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Biomedical subjects

A Sebastian

Publications and source records attributed to A Sebastian.

At least 55 records · Page 3Linked to original sources

Improved mineral balance and skeletal metabolism in postmenopausal women treated with potassium bicarbonate.

BACKGROUND: In normal subjects, a low level of metabolic acidosis and positive acid balance (the production of more acid than is excreted) are typically present and correlate in degree with the amount of endogenous acid produced by the metabolism of foods in ordinary diets abundant in protein. Over a lifetime, the counteraction of retained endogenous acid by base mobilized from the skeleton may contribute to the decrease in bone mass that occurs normally with aging. METHODS: To test that possibility, we administered potassium bicarbonate to 18 postmenopausal women who were given a constant diet (652 mg [16 mmol] of calcium and 96 g of protein per 60 kg of body weight). The potassium bicarbonate was given orally for 18 days in doses (60 to 120 mmol per day) that nearly completely neutralized the endogenous acid. RESULTS: During the administration of potassium bicarbonate, the calcium and phosphorus balance became less negative or more positive--that is, less was excreted in comparison with the amount ingested (mean [+/- SD] change in calcium balance, +56 +/- 76 mg [1.4 +/- 1.9 mmol] per day per 60 kg; P = 0.009; change in phosphorus balance, +47 +/- 64 mg [1.5 +/- 2.1 mmol] per day per 60 kg; P = 0.007) because of reductions in urinary calcium and phosphorus excretion. The changes in calcium and phosphorus balance were positively correlated (P < 0.001). Serum osteocalcin concentrations increased from 5.5 +/- 2.8 to 6.1 +/- 2.8 ng per milliliter (P < 0.001), and urinary hydroxyproline excretion decreased from 28.9 +/- 12.3 to 26.7 +/- 10.8 mg per day (220 +/- 94 to 204 +/- 82 mumol per day; P = 0.05). Net renal acid excretion decreased from 70.9 +/- 10.1 to 12.8 +/- 21.8 mmol per day, indicating nearly complete neutralization of endogenous acid. CONCLUSIONS: In postmenopausal women, the oral administration of potassium bicarbonate at a dose sufficient to neutralize endogenous acid improves calcium and phosphorus balance, reduces bone resorption, and increases the rate of bone formation.

Aged↗

5 beta-Methyl-14 beta-(p-nitrocinnamoylamino)-7,8-dihydromorphinone and its corresponding N-cyclopropylmethyl analog, N-cyclopropylmethylnor-5 beta-methyl-14 beta-(p-nitrocinnamoylamino)- 7,8-dihydromorphinone: mu-selective irreversible opioid antagonists.

5 beta-Methyl-14 beta-(p-nitrocinnamoylamino)-7,8-dihydromorphinone (MET-CAMO) and its corresponding N-cyclopropylmethyl analog, N-cyclopropylmethylnor-5 beta-methyl-14 beta-(p-nitrocinnamoylamino)- 7,8-dihydromorphinone (N-CPM-MET-CAMO) were tested in opioid receptor binding assays and in the mouse tail-flick test in order to characterize the affinity, selectivity and antinociceptive properties of these two compounds. Incubating bovine striatal membranes with either MET-CAMO or N-CPM-MET-CAMO produced a wash-resistant, concentration- and time-dependent inhibition of the binding of the mu-selective ligand, [3H]-[D-Ala2,MePhe4,Gly(ol)5]enkephalin, but with no change in delta or kappa binding. Preincubating membranes with N-CPM-MET-CAMO decreased the maximum binding value for [3H]-[D-Ala2,MePhe4,Gly(ol)5]enkephalin binding without changing the Kd value. In the mouse tail-flick assay, MET-CAMO and N-CPM-MET-CAMO did not produce any antinociception up to a dose of 100 nmol after i.c.v. administration. However, pretreatment of mice with either compound produced a time- and dose-dependent antagonism of morphine-induced antinociception. Analgesia mediated by delta or kappa opioids was not altered by either MET-CAMO or N-CPM-MET-CAMO at a dose of up to 100 nmol. The mu antagonistic effect of 1 nmol of MET-CAMO and N-CPM-MET-CAMO appeared at 8 hr and lasted up to 72 hr, with a maximal effect at 16 to 24 hr after i.c.v. administration. Pretreatment of mice with 1 nmol of MET-CAMO or N-CPM-MET-CAMO, given by i.c.v. administration at -24 hr, produced a rightward and downward shift of dose-response line of i.c.v. morphine.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗

14 beta-[(p-nitrocinnamoyl)amino]morphinones, 14 beta-[(p-nitrocinnamoyl)amino]-7,8-dihydromorphinones, and their codeinone analogues: synthesis and receptor activity.

