Soup Kettle Topics: Hydration – Electrolytes, Other Physiology

Title: Deleterious Effects of Salt Intake Other Than Effects on Blood Pressure
Author: Antonios, T. F.; MacGregor, G. A.; (Date: Mar, 1995)
Journal: Clin Exp Pharmacol Physiol; V. 22; Issue: 3; Pages: 180-4

Abstract: 1. Salt intake is not only known to play an important role in determining blood pressure (BP) but has been shown to have other deleterious effects independent of BP. 2. Epidemiological and animal studies have provided evidence that salt intake may have an adverse effect on stroke mortality independent of BP. 3. Significant correlation between sodium excretion (as a measure of salt intake) and left ventricular (LV) hypertrophy has been shown in many clinical studies. Salt restriction has also been found to produce a significant reduction in LV mass. 4. In animal studies, salt restriction in uninephrectomized spontaneously hypertensive rats retarded renal glomerular injury and suppressed compensatory growth independent of hypertension. Moreover, a high sodium diet accelerated cerebral arterial disease even when no increases in BP could be detected. 5. Epidemiological data have shown an association between asthma mortality and regional purchases of table salt. Furthermore, dietary salt restriction in asthmatic patients results in improvement of symptomatology with lower consumption of bronchodilators. 6. Patients with essential hypertension are known to have increased urinary calcium excretion, and hypertension may be one factor that may increase the likelihood of osteoporosis. High salt intake is also associated with increased hydroxyproline excretion indicating increased resorption of bone. Sodium restriction reduces calcium excretion and may reduce bone demineralization and hip fractures in a similar manner to that seen with diuretics.
Notes: Journal Article
Review, Tutorial
Author Address: Department of Medicine, St George’s Hospital Medical School, London, UK.

Title: Katp Channel Openers for the Treatment of Airways Hyperreactivity
Author: Buchheit, K. H.; Fozard, J. R.; 1999)
Journal: Pulm Pharmacol Ther; V. 12; Issue: 2; Pages: 103-5

Notes: Journal Article
Review, Tutorial
Author Address: Department of Research, Novartis Pharma AG, CH-4002 Basel, Switzerland.

Title: The Causes of Asthma–Does Salt Potentiate Bronchial Activity? Discussion Paper
Author: Burney, P. G.; (Date: Jun, 1987)
Journal: J R Soc Med; V. 80; Issue: 6; Pages: 364-7

Notes: Journal Article

Title: Effect of Changing Dietary Sodium on the Airway Response to Histamine
Author: Burney, P. G.; Neild, J. E.; Twort, C. H.; Chinn, S.; Jones, T. D.; Mitchell, W. D.; Bateman, C.; Cameron, I. R.; (Date: Jan, 1989)
Journal: Thorax; V. 44; Issue: 1; Pages: 36-41

Abstract: The airway response to histamine has been shown to be related to the 24 hour urinary excretion of sodium. To assess whether this relation is likely to represent a direct causal association a randomised double blind crossover trial of slow sodium (80 mmol/day) was compared with placebo in 36 subjects having a low sodium diet. The dose of histamine causing a 20% fall in FEV1 (PD20) was 1.51 doubling doses lower when the men were taking sodium than when they were taking placebo (p less than 0.05). On the basis of PD10 values, the difference in men was 1.66 doubling doses of histamine (p less than 0.05). There was no corresponding effect in women. Regressing PD10 against urinary excretion of electrolytes with data from the two occasions during the trial and the measurements made before the trial showed a significant association with sodium excretion after allowance had been made for any effect associated with potassium or creatinine excretion, the latter being a marker of the completeness of the urine collection. Again there was no corresponding effect among women. These findings are compatible with the differences in regional mortality data for England and Wales, which show a relation between asthma mortality and regional per person purchases of table salt for men but not for women.
Notes: Clinical Trial
Journal Article
Randomized Controlled Trial
Author Address: Department of Community Medicine, United Medical School, Hospital, London.

Title: Effect of Alterations of Dietary Sodium on the Severity of Asthma in Men
Author: Carey, O. J.; Locke, C.; Cookson, J. B.; (Date: Jul, 1993)
Journal: Thorax; V. 48; Issue: 7; Pages: 714-8

Abstract: BACKGROUND–There is some evidence of a positive association between increased dietary salt consumption and both increased bronchial reactivity and mortality from asthma in men. This study assesses the effects of alterations in dietary salt consumption on the clinical severity of asthma in adult male asthmatic patients. METHODS–A randomised, double blind, placebo controlled, crossover design was employed. Twenty seven mild to moderate asthmatic patients were established on a low sodium diet (80 mmol/day) at the end of a 4-5 day run in period and then randomised to receive 200 mmol/day slow sodium or matching placebo for five weeks, crossing over to the alternative regime for a further five weeks. Patients used diary cards to record twice daily peak expiratory flow rates, daily symptom scores, and bronchodilator consumption. Spirometry and degree of bronchial responsiveness (methacholine challenge test) were measured at screening and at the end of each treatment period. Twenty four hour urinary sodium excretion was measured at screening and in duplicate for each treatment period. RESULTS–Twenty two patients completed the study. For these patients the mean (95% confidence interval (CI)) difference in 24 hour sodium excretion between treatments was 204 (175 to 235) mmol. Compared with placebo, sodium supplementation resulted in deleterious alterations of all measured parameters. Bronchial reactivity rose on slow sodium with a 0.73 (0.2 to 1.3) doubling dose methacholine difference compared with placebo. Estimated median (95% CI) difference in bronchodilator consumption was 1.3 (0.4 to 2.1) puffs per day, the estimated median difference in symptom score was 0.6 (0.2 to 0.9), and mean forced expiratory volume in one second fell by 0.21 (0.05 to 0.37) 1. The peak expiratory flow rate rose on placebo and fell on slow sodium. Median differences between treatments were 5.6% (2.2% to 9.8%) for morning and 7.8% (3.9% to 12.9%) for evening peak expiratory flow rate. CONCLUSIONS–Our results suggest that large increases in dietary sodium result in physiological deterioration and increased morbidity in male asthmatic patients.
Notes: Clinical Trial
Journal Article
Randomized Controlled Trial
Author Address: Glenfield General Hospital, Leicester.

Title: Usual Dietary Salt Intake and Asthma in Children: A Case-Control Study
Author: Demissie, K.; Ernst, P.; Gray Donald, K.; Joseph, L.; (Date: Jan, 1996)
Journal: Thorax; V. 51; Issue: 1; Pages: 59-63

Abstract: BACKGROUND: A decline in host resistance due to an alteration in diet–primarily of salt–was recently put forward as a possible explanation for rising rates of asthma. METHODS: A case-control study was conducted in participants in a prevalence survey which included 187 children with asthma (defined by prior diagnosis and/or a decline in forced expiratory volume in one second (FEV1) of > or = 10% after exercise) and 145 age and sex matched controls. Subjects were selected from 989 children aged 5-13 years attending 18 elementary schools on the island of Montreal. Usual dietary salt intake was estimated from a food frequency questionnaire administered to the mother, and a salt intake score was used to group the children into quartiles from I (lowest) to IV (highest salt intake). Bronchial hyperresponsiveness to methacholine was assessed by Yan’s method. Cases and controls were combined in one group to examine the relationship of salt intake to bronchial hyperresponsiveness to methacholine. Methacholine responsiveness was expressed as a dose-response slope and ranks of dose-response slopes were used in the analysis. RESULTS: After accounting for important confounding variables, there was no association between asthma and salt intake, while methacholine dose-response slope ranks increased with increasing salt intake and methacholine responsiveness was greater in the highest quartile than in the lowest quartile of salt intake. The median dose-response slopes in % fall in FEV1 per mumol methacholine for quartiles I, II, III, and IV were 5.4, 5.9, 7.7, and 8.7. CONCLUSIONS: No association was found between asthma or exercise-induced bronchospasm and dietary salt intake. Bronchial hyperresponsiveness to methacholine did, however, appear to increase with greater salt intake, but the relevance of this association to asthma is unclear.
Notes: Journal Article
Author Address: Respiratory Epidemiology Unit, McGill University, Montreal, Quebec, Canada.

Title: Intracellular Magnesium Loss after Diuretic Administration
Author: Dyckner, T.; Wester, P. O.; (Date: Oct, 1984)
Journal: Drugs; V. 28 Suppl 1; Pages: 161-6

Abstract: Diuretic agents influence the renal handling of magnesium, causing increased losses of the ion. Continuing magnesium losses may, in the long term, result in a magnesium deficiency. 296 patients with congestive heart failure or arterial hypertension receiving long term diuretic therapy were studied by skeletal muscle biopsies to assess their magnesium status. 65% of the congestive heart failure patients and 42% of the patients with arterial hypertension were found to have subnormal values for skeletal muscle magnesium. Studies with the potassium-sparing diuretics amiloride, spironolactone and triamterene demonstrate that these drugs significantly increase the muscle magnesium content in patients on long term diuretic treatment for congestive heart failure and/or arterial hypertension–in addition to their well known positive effect on potassium balance.
Notes: Journal Article

Title: Atp Sensitive Potassium Channels: Potential Drug Targets in Neuropsychopharmacology
Author: Gehlert, D. R.; Robertson, D. W.; (Date: Nov, 1994)
Journal: Prog Neuropsychopharmacol Biol Psychiatry; V. 18; Issue: 7; Pages: 1093-102

Abstract: 1. K channels are a diverse and ubiquitous class of proteins that regulate a number of biological functions. 2. Ligands for the study of a variety of K channels are available. These include “openers” and antagonists for the ATP sensitive K channel and peptide toxins such as apamin and charybdotoxin that block other subtypes. 3. Antagonists of the ATP sensitive K channel are useful in the treatment of type II diabetes while “openers” of this channel are being tested in asthma and cardiovascular disease. 4. Intracerebroventricular administration of K channel “openers” block experimentally induced seizures in rodents through a hyperpolarization of neurons. K channel openers may also be useful in the treatment of neurodegenerative diseases, pain and cerebral ischemia. 5. A key to the development of psychopharmacological agents to modify brain K channel function is CNS selectivity. The promise of the ATP sensitive K channel openers suggests a bright future for this mechanism.
Notes: Journal Article
Review, Tutorial
Author Address: Lilly Research Laboratories, Indianapolis, IN.

Title: Effect of Dietary Salt on Bronchial Reactivity to Histamine in Asthma
Author: Javaid, A.; Cushley, M. J.; Bone, M. F.; (Date: Aug 13, 1988)
Journal: Bmj; V. 297; Issue: 6646; Pages: 454

Notes: Journal Article
Author Address: Department of Thoracic Medicine, Russells Hall Hospital, Dudley, West Midlands.

Title: Are Asthmatics Salt-Sensitive? A Preliminary Controlled Study
Author: Medici, T. C.; Schmid, A. Z.; Hacki, M.; Vetter, W.; (Date: Oct, 1993)
Journal: Chest; V. 104; Issue: 4; Pages: 1138-43

Abstract: OBJECTIVE: Epidemiologic evidence suggests that high levels of salt consumption are associated with “spastic” disorders of smooth muscles, ie, essential hypertension and bronchial asthma. Experimentally, it has been shown that high intake of salt leads to increased bronchial hyperreactivity in asthmatics, ie, enhanced contractility of bronchial muscle to spasmogenic stimuli. On the basis of these observations, the following questions were asked: (1) Does salt loading worsen the clinical and functional findings in asthmatics? (2) Is it the sodium or the chloride in salt that is important? METHODS: To answer these questions, the effect of salt restriction (= 5 to 6 g NaCl/d = 86 to 103 mmol Na), salt loading (+ 6.1 +/- 2.8 g NaCl/d = + 105 +/- 48 mmol Na), and loading with sodium citrate in nearly equimolar concentrations (+ 140 +/- 40 ml Shohl’s solution, = + 120 +/- 30 mmol Na) was investigated in 14 asthmatics in a controlled crossover study. The total sodium load during the high salt diet was 191 to 209 mmol of sodium per day and during the sodium-citrate phase, 206 to 223 mmol of sodium per day. RESULTS: Statistical analysis showed that salt loading worsened symptoms (p = 0.06) and increased the use of inhaled steroids (p < 0.05). The effect on lung function was less equivocal: salt loading worsened the forced expiratory volume in 1 s (p < 0.01) and the peak expiratory flow rate (p < 0.05). This effect was presumably mediated by sodium, not chloride, as is demonstrated by loading with sodium citrate. CONCLUSION: Patients with bronchial asthma seems to be salt-sensitive, the responsible ion being presumably sodium. A low-salt diet appears to have a favorable effect in patients with asthma and to reduce the need for anti-asthma drugs.
Notes: Clinical Trial
Journal Article
Randomized Controlled Trial
Author Address: Department of Internal Medicine, University Hospital, Zurich, Switzerland.

Title: Potassium Channel Openers and Asthma
Author: Morley, J.; (Date: Spring, 1994)
Journal: Clin Rev Allergy; V. 12; Issue: 1; Pages: 109-20

Notes: Journal Article
Review, Tutorial
Author Address: Department of Applied Pharmacology, National Heart and Lung Institute, London, UK.

Title: Potassium Channel Modