

Several pituitary hormones, including corticotropin (ACTH), growth hormone (GH), prolactin, and beta-endorphin (but not thyrotropin, follicle-stimulating hormone, or luteinizing hormone), are released in response to hypoglycemia in normal subjects. In patients with insulin-dependent diabetes mellitus (IDDM), the degree of glycemic control is known to alter ACTH and GH responses to hypoglycemia. The current study was performed to examine the effect of glycemic control on prolactin and beta-endorphin responses to hypoglycemia in subjects with IDDM. We performed 3-hour stopped hypoglycemic-hyperinsulinemic clamp studies (12 pmol/kg/min) during which plasma glucose was decreased from 5.0 mmol/L to 2.2 mmol/L in steps of 0.6 mmol/L every 30 minutes in 20 subjects with uncomplicated IDDM (12 males and eight females; age, 26 +/- 2 years; IDDM duration, 10 +/- 1 years; body mass index, 23.6 +/- 0.6 kg/m2) and 10 healthy subjects (five males and five females aged 30 +/- 1 years). The 10 diabetic subjects in good glycemic control (mean hemoglobin A1 [HbA1], 7.5% +/- 0.3%; normal range, 5.4% to 7.4%) were compared with the 10 poorly controlled patients (mean HbA1, 12.6% +/- 0.5%; P < .001 v well-controlled diabetic group). During hypoglycemia, prolactin levels in the well-controlled diabetic group did not change (7 +/- 1 microgram/L at plasma glucose 5.0 mmol/L to 9 +/- 2 micrograms/L at plasma glucose 2.2 mmol/L), whereas prolactin levels increased markedly in the poorly controlled diabetic group (7 +/- 2 micrograms/L to 44 +/- 17 micrograms/L) and healthy volunteers (12 +/- 2 micrograms/L to 60 +/- 19 micrograms/L, P < .05 between IDDM groups). The plasma glucose threshold required for stimulation of prolactin secretion was 2.2 +/- 0.1 mmol/L in well-controlled IDDM, 3.0 +/- 0.4 mmol/L in poorly controlled IDDM, and 2.4 +/- 0.1 mmol/L in healthy subjects (P < .05 between IDDM groups). Responses in males and females were similar. The increase in beta-endorphin levels was also attenuated in well-controlled IDDM patients (4 +/- 1 pmol/L at plasma glucose 5.0 mmol/L to 11 +/- 4 pmol/L at plasma glucose 2.2 mmol/L) versus poorly controlled IDDM patients (5 +/- 1 pmol/L to 26 +/- 7 pmol/L) and healthy subjects (8 +/- 1 pmol/L to 56 +/- 13 pmol/L). The plasma glucose threshold required for stimulation of beta-endorphin release was again lower in well-controlled IDDM versus poorly controlled IDDM patients (2.2 +/- 0.1 v 3.0 +/- 0.3 mmol/L) and healthy subjects (2.5 +/- 0.4 mmol/L, P < .05 between IDDM groups). In conclusion, prolactin and beta-endorphin responses to a standardized hypoglycemic stimulus (plasma glucose, 2.2 mmol/L) are reduced and plasma glucose levels required to stimulate release of prolactin and beta-endorphin are lower in well-controlled IDDM compared with poorly controlled IDDM and healthy subjects. Thus, stress hormones not previously considered to have a primary role in plasma glucose recovery from hypoglycemia are affected by glycemic control, suggesting a more generalized alteration of hypothalamic-pituitary responses to hypoglycemia in IDDM patients with strict glycemic control.     

Low urinary dopamine excretion associated to low sodium excretion in normotensive Piaroa Amazonian ethnia compared to urban subjects

The objective of this work was to compare urinary dopamine, noradrenaline, adrenaline, sodium and potassium excretion in a group of normotensive Piaroa Amazonic ethnia who do not use salt in their regular food intake, against a group of urban normotensive citizens known to have a high salt intake in their regular meals. Twenty adult normotensive Piaroa subjects living in the Amazonas forest, 11 men and 9 women, 23-72 years old, and 33 normotensive urban citizens, 25-70 years old, 17 men and 17 women, were included in the study. After a 10 min. rest, an average of three supine systolic (SBP) and diastolic (DBP) blood pressure recordings was obtained. Piaroas subjects SBP and DBP were 111.3 +/- 2.9 mmHg and 62.7 +/- 1.9 mmHg respectively; urban subjects SBP and DBP were 111.8 +/- 2.2 mmHg and 70.3 +/- 1.6 mmHg respectively. Supine heart rate was lower in Piaroas (58.0 +/- 1.8 beats/min) than in urban subjects (76.5 +/- 1.9 beats/min), p < 0.05. Sodium urinary excretion was much lower in Piaroas (12.6 +/- 5.2 mmol/24 h) when compared to urban subjects (210.7 +/- 24.5 mmol/24 h), p < 0.01. No difference was found in daily urinary potassium excretion between Piaroas and urban subjects (50.4 +/- 7.2 mmol/24 h vs 45.1 +/- 7.4 mmol/24 h). Urinary dopamine excretion was lower in Piaroas (314.7 +/- 40.1 micrograms/24 h) in comparison to urban subjects (800.4 +/- 59.2 micrograms/24 h), p < 0.05. Daily urinary noradrenaline and adrenaline excretion were 67.9% and 85.4% respectively lower in Piaroas than in urban subjects. In conclusion, lower amounts of sodium daily intake are associated to lower kidney dopamine production in Piaroas as compared to urban subjects. Apparently indigenous tribes might require less kidney dopamine synthesis to excrete the very small amounts of salt they consume in their regular food intake. The opposite was found in urban subjects; more kidney dopamine synthesis would be required for larger amounts of urinary sodium excretion. In this population, essential hypertension has been associated to a failure of the natriuretic mechanism triggered by dopamine onkidney tubules.     

Effects of an isotonic oral rehydration solution, enriched with glutamine, on fluid and sodium absorption in patients with a short-bowel

AIM: To compare the effects of a standard oral rehydration solution with a polymeric glucose isotonic solution enriched with glutamine on water and sodium absorption in the short bowel. METHODS: Six patients with high jejunostomy were tested in a random order on 2 consecutive days with the standard solution (20 g/L glucose, 94 mmol/L sodium, 292 mOsm/kg osmolality) and a solution containing maltodextrins (18 g/L Glucidex 12; hydrolysis of 18 g of Glucidex 12 yields 20 g glucose) enriched with 14.6 g/L of glutamine (94 mmol/L sodium, 282 mOsm/kg osmolality). Solutions were administered via a naso-gastric tube at a rate of 2 mL/min. Jejunal effluent for each solution was collected during an 8-h period, after a 14-h equilibrium period. RESULTS: The net 8-h fluid absorption was not significantly different between the standard solution and the solution with glutamine (333 +/- 195 and 213 +/- 251 mL, respectively (mean +/- S.E.M.)). Net sodium absorption was higher for the standard solution than for the solution with glutamine (15 +/- 15 vs. 2 +/- 20 mmol, P < 0.05). The rate of glucose absorption was not different between the solutions. CONCLUSION: The replacement of glucose by maltodextrins and the addition of glutamine to the standard oral rehydration solution, without changing its sodium content or osmolality, results in a reduction of sodium absorption in the short-bowel syndrome.     

Inhibition of Na+/K+ ATPase under hypertonic conditions in rat mast cells

Ionic fluxes that contribute to changes in membrane potential and variations of pHi (intracellular pH) are not well known in mast cells, although they can be important in the stimulus-secretion coupling. Cellular volume regulation implies changes in the concentration of intracellular ions, such as sodium and potassium and volume changes can be imposed varying the tonicity of the medium. We studied the physiology of sodium and examined the effect of ouabain on [22Na] entry in mast cells in isotonic and hypertonic media. We also recorded changes in membrane potential and pHi using the fluorescent dyes bis-oxonol (Bis-(1,3-diethylthiobarbituric acid) trimethineoxonol) a n d BCECF (2',7'-bis(carboxyethyl)-5(6)-carboxyfluorescein acetoxymethyl ester) in hypertonic conditions. The results show that [22Na] influx increases four fold in hypertonic solutions and it is mediated mainly by an amiloride-sensitive Na+/H+ exchanger. This transporter is involved in the shrinkage-activated cellular alkalinization and the pHi recovery is accelerated by inhibition of the Na+/K+ ATPase with ouabain in the absence of extracellular calcium. Under hypertonic conditions 22Na influx is apparently not increased by ouabain, while the Na+/K+ ATPase inhibitor clearly increases [22Na] uptake and also induces membrane depolarization in isotonic conditions. All together, these findings suggest that Na+/K+ ATPase is partially inhibited in hypertonic conditions.     

Pathways of Rb+ influx and their relation to intracellular [Na+] in the perfused rat heart. A 87Rb and 23Na NMR study

The aims of this study were to characterize the routes of influx of the K+ congener, Rb+, into cardiac cells in the perfused rat heart and to evaluate their links to the intracellular Na+ concentration ([Na+]i) using 87Rb and 23Na nuclear magnetic resonance (NMR) spectroscopy. The rate constant for Rb+ equilibration in the extracellular space was 8.5 times higher than that for the intracellular space. The sensitivity of the rate of Rb+ accumulation in the intracellular space of the perfused rat heart to the inhibitors of the K+ and Na+ transport systems has been analyzed. The Rb+ influx rates were measured in both beating and arrested hearts: both procaine (5 mmol/L) and lidocaine (1 mmol/L) halved the Rb+ influx rate. In procaine-arrested hearts, the Na+,K(+)-ATPase inhibitor ouabain (0.6 mmol/L) decreased Rb+ influx by 76 +/- 24% relative to that observed in untreated but arrested hearts. Rb+ uptake was insensitive to the K+ channel blocker 4-aminopyridine (1 mmol/L). The inhibitor of Na+/K+/2 Cl- cotransport bumetanide (30 mumol/L) decreased Rb+ uptake only slightly (by 9 +/- 8%). Rb+ uptake was dependent on [Na+]i: it increased by 58 +/- 34% when [Na+]i was increased with the Na+ ionophore monensin (1 mumol/L) and decreased by 48 +/- 9% when [Na+]i was decreased by the Na+ channel blockers procaine and lidocaine. Dimethylamiloride (15 to 20 mumol/L), an inhibitor of the Na+/H+ exchanger, slightly reduced [Na+]i and Rb+ entry into the cardiomyocytes (by 15 +/- 5%). 31P NMR spectroscopy was used to monitor the energetic state and intracellular pH (pHi) in a parallel series of hearts. Treatment of the hearts with lidocaine, 4-aminopyridine, dimethylamiloride, or bumetanide for 15 to 20 minutes at the same concentrations as used for the Rb+ and Na+ experiments did not markedly affect the levels of the phosphate metabolites or pHi. These data show that under normal physiological conditions, Rb+ influx occurs mainly through Na+,K(+)-ATPase; the contribution of the Na+/K+/2 Cl- cotransporter and K+ channels to Rb+ influx is small. The correlation between Rb+ influx and [Na+bdi during infusion of drugs that affect [Na+]i indicates that, in rat hearts at 37 degrees C, Rb+ influx can serve as a measure of Na+ influx. We estimate that, at normothermia, at least 50% of the Na+ entry into beating cardiac cells is provided by the Na+ channels, with only minor contributions (< 15%) from the Na+/K+/2 Cl- cotransporter and the Na+/H+ exchanger.     

Morphologic and cytochemical characteristics of blood cells from Hawaiian green turtles

Previous studies have shown that hypoglycemia may reduce counterregulatory responses to subsequent hypoglycemia in healthy subjects and in patients with diabetes. The effect of hypoglycemia on the hormonal response to a nonhypoglycemic stimulus is uncertain. To test the hypothesis that the cortisol response to corticotropin (ACTH) infusion is independent of antecedent hypoglycemia, 10 healthy subjects received a standard ACTH infusion (0.25 mg Cosyntropin [Organon, West Orange, NJ] intravenously over 240 minutes) at 8:00 AM on day 1 and day 3 and a hypoglycemic insulin clamp study (1 mU/kg/min) at 8:00 AM on day 2. During the hypoglycemic clamp, plasma glucose decreased from 5.0 mmol/L to 2.8 mmol/L for two periods of 120 minutes (mean glucose, 2.9 +/- 0.03 and 2.8 +/- 0.02 mmol/L, respectively) separated by a 60-minute interval of euglycemia (mean glucose, 4.7 +/- 0.01 mmol/L). Seven subjects also had paired control studies in random order during which a 330-minute euglycemic clamp (mean glucose, 5.0 +/- 0.11 mmol/L) instead of a hypoglycemic clamp was performed on day 2. Basal ACTH (4.6 +/- 0.7 v 2.6 +/- 0.4 pmol/L, P < .02) and basal cortisol (435 +/- 46 v 317 +/- 40 nmol/L, P < .02) both decreased from day 1 to day 3 following intervening hypoglycemia. In contrast, with intervening euglycemia, neither basal ACTH (5.9 +/- 1.5 v 4.5 +/- 1.0 pmol/L) nor basal cortisol (340 +/- 38 v 318 +/- 60 nmol/L) were reduced significantly on day 3 compared with day 1. Following interval hypoglycemia, the area under the curve (AUC) for the cortisol response to successive ACTH infusions was increased (4,734 +/- 428 nmol/L over 240 minutes [day 3] v 3,526 +/- 434 nmol/L over 240 minutes [day 1], P < .01). The maximum incremental cortisol response was also significantly increased (805 +/- 63 nmol/L (day 3) v 583 +/- 58 nmol/L (day 1), P < .05). In contrast, the AUC for the cortisol response to successive ACTH infusions with interval euglycemia (3,402 +/- 345 nmol/L over 240 minutes [day 3] v 3,709 +/- 391 nmol/L over 240 minutes [day 1] and the incremental cortisol response (702 +/- 62 nmol/L [day 3] v 592 +/- 85 nmol/L [day 1] were unchanged. Following exposure to intermittent hypoglycemia in healthy humans, fasting morning ACTH and cortisol levels are reduced and the incremental cortisol response to an infusion of ACTH is enhanced. The enhanced cortisol response to exogenous ACTH infusion after intervening hypoglycemia (but not intervening euglycemia) may reflect priming of the adrenal gland by endogenous ACTH produced during the hypoglycemia. These data suggest that adrenal function testing by exogenous ACTH administration is not impaired by prior exposure to hypoglycemia. Moreover, the reduced cortisol response to recurrent hypoglycemia in patients with well-controlled diabetes is not likely the result of impaired adrenal responsiveness.     

Assessment of the salt-arterial pressure relationship in mild hypertensive subjects by 24-hour ambulatory monitoring

1. We have assessed the relationship between salt intake and 24 h ambulatory arterial pressure in middle aged men with essential hypertension. 2. During the run-in phase (1 month) we estimated the habitual sodium intake (the average Na excretion of two 24 h urine collections) of each participant (n = 14). In the randomized and crossover part of the study we contemplated a 'habitual' sodium intake phase, in which each individual received a fixed diet (about 30 mmol of Na+ and 65 mmol of K+) with additional salt so as to equalize the average intake of the run-in phase, as well as high sodium phases (habitual intake +50 and +100 mmol/day) and low sodium phases (habitual intake -50 and -100 mmol/day). After the trial, 10 patients underwent an additional week of fixed salt intake to assess the reproducibility of 24 h ambulatory monitoring. 3. Average 24 h arterial pressure at habitual sodium intake was significantly lower than that at high intake and significantly higher than at low sodium intake. Clinic arterial pressure showed similar trends but only systolic pressure changes at low sodium intake achieved statistical significance. 4. Analysis of the data on an individual basis showed a linear increase in 24 h mean arterial pressure with increasing levels of sodium intake in all but two cases (flat response in one case and a non-linear rise in the other case). The response pattern of clinic measurements was much less homogeneous. In the aggregate, there was a highly significant linear trend for ambulatory arterial pressure to rise with increasing levels of salt intake.(ABSTRACT TRUNCATED AT 250 WORDS)     

An autopsy case of primary squamous cell carcinoma of the liver associated with hepatitis C virus antibody positive liver cirrhosis

An increase in potassium (K) intake may lower blood pressure (BP), but inconsistent results have been obtained in clinical trials. We studied the effects of K supplementation in hypertensive patients with monitoring of home and ambulatory BP. Fifty-five patients with essential hypertension (26 men, 29 women, 36-77 years old) participated in this study. A 4-week K supplementation period and 4-week control period were assigned in a randomized crossover manner. During the K period, the subjects were given 64 mmol/day of K as slow-release KCl tablets. Office, home, and 24-h BP, as well as serum and urinary electrolytes, were measured at the end of each period. In the control period, office, home, and 24-h BP were 151 +/- 2/88 +/- 1 (mean +/- SE), 138 +/- 1/83 +/- 1, and 137 +/- 1/81 +/- 1 mm Hg, respectively. Serum K increased from 4.15 +/- 0.04 to 4.42 +/- 0.05 mmol/L, and urinary K increased from 54 +/- 2 to 96 +/- 3 mmol/day with the K supplementation. Office, home, and 24-h BP were significantly lower in the K period than in the control period, although the differences were small (2.7 +/- 1.1/1.4 +/- 0.6, 3.6 +/- 0.9/1.7 +/- 0.5, 3.4 +/- 1.0/1.2 +/- 0.5 mm Hg, respectively). Changes in home and 24-h systolic BP with K supplementation were highly significant (P < .001), compared with office BP (P < .05). The change in 24-h systolic BP was correlated negatively with baseline BP and urinary Na/K ratio, and positively with baseline urinary K excretion. The changes in daytime and nighttime BP were comparable. These results indicate that increasing K intake lowers BP in hypertensive subjects, especially in those with higher BP and lower K intake. Our study supports the usefulness of K supplementation in the treatment of hypertension, although its antihypertensive effect may be small.     

The effect of transport-blocking drugs on secretion of fluid and electrolytes by the mandibular gland of red kangaroos, Macropus rufus

Mechanisms of primary fluid formation by macropodine mandibular glands were investigated in anaesthetized red kangaroos using ion-transport and carbonic anhydrase inhibitors. Bumetanide at carotid plasma concentrations of 0.005-0.1 mmol/l progressively reduced a stable, acetylcholine-evoked flow rate of 1.02 +/- 0.024 ml/min to 0.16 +/- 0.016 ml/min (mean +/- SEM). Concurrently, saliva [Na], [Cl] and osmolality decreased, [K] and [HCO3] increased and HCO3 excretion was unaffected. High-rate cholinergic stimulation was unable to increase salivary flow above 12 +/- 1.5% of that for equivalent pre-bumetanide stimulation. Furosemide (1.0 mmol/l) and ethacrynate (0.5 mmol/l) caused depression of salivary flow and qualitatively similar effects on ion concentrations to those of bumetanide. Amiloride (up to 0.5 mmol/l) caused no reduction in salivary flow rates or [Na] but decreased [K] and [Cl] and increased [HCO3]. When compared with bumetanide alone, amiloride combined with bumetanide further augmented [K] and [HCO3] and lowered [Cl], but had no additional effects on Na or flow. At the higher level, 4-acetamido-4'- isothiocyanatostilbene-2,2'disulphonic acid (SITS) (0.05 and 0.5 mmol/l) stimulated fluid output, increased [HCO3] and [protein], and depressed [Na], [K] and [Cl]. Relative to bumetanide alone, SITS given with bumetanide had no additional effects on salivary flow or electrolytes. Methazolamide (0.5 mmol/l) in combination with bumetanide curtailed the decrease in [Cl] and the increases in [K] and [HCO3] associated with bumetanide. The residual methazolamide-resistant HCO3 excretion was sufficient to support 2-6% of primary fluid secretion. It was concluded that secretion of primary fluid by the kangaroo mandibular gland is initiated mainly (> 90%) by Cl transport resulting from Na-K-2Cl symport activity. A small proportion of the fluid secretion (up to 6%) appears to be supported by HCO3 secretion. No evidence was found for fluid secretion being dependent on Cl transport involving Na/H and Cl/HCO3 antiports or on HCO3 synthesis involving carbonic anhydrase.     

Effect of sodium in a rehydration beverage when consumed as a fluid or meal

To investigate the impact of fluid composition on rehydration effectiveness, 30 subjects (15 men and 15 women) were studied during 2 h of rehydration after a 2.5% body weight loss. In a randomized crossover design, subjects rehydrated with water (H2O), chicken broth (CB: 109.5 mmol/l Na, 25.3 mmol/l K), a carbohydrate-electrolyte drink (CE: 16.0 mmol/l Na, 3.3 mmol/l K), and chicken noodle soup (Soup: 333.8 mmol/l Na, 13.7 mmol/l K). Subjects ingested 175 ml at the start of rehydration and 20 min later; H2O was given every 20 min thereafter for a total volume equal to body weight loss during dehydration. At the end of the rehydration period, plasma volume was not significantly different from predehydration values in the CB (-1.6 +/- 1.1%) and Soup (-1.4 +/- 0.9%) trials. In contrast, plasma volume remained significantly (P < 0.01) below predehydration values in the H2O (-5.6 +/- 1.1%) and CE (-4.2 +/- 1.0%) trials after the rehydration period. Urine volume was greater in the CE (310 +/- 30 ml) than in the CB (188 +/- 20 ml) trial. Urine osmolality was higher in the CB and Soup trials than in the CE trial. Urinary sodium concentration was higher in the Soup and CB trials than in the CE and H2O trials. These results provide evidence that the inclusion of sodium in rehydration beverages, as well as consumption of a sodium-containing liquid meal, increases fluid retention and improves plasma volume restoration.     

Effect of beta blockade on the erythrocyte transport of Na+: evaluation during stimulation by cold pressure test in patients with essential hypertension

Several studies have shown in essential hypertension alterations of the transmembrane red blood cells sodium fluxes, as an involvement, especially in the early phases, also of the adrenergic system. In this study we evaluated the behaviour of red blood cells fluxes of sodium before, during and after the cold pressor test, a method used also to evoke an adrenergic stimulation, in twenty hypertensive subjects, 14 males and 6 females, with an average age of 43.2 +/- 5.7 years, with normal weight and without cardiovascular complications and metabolic diseases. The behaviour of the Na+ total efflux (Na+ TE), of the Na+/K+ pump, of the Na+K+ cotransport (Na+/K+ CT), of the Na+/Li+ counter transport (Na+/Li+ Cnt), of the Na+ passive permeability (Na+ PP), of the intracellular Na+ (I Na+) and of the plasmatic noradrenaline (NE) was evaluated basally, at the third minute during cold pressor test (CPT) and 20 minutes after the end of the test. The test, which the same method, was repeated after a 30 day treatment with propranolol at the dose of 240 mg/day in three daily administrations. The beta-blockade caused, besides the reduction of both the systolic and diastolic pressure values, a significant increase in the Na+/K+ CT (from 248 +/- 41 to 314 +/- 71 mmol/l/cells/h, p < 0.001) and a decrease in the Na+ PP (from 0.039 +/- 0.004 to 0.023 +/- 0.007 hr-1, p < 0.00001), probably directed towards the reduction of the accumulation of intracellular Na+, that could compete, among the other mechanisms, with the anti-hypertensive action of the beta-blockers. The CPT caused, before the beta-blockade, a significant depression of the Na+/K+ pump (from 2057 +/- 149 to 1610 +/- 101 mmol/l/cells/h, p < 0.00001) and of the Na+ TE (from 2640 +/- 397 to 2032 +/- 179 mmol/l/cells/h, p < 0.00001) inversely correlated to the levels of NE (r = -0.60, p < 0.003), with a consequent increase in I Na+ (from 6.2 +/- 0.6 to 7.5 +/- 1.5 mmol/l/cells, p < 0.001), showing how the adrenergic activation in hypertensive subjects is able to interfere with the systems of transmembrane transport with an inhibitory attitude, that is expressed by an increase in the levels of I Na+. The beta-blockade was able to outweigh the depression of the Na+/K+ pump (from 1843 +/- 584 to 1728 +/- 640 mmol/l/cells/h, p: ns) and the reduction of the Na+ TE, preventing the accumulation of I Na+ (from 6.3 +/- 1.6 to 6.6 +/- 1.3 mmol/l/cells, p: ns). Such data show an increased susceptibility of the Na+ transport systems to the adrenergic stimuli in hypertensive subjects with a tendency to favor the accumulation of I Na+ and that the beta-blockade is able to antagonize the effects, with a maintenance of the intracellular levels of Na+.     

Effects of concentrated electrolytes administered via a paste on fluid, electrolyte, and acid base balance in horses

OBJECTIVES: To test effectiveness of an electrolyte paste in correcting fluid, electrolyte and acid base alterations in response to furosemide administration. ANIMALS: 6 Standardbreds. PROCEDURES: Horses received electrolyte paste or water only (control). The paste was given orally 3 hours after furosemide administration (1 mg/kg of body weight, IM). Water was given ad libitum soon after the paste and 3 hours after furosemide administration to treated and control groups, respectively. Paste Na+, K+, and Cl- composition was approximately 2,220, 620, and 2,840 mmol, respectively. The PCV and plasma concentrations of total protein ([TP]), [Na+], [K+], [Cl-]), and bicarbonate ([HCO3-]) were determined, and urinary fluid and electrolyte excretion, fecal water, and body weight changes were measured. RESULTS: At the end of a 6-hour period, the paste-treated group had higher water consumption, which resulted in lower plasma [TP]; net electrolyte losses also were substantially less. With paste administration, [Na+] was approximately 2 mmol/L above a prefurosemide value of 137.3 mmol/L; control horses had values similar to the prefurosemide value. Plasma [Cl-] remained at the prefurosemide value, but values in control horses decreased by 7 mmol/L with water consumption. Plasma [K+] remained approximately 0.8 mmol/L below prefurosemide values in both groups. Venous [HCO3-] returned to prefurosemide values after paste administration, but alkalosis persisted in control horses after consumption of water only. Body weight loss was less after paste administration. CONCLUSIONS: Administration of electrolyte paste is advantageous over water alone in restoring fluid, electrolyte, and acid base balance after fluid and electrolyte loss attributable to furosemide administration.     

Protein balance in the first week of life in ventilated neonates receiving parenteral nutrition

BACKGROUND: Protein intake is frequently delayed in ill neonates because of concerns about their ability to metabolize substrates. OBJECTIVE: We aimed to determine the factors affecting protein balance in ventilated, parenterally fed newborns during the first week of life. DESIGN: Leucine kinetic studies were performed in 19 neonates by using the [1-(13)C]leucine tracer technique after 24 h of a stable total parenteral nutrition (TPN) regimen. TPN intakes were prescribed by rotating attending physicians, enabling assessment of protein metabolism over a range of clinically used nutrient intakes. RESULTS: Mean (+/-SD) birth weight was 1.497 +/- 0.779 kg, gestational age at birth was 30.3 +/- 4.0 wk, and age at study was 3.9 +/- 1.4 d. Amino acid intakes (AAIs) ranged from 0.0 to 2.9 g x kg(-1) x d(-1). Based on leucine kinetic data, protein balance was calculated as the difference between protein synthesis and catabolism. By multiple regression analysis, AAI was the only predictor associated independently with protein balance (P < 0.01); energy intake, lipid intake, glucose intake, birth weight, and gestational age were not. Both leucine oxidation and nonoxidative leucine disposal rates were significantly correlated with leucine intake (P < 0.0005 and P < 0.01, respectively). Of the 12 infants with AAIs > 1 g x kg(-1) x d(-1), only 1 infant was significantly catabolic (protein balance <-1 g x kg(-1) x d(-1)). There was no evidence of protein intolerance as determined by elevated creatinine (69 +/- 31 micromol/L), plasma urea nitrogen (6.7 +/- 2.53 mmol/L), or metabolic acidosis (pH: 7.36 +/- 0.05). CONCLUSIONS: Ill neonates can achieve a positive protein balance in the first days of life without laboratory evidence of protein toxicity.     

Cortical reorganisation of sensory, motor and language functions due to early cortical damage

OBJECTIVES: To compare the pharmacokinetics and dynamics of omeprazole in white and Chinese subjects. METHODS: This double-blind two-stage study, performed in the clinical research center of a university hospital, evaluated 15 healthy nonsmoking men (eight white subjects and seven Chinese extensive metabolizers of mephenytoin). Blood samples were obtained over 24 hours after the eighth omeprazole dose (40 mg/day). Omeprazole, omeprazole sulfone, and hydroxyomeprazole pharmacokinetics were calculated from the respective plasma concentration-time curves. Twelve- and 24-hour integrated plasma gastriun (AUCgas12 and AUCgas24) were calculated from the respective plasma gastrin concentrations. A week before the initiation of omeprazole the activities of CYP2D6, CYP2C19, and CYP3A4 were determined by previously established methods. RESULTS: Omeprazole concentrations were significantly lower (mean area under the plasma concentration time curve extrapolated to infinity [AUCO-infinity] +/- SEM; 7.53 +/- 1.21 versus 12.80 +/- 2.13 mumol.hr.L-1, respectively; p < 0.05) and its oral clearance greater (319 +/- 60 versus 183 +/- 35 ml/min, respectively; p < 0.05) in the white subjects than in the Chinese subjects. Omeprazole and omeprazole sulfone AUCO-infinity values were well correlated with the S/R mephenytoin ratio (r = 0.82 and r = 0.84, respectively; p < 0.001) and with urinary 4'-hydroxymephenytoin (r = -0.58 [p < 0.03] and r = -0.52 [p < 0.02], respectively). Fasting gastrin, AUCgas12, and AUCgas24 were significantly greater in the Chinese subjects than in the white subjects (30.0 +/- 6.4 versus 14.4 +/- 1.2 pmol, respectively [p < 0.02]; 661 +/- 114 versus 334 +/- 38 pmol.hr.L-1, respectively [p < 0.002]; and 1414 +/- 228 versus 747 +/- 99 pmol.hr.L-1, respectively [p < 0.004]). In addition, the S/R mephenytoin ratio and omeprazole AUCO-infinity correlated with the extent of omeprazole induced hypergastrinemia. CONCLUSION: The metabolism of omeprazole and the rise in gastrin concentration after its administration is genetically determined and ethnically dependent.     

Test/retest reproducibility of iodine-123-betaCIT SPECT brain measurement of dopamine transporters in Parkinson's patients

Iodine-123-beta-CIT has been used as a probe of dopamine transporters in Parkinson's disease patients using SPECT. We studied the test/retest reproducibility of SPECT measures in Parkinson's disease patients and healthy controls obtained after injection of [123I])beta-CIT in part to assess the utility of this tracer for longitudinal evaluation of striatal dopamine transporters as a marker of disease progression. METHODS: Seven Parkinson's disease patients and seven healthy control subjects participated in two [123I]beta-CIT SPECT scans separated by 7-21 days. Subjects were imaged at 24 hr post injection of 360 MBq (9.7 mCi) of [123I]beta-CIT. Two outcome measures were evaluated; 1) the ratio of specific striatal (activity associated with DA transporter binding) to nondisplaceable uptake, also designated V3," and 2) the total specific striatal uptake (%SSU) expressed as a percentage of injected radiotracer dose. For both measures, test/retest variability was calculated as the absolute difference of test minus retest divided by the mean of test/retest and expressed as a percent. In addition, the reproducibility of left and right striatal asymmetry and putamen:caudate ratios were determined. RESULTS: The two outcome measures demonstrated excellent test/retest reproducibility for both the Parkinson's disease and healthy subject groups with variability of striatal V3" = 16.8 +/- 13.3% and percent striatal uptake = 6.8 +/- 3.4% for Parkinson's disease patients and V3" = 12.8 +/- 8.9% and %SSU = 7.0 +/- 3.9% for control subjects. There were no statistically significant differences in test/retest variability between control subjects and Parkinson's disease patients for either outcome measure. The reproducibility of left/right asymmetry indices and putamen-to-caudate ratios showed no patient versus control subject differences. The asymmetry index had greater test/retest variability than the other outcome measures. CONCLUSION: These data suggest that SPECT imaging performed at 24 hr postinjection of [123I]beta-CIT permits calculation of reliable and reproducible measures of dopamine transporters in both Parkinson's disease patients and control subjects and supports the feasibility of using [123I]beta-CIT in the evaluation of disease progression in Parkinson's disease.     

Refractory ascites in cirrhosis: roles of volume expansion and plasma atrial natriuretic factor level elevation

Cirrhotic patients with ascites refractory to diuretics also have blunted response to marked elevations of plasma atrial natriuretic factor levels alone or to moderate intravascular volume expansion by head-out water immersion. However, these patients usually undergo natriuresis after peritoneovenous shunting. To dissect the factors responsible for this response, we studied the effects on separate days of moderate intravascular volume expansion and highly elevated plasma atrial natriuretic factor levels (head-out water immersion and atrial natriuretic factor infusion) or marked volume expansion and moderate plasma atrial natriuretic factor level elevation (head-out water immersion and albumin infusion) in 13 alcoholic cirrhotic patients with massive ascites. Three of these patients, who responded to initial head-out water immersion with a negative sodium balance, served as controls. Unresponsiveness to head-out water immersion was confirmed in the remaining 10 patients on both days on the basis of blunted natriuretic response (urinary sodium excretion < 0.8 mmol/hr after 2 hr). In contrast, these 10 refractory patients were able to achieve negative sodium balance with both combinations. Mean urinary sodium excretion increased from a baseline level of 0.13 +/- 0.10 mmol/hr to a peak level of 2.29 +/- 0.61 mmol/hr after head-out water immersion and atrial natriuretic factor infusion and from 0.10 +/- 0.3 mmol/hr to 1.61 +/- 0.62 mmol/hr after head-out water immersion and albumin infusion. Both maneuvers were associated with suppression of plasma renin activity and serum aldosterone levels. With head-out water immersion and atrial natriuretic factor infusion, we noted a significant increase in 5' cyclic GMP levels, a second messenger of atrial natriuretic factor, indicating possible activation of atrial natriuretic factor receptors at the inner medullary collecting ducts. In contrast, with head-out water immersion and albumin infusion no such increase in levels occurred, indicating that the increase in urinary sodium excretion was mainly due to increased delivery of sodium to the cortical distal nephron, as indicated by a disproportionate increase in urinary potassium excretion. In conclusion, massive (as opposed to moderate) volume expansion or greatly elevated levels of plasma atrial natriuretic factor associated with moderate volume expansion can improve blunted atrial natriuretic factor responsiveness in cirrhotic patients with refractory ascites. This appears to be achieved by way of a marked increase in distal delivery of filtrate in the kidney, with or without activation of distal atrial natriuretic factor receptors in the inner medullary collecting ducts.     

Amobarbital--a probe of hepatic drug oxidation in man

Some aspects of the fate of amobarbital were investigated since this drug is being used as a probe to gauge drug oxidation in man. The mean ratio of orally available over intravenously injected amobarbital was established as 0.99 +/- 0.11 (SD), by comparing integrated concentration-time curves, indicating complete absorption and absence of a first-pass effect. One subject ingested 200 mg of amobarbital sodium, and amobarbital concentrations in serum were monitored for 5 days thereafter. Elimination of amobarbital under these conditions followed first-order kinetics. One subject ingested amobarbital 7 times over a period of 3 yr; plasma clearances (32.1 +/- 1.8 [SD]ml/min) exhibited remarkable constancy, while biologic half-lives (26.5 +/- 3.1 hr) and distribution volumes (73.6 +/- 8.0 L) showed some fluctuation. The distribution of parameters of amobarbital elimination was investigated in 36 unrelated subjects. Amobarbital half-lives (23.8 +/- 6.7 hr) appeared to be normally distributed, while the clearances (36.7 +/- 10.0 ml/min) might not follow a normal distribution.     

Effects of hypervolemia on interdialytic hemodynamics and blood pressure control in hemodialysis patients

The influence of hypervolemia on hemodynamics and interdialytic blood pressure, as well as in relation to vascular compliance, was investigated in 10 hemodialysis patients who were not receiving vasoactive medication. All subjects were studied during a relative normovolemic interdialytic period (from 1 kg below dry weight postdialytic until dry weight predialytic) and a hypervolemic interdialytic period (from 1 kg above dry weight postdialytic until 3 kg above dry weight predialytic). Interdialytic blood pressure was measured with an ambulatory blood pressure monitor. Cardiac output was echographically measured and total peripheral resistance calculated postdialytic, mid-interdialytic, and predialytic. At the same time, a blood sample was drawn for analyzing vasoactive hormones, sodium, and hematocrit. In all patients, ideal dry weight was estimated by echography of the caval vein. Arterial and venous compliance were measured with an ultrasound vessel wall movement detector system and a strain-gauge plethysmograph. After fluid load, an increase in intravascular volume, an increase in caval vein diameter and cardiac output, and a decrease in peripheral resistance was observed. No significant influence of a 3-L fluid load was found on interdialytic blood pressure course (153+/-24 mm Hg/90+/-19 mm Hg in the hypervolemic period and 146+/-27 mm Hg/89+/-22 mm Hg in the normovolemic period). Sodium and osmolality were similar in the hypervolemic and normovolemic interdialytic periods. After fluid load, a decrease in arginine vasopressin and angiotensin II was observed, which probably contributed to the decreased systemic vascular resistance. Catecholamines were not influenced by fluid load, but increased during the interdialytic period, suggesting accumulation after dialysis. Three of the 10 patients had higher systolic but not diastolic blood pressures after fluid load (159+/-13 mm Hg/81+/-22 mm Hg in the hypervolemic period and 135+/-16 mm Hg/81+/-22 mm Hg in the normovolemic period). No correlation could be found between arterial or venous compliance and blood pressure changes. We concluded that a 3-L interdialytic fluid load does not result in higher blood pressure in most hemodialysis patients.     

Preservation of physiological responses to hypoglycemia 2 days after antecedent hypoglycemia in patients with IDDM

OBJECTIVE: To assess the effects of short-term antecedent hypoglycemia on responses to further hypoglycemia 2 days later in patients with IDDM. RESEARCH DESIGN AND METHODS: We studied eight type I diabetic patients without hypoglycemia unawareness or autonomic neuropathy during two periods at least 4 weeks apart. On day 1, 2 h of either clamped hyperinsulinemic (60 mU.m-2.min-1) hypoglycemia at 2.8 mmol/l or euglycemia at 5.0 mmol/l were induced. Hyperinsulinemic hypoglycemia was induced 2 days later with 40 min glucose steps of 5.0, 4.0, 3.5, 3.0, and 2.5 mmol/l. Catecholamine levels and symptomatic and physiological responses were measured every 10-20 min. RESULTS: When compared with the responses measured following euglycemia, the responses of norepinephrine 2 days after hypoglycemia were reduced (peak, 1.4 +/- 0.4 [mean +/- SE] vs.1.0 +/- 0.3 nmol/l [P < 0.05]; threshold, 3.4 +/- 0.1 vs. 2.9 +/- 0.1 mmol/l glucose [P < 0.01]). The responses of epinephrine (peak, 4.0 +/- 1.4 vs. 3.5 +/- 0.8 nmol/l [P = 0.84]; threshold, 3.8 +/- 0.1 vs. 3.6 +/- 0.1 mmol/l glucose [P = 0.38]), water loss (peak, 194 +/- 34 vs. 179 +/- 47 g-1.m-2.h-1 [P = 0.73]; threshold, 2.9 +/- 0.2 vs. 2.9 +/- 0.2 mmol/l glucose [P = 0.90]), tremor (peak, 0.28 +/- 0.05 vs. 0.37 +/- 0.06 root mean square volts (RMS V) [P = 0.19]; threshold, 3.2 +/- 0.2 vs. 3.1 +/- 0.2 mmol/l glucose [P = 0.70]), total symptom scores (peak, 10.6 +/- 2.1 vs. 10.8 +/- 1.9 [P = 0.95]; threshold, 3.3 +/- 0.2 vs. 3.6 +/0 0.1 mmol/l glucose [P = 0.15]), and cognitive function (four-choice reaction time: threshold, 2.9 +/- 0.2 vs. 3.0 +/- 0.2 mmol/l glucose [P = 0.69]) were unaffected. CONCLUSIONS: The effect on hypoglycemic physiological responses of 2 h of experimental hypoglycemia lasts for 1-2 days in these patients with IDDM . The pathophysiological effect of antecedent hypoglycemia may be of shorter duration in IDDM patients, compared with nondiabetic subjects.     

Glucose production, utilization, and cycling in response to moderate exercise in obese subjects with type 2 diabetes and mild hyperglycemia

The glucoregulatory and hormonal responses to moderate-intensity exercise (50% VO2max for 45 min) were examined in subjects with type 2 diabetes and mild hyperglycemia. We studied seven obese subjects with type 2 diabetes and seven lean and seven obese control subjects (fasting plasma glucose levels, 7.5 +/- 0.5, 4.8 +/- 0.1, and 5.2 +/- 0.1 mmol/l, respectively). Glucose production, utilization, and cycling (flux between glucose and glucose-6-phosphate [G-6-P]) were measured with [6-(3)H]glucose and [2-(3)H]glucose using the constant specific-activity method. Insulin levels decreased normally during exercise in diabetic subjects. Plasma glucose levels decreased in diabetic subjects, but remained constant in control subjects. Basal glucose production was not different among groups and increased similarly during exercise. The decrease in plasma glucose in diabetic subjects was due to greater glucose utilization (867 +/- 83 vs. 726 +/- 143 micromol x m(-2) x min(-1); P < 0.05). This was a consequence of the mass effect of hyperglycemia, since glucose metabolic clearance increased similarly in all groups. Glucose cycling, expressed as a percentage of total glucose output (i.e., flux through G-6-P) was elevated at rest (P < 0.01), but decreased during exercise (P < 0.01). The catecholamine response to exercise was blunted in diabetic subjects, presumably indicating autonomic dysfunction. In conclusion, during moderate-intensity exercise in obese diabetic subjects with mild hyperglycemia, 1) insulin secretory responses were normally regulated; 2) glucose homeostasis was different from that in nondiabetic subjects because glucose levels decreased during exercise; 3) the decrease in plasma glucose was due to greater-than-normal rates of glucose utilization, which were sustained by hyperglycemia; and 4) elevated basal rates of glucose cycling decreased during exercise, presumably because exercise simultaneously lowered plasma glucose, was associated with a blunted catecholamine response, and accentuated an underlying defect in hepatic glucokinase activity in type 2 diabetes.