A series of 14 beta-[(nitrocinnamoyl)amino]codeinones and morphinones, some of which contain a 5 beta-methyl group, were prepared from 14 beta-aminocodeinones and 14 beta-[N-(cyclopropylmethyl)-amino]norcodeinones. The affinities of the target compounds for the mu, delta, and kappa opioid receptors were determined by radiolabeled binding experiments using bovine brain membranes. An analogous series of 7,8-dihydrocodeinones and morphinones was prepared and assayed in the same systems. The 3-methoxy derivatives 3 and 4 were more selective than the corresponding morphinones for the mu receptor. The 5 beta-methylcodeinones 25 and 27 had lower affinity at all receptors than the corresponding morphinones, but the 5 beta-methylmorphinones had affinities similar to the morphinones 5 and 6. A similar pattern was observed in the 7,8-dihydro series. Two compounds, 5 beta-methyl-14 beta-[(p-nitrocinnamoyl)amino]-7,8-dihydromorphinone, 20 (MET-CAMO), and N-(cyclopropylmethyl)-14 beta-[(p-nitrocinnamoyl)amino]-7,8-dihydronormorphinone, 22 (N-CPM-MET- CAMO), acted as nonequilibrium ligands in antinociception and membrane binding studies. In mice after icv administration, neither ligand showed any agonist activity but 8-24 h after administration both compounds acted as potent mu antagonists. A Scatchard plot of the effect of N-CPM-MET-CAMO on [3H]DAMGO ([3H]D-Ala2, (Me)-Phe4, Gly(ol)5] enkephalin) binding to bovine striatal membranes showed that there was a significant decrease in the Bmax value and a marginal effect on the Kd value suggesting that the number of binding sites was reduced. When taken together, these results support the view that 20 and 22 bind covalently to the mu receptor. On the other hand, when N-acetylcysteine and 22 were allowed to react in a buffered solution, 22 was recovered unchanged. Under these conditions no Michael reaction was observed.

Animals↗

5 beta-Methyl-14 beta-(p-nitrocinnamoylamino)-7,8-dihydromorphinone: a long-lasting mu-opioid receptor antagonist devoid of agonist properties.

5 beta-Methyl-14 beta-(p-nitrocinnamoylamino)-7,8-dihydromorphinone (MET-CAMO) suppressed morphine-induced antinociception but had no effect on antinociception mediated by delta- or kappa-opioid receptors after a single i.c.v. 1-nmol injection from 8 to 72 h before testing. MET-CAMO had no agonist effects in the mouse tail-flick assay in doses up to 100 nmol. MET-CAMO is the first N-methylated morphine derivative which shows such long-lasting mu-selective opioid receptor antagonism with no agonistic properties.

Analgesics↗

Precision and accuracy for rat whole body and femur bone mineral determination with dual X-ray absorptiometry.

Precision and accuracy for rat whole body and excised femur bone mineral density (BMD) measurements were evaluated with two dual X-ray absorptiometry (DXA) systems. The 'small subject' mode on the Norland XR-26 (XR), and the 'ultra high resolution mode' on the Hologic QDR-1000/W(QDR) were used for the analysis. The whole body mode was only available on the XR. The lowest precision error for the whole body was found using a scan resolution of 1.0 x 1.0 mm and a scan speed of 15 mm/s. The scan spatial resolution of the femur measurement was approximately eight times higher on the QDR than on the XR. However, the XR allowed analysis of an arbitrary region of interest within the femur, which was not easily done with the QDR. Precision for the total femur measurement on the QDR (0.5-0.9%) was approximately two to four times superior to that of the XR (1.5-4.3%). The difference may be due to the superior scan resolution of the QDR. Bone mineral content and BMD on the QDR significantly declined with an increase of water depth (P < 0.001). No significant change was observed on the XR. Both DXA systems demonstrated an excellent correlation (r > or = 0.98) with ash weight under the scan conditions examined. The optimal scan condition for the excised femur measurement on the XR was obtained with 1.5-2.5 cm of perspex or water and a scan speed of 10 mm/s. For the QDR, we recommend scanning the rat femur with approximately 2.5 cm of perspex or water in terms of precision and accuracy.

Absorptiometry, Photon↗

Diuretics, serum and intracellular electrolyte levels, and ventricular arrhythmias in hypertensive men.

OBJECTIVE: To investigate the patterns of electrolyte abnormalities resulting from thiazide administration and whether they cause ventricular arrhythmias, and to help resolve the controversy over whether clinicians should routinely prescribe potassium-conserving therapy to all patients treated with thiazides. DESIGN: Double-blind, randomized controlled trial. PARTICIPANTS: A total of 233 hypertensive men aged 35 to 70 years. INTERVENTIONS: Participants were withdrawn from prior diuretic treatment and were replenished with oral potassium chloride and magnesium oxide. They were then randomized to 2 months of treatment with (1) hydrochlorothiazide; (2) hydrochlorothiazide with oral potassium; (3) hydrochlorothiazide with oral potassium and magnesium; (4) hydrochlorothiazide and triamterene; (5) chlorthalidone; or (6) placebo. MAIN OUTCOME MEASURES: Ventricular arrhythmias on 24-hour Holter monitoring and serum and intracellular potassium and magnesium levels. RESULTS: Of the 233 participants, 212 (91%) completed the study. Serum potassium levels were 0.4 mmol/L lower in the hydrochlorothiazide group than in the placebo group (P less than 0.01), and this mean difference was not affected by supplementation with potassium, with potassium and magnesium, or with triamterene. However, the supplements did prevent the occasional occurrence of marked hypokalemia; all 12 of the men who developed serum potassium levels of 3.0 mmol/L or less were among the 90 who received diuretics without supplementation (P less than 0.01). Similarly, the overall proportion of men with ventricular arrhythmias was not affected by randomized treatment, but there was a twofold increase in the proportion with arrhythmias among the 12 men with serum potassium levels of 3.0 mmol/L or less (P = .02). Serum magnesium and intracellular potassium and magnesium levels were not reduced by hydrochlorothiazide, nor were they related to ventricular arrhythmias. CONCLUSIONS: In the majority of hypertensive patients, treatment with 50 mg/d of hydrochlorothiazide does not cause marked hypokalemia or ventricular arrhythmias. However, because some individuals will develop hypokalemia after starting diuretic therapy, serum potassium levels should be monitored and potassium-sparing strategies should be used when indicated.

Adult↗

Measurement of aortic blood flow by Doppler echocardiography: day to day variability in normal subjects and applicability in clinical research.

To assess the reliability of Doppler ultrasound for detecting serial changes in cardiac output in response to experimental interventions, the day to day variability of the minute distance of aortic flow was determined in seven normal subjects maintained in a tightly controlled environment with regard to diet and activities. Measurements were made at the same time on 5 to 6 sequential days from an apical window with use of both continuous wave and pulsed wave Doppler techniques. Two statistical measures of reliability were calculated, the intraclass coefficient of correlation (R), which varies between 0 (null reliability) and +1 (perfect reliability), and the 95% confidence interval for the error-free value of a single measurement. For sequential measurements of arterial pressure, 24 h urinary volume and sodium excretion and body weight, the intraclass coefficients of correlation ranged from 0.85 to 0.99, indicating low day to day variability consistent with tight environmental control. Continuous and pulsed wave modes were proved equally and highly reliable for measuring minute distance of aortic flow. However, continuous wave Doppler ultrasound provided acceptable signals more frequently than did the pulsed wave technique. For continuous wave Doppler ultrasound, R was 0.87 (p less than 0.00001); the 95% confidence interval was +/- 1.81 m/min (or 11% of the mean of all measurements), which indicates that this method can be used in a single individual to detect a greater than 11% change in minute distance measured once before and after an intervention.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

Synthesis and structure-activity relationships of a novel series of non-peptide angiotensin II receptor binding inhibitors specific for the AT2 subtype.

Structure-activity relationships are reported for a novel class of 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid derivatives that displace 125I-labeled angiotensin II from a specific subset of angiotensin II (Ang II) binding sites in rat adrenal preparations. This binding site is not the Ang II receptor mediating vascular contraction or aldosterone release, but, rather, is one whose function has not yet been fully elucidated. It has been identified in a number of tissues and has a similar affinity for Ang II and its peptide analogues as does the vascular receptor. The non-peptide compounds reported here are uniquely specific in displacing Ang II at this binding site and are inactive in antagonizing Ang II at the vascular receptor or in pharmacological assays measuring vascular effects. PD 123,319 (79), one of the most potent compounds, has an IC50 of 34 nM. Certain of these compounds may have utility in the definition and study of Ang II receptor subtypes.

Adrenal Glands↗

Dietary potassium influences kidney maintenance of serum phosphorus concentration.

In studying the metabolic effects of diet potassium (K+) variation in normal humans, we noted that varying diet K+ within its normal range influenced inorganic phosphorus (Pi) homeostasis and serum calcitriol (1,25-dihydroxyvitamin D) levels. In six men who ingested a constant whole-foods diet containing (per 70 kg body wt) 27 mmol/day Pi and 52 mEq/day K+, we increased diet K+ to 156 mmol/day with supplements first of potassium bicarbonate (KHCO3) alone and then of potassium chloride (KCL) alone, each for eight days interrupted by an eight-day recovery period of no K+ supplement. Urine Pi decreased promptly with either K(+)-salt, each inducing a persisting retention of 7 to 10 mmoles Pi, which was dumped during recovery. Fasting serum [Pi] increased with either K+ supplement (P = 0.022, repeated measures analysis of variance); the composite mean serum [Pi] for the two K(+)-supplement periods exceeded that for the two periods without supplements (P less than 0.01, paired t-test). Conversely, the concentrations of serum calcitriol decreased with either K+ supplement (P = 0.020). Among subjects, the diet K(+)-induced increases in serum [Pi] correlated with those in plasma [K+] (r = 0.64, P = 0.027); the decreases in serum calcitriol concentration correlated with the increases in serum [Pi] (r = -0.69, P = 0.014). There were no significant differences among periods in serum parathyroid hormone, ionized calcium, urine cyclic AMP excretion, plasma renin activity, body weight, serum albumin, or creatinine clearance; plasma volume decreased slightly during KCL but not during KHCO3 periods.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

Normal diet NaCl variation can affect the renal set-point for plasma pH-(HCO3-) maintenance.

In humans who are ingesting abundant NaCl, blood pH (pHb) and plasma bicarbonate concentration [HCO3-)p) change little or imperceptibly in response to the ingestion of alkali salts. We tested the hypothesis that such tight homeostatic regulation is an artifact of eating a culturally imposed NaCl-enriched diet, not a fundamental physiological trait of humans. In five normal men ingesting a constant acid-producing diet with a low intrinsic NaCl content (0.15 mEq/kg of body weight per day), we measured plasma and urine acid-base composition during four 7-day periods in which the diet was supplemented as follows: no supplements----NaHCO3 only----NaHCO3 plus NaCl----NaCl only. Each sodium supplement was 2.0 mmol/kg body weight per day. With no supplements, pHb was 7.43 +/- 0.005 and (HCO3-)p was 25.0 +/- 0.4 mEq/L. When NaHCO3 only was added, pHb rose 0.02 (to 7.45 +/- 0.004; P less than 0.01) and (HCO3-)p rose nearly 4 mEq/L (to 28.9 +/- 0.6 mEq/L, P less than 0.001). The rise in (HCO3-)p was sustained predominantly by an increased rate of renal bicarbonate reabsorption. When NaCl was added, (HCO3-)p returned to the earlier level, despite continued NaHCO3 supplementation (24.9 +/- 0.6 mEq/L), and remained there when NaHCO3 supplementation was subsequently stopped (24.1 +/- 0.5 mEq/L). Thus, tight homeostatic regulation of plasma acid-base composition in response to a change in dietary base occurred only when dietary NaCl was abundant. To our knowledge, this is the first study in normal humans that demonstrates that diet NaCl variations within the normal range significantly influence plasma acid-base composition.(ABSTRACT TRUNCATED AT 250 WORDS)

Acid-Base Equilibrium↗

Serial assessment of glomerular filtration rate in lupus nephropathy.

In patients with lupus nephropathy (LN), previous studies have shown that creatinine clearance (CCr) overestimates true glomerular filtration rate as measured by inulin clearance (CIn), and that among patients the degree of overestimation is highly variable. We sought to determine whether the discrepancy between CCr and CIn remains constant over time (months, years) in each individual patient, and therefore whether serial measurements of CCr reliably reflect the direction and magnitude of change in CIn. Twenty-five patients with LN underwent simultaneous determinations of CCr and CIn performed two to four (mean 3.3) times over three years. In a given patient, it was found that the ratio of CCr/CIn changed substantially over time (mean SD 0.16 with 95% confidence interval of 0.12 to 0.20). Thus, in about 32% of cases the ratio of CCr/CIn will vary more than +/- 16% from a previously measured value of CCr/CIn. Patients with both high and low values of CIn showed similar variability in CCR/CIn over time. Variability in CCr/CIn was found regardless of whether CIn was increasing, decreasing, or constant over time. In nearly one-half of all measurements of CCr, the corresponding change in CIn was directionally discordant. Iothalamate and technetium-DTPA renal clearances correlated highly with CIn (R2 = 0.99). We conclude that the discrepancy between CCr and CIn can vary greatly over time in an individual patient. Consequently, serial CCr does not accurately measure the direction or magnitude of change in glomerular filtration rate in lupus nephropathy.

Adult↗

Food chloride distribution in nature and its relation to sodium content.

Because of growing interest in the biological and clinical effects of dietary chloride as the anion accompanying the dietary cation sodium and because the standard food composition tables used in the United States to estimate sodium content do not contain data on chloride content, we analyzed the nutrient data base of the English workers Paul and Southgate, which contains an extensive listing of both chloride and sodium contents in foods. To examine food chloride distribution in nature, we focused on the uncooked, unadulterated, discrete, primitive foods in the data base (no. = 216 food items). The findings indicate the existence of both a large variability of chloride content among foods and a high degree of coupling of chloride with sodium. The contents of chloride and sodium varied over a similarly large range (coefficients of variation, 229% vs. 263%), differed very little from each other on the average (less than 20%), and correlated (r = 0.84, p less than 0.001) to the extent that greater than two-thirds of the overall variation of chloride content was linked to that of sodium content. Those findings accord with the often posited but untested assertion that the chloride content of foods approximates and parallels that of sodium.(ABSTRACT TRUNCATED AT 250 WORDS)

Chlorides↗

Dietary NaCl determines severity of potassium depletion-induced metabolic alkalosis.

It is uncertain whether, in humans, potassium depletion can cause or sustain metabolic alkalosis of clinically important degree in the absence of coexisting known alkalosis-producing conditions. Previously we found, in normal humans ingesting abundant NaCl, that dietary K+ depletion alone can induce and sustain a small decrease in blood acidity and increase in plasma bicarbonate concentration; we hypothesized that more severe alkalosis was prevented by mitigating mechanisms initiated by renal retention of dietary NaCl that was induced by K+ depletion. To ascertain the acid-base response to dietary K+ depletion under conditions in which the availability of NaCl for retention is greatly limited, in the present study of six normal men we restricted dietary K+ as in the previous study except that intake of NaCl was maintained low (2 to 7 mEq/day, Low NaCl Group) instead of high (126 mEq/day, High NaCl Group). Plasma acid-base composition and renal net-acid excretion (NAE) did not differ significantly between groups during the control period. In the steady state of K+ depletion (days 11 to 15 of K+ restriction), neither plasma K+ concentration (2.9 +/- 0.9 mEq/liter vs. 3.0 +/- 0.1 mEq/liter) nor cumulative K+ deficit (399 +/- 59 mEq vs. 466 +/- 48 mEq) differed significantly between groups. During K+ restriction, persisting metabolic alkalosis developed in both groups, which was more severe in the Low NaCl Group: increment in [HCO3-]p, 7.5 +/- 1.0 mEq/liter versus 2.0 +/- 0.3 mEq/liter, P less than 0.001; decrement in [H+]p, 5.5 +/- 0.6 nEq/liter versus 2.9 +/- 0.4 nEq/liter, P less than 0.003. A significantly more severe alkalosis in the Low NaCl Group was evident at all degrees of K+ deficiency achieved during the course of the 15 days of K+ restriction, and the severity of alkalosis in the Low NaCl Group correlated with the degree of K+ deficiency. During the generation of alkalosis (days 1 to 7 of K+ restriction), NAE increased in the Low NaCl Group whereas it decreased in the High NaCl Group. During the maintenance of alkalosis (days 11 to 15), NAE stabilized in both groups after it returned to values approximating the control values. In both groups, urine Cl- excretion decreased during K+ restriction even though Cl- intake had not been changed, with the result that body Cl- content increased negligibly in the Low NaCl Group (28 +/- 6 mEq) and substantially in the High NaCl Group (355 +/- 64 mEq).(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗

Adrenocortical hormone secretory response to chronic NH4Cl-induced metabolic acidosis.

We examined the effect of chronic metabolic acidosis on adrenocortical hormone production by administering NH4Cl for 5 days to four normal subjects. Plasma aldosterone concentration, aldosterone secretion, and urinary excretion of aldosterone-18-glucuronide increased significantly, whereas there were no significant changes in the plasma concentrations of cortisol, corticosterone, or deoxycorticosterone, or in the urinary excretion of 17-hydroxycorticoids. By day 2, plasma renin activity (PRA) and concentration (PRC) were not significantly different from control, and the slope of the regression line relating plasma aldosterone concentration to PRA was significantly greater than the slope in the control period, i.e., the sensitivity of aldosterone secretion to renin stimulation was increased. By day 5, however, PRA and PRC were increased above control. Plasma potassium concentration did not change significantly. Thus chronic NH4Cl-induced acidosis induces a sustained stimulation of aldosterone secretion in the absence of a change in adrenocorticotropin-dependent adrenocortical hormone secretion. Factors other than an increase in renin secretion and plasma potassium concentration may be involved in at least the early phase of aldosterone stimulation, suggesting that plasma hydrogen ion concentration might be a separate regulator of aldosterone secretion.

Acidosis↗

Reduced glomerular filtration rate can maintain a rise in plasma bicarbonate concentration in humans.

In humans, deficiency of chloride and potassium were found to perpetuate the hyperbicarbonatemia that attends metabolic alkalosis induced by gastric aspiration partly by increasing renal bicarbonate reabsorption, commensurate with the attendant increase in filtered bicarbonate load, and partly by decreasing glomerular filtration rate (GFR), which minimizes the degree of which the filtered bicarbonate load increases and thereby minimizes the requisite increase in bicarbonate reabsorption. The relative contribution of stimulated renal bicarbonate reabsorption might increase, however, if the supply of extrarenal bicarbonate is increased, in which case a greater degree of hyperbicarbonatemia would be sustained. To investigate that possibility, we reexamined the mechanism of perpetuation of gastric alkalosis in normal subjects eating a low NaCl diet supplemented with bicarbonate salts. Prior to gastric aspiration, plasma bicarbonate concentration ([HCO3]p) and pH were higher than in similarly studied subjects not receiving bicarbonate: 29.9 +/- 0.6 vs. 25.3 +/- 0.1 and 7.43 +/- 0.008 vs. 7.41 +/- 0.002 mEq/l, respectively. With continued bicarbonate supplementation, gastric aspiration induced a further significant increase (p less than 0.05) in [HCO3]p of 10.8%, to values not significantly different from those in nonbicarbonate-loaded subjects with gastric alkalosis: 33.2 +/- 1.2 mEq/l. GFR decreased significantly by 8.4% (from 98 +/- 4 to 90 +/- 3 ml/min, p less than 0.025), offsetting nearly commensurately the increase in [HCO3]p so that total bicarbonate reabsorption was not significantly increased (2.90 +/- 0.12 vs. 2.97 +/- 0.19 mEq/min, p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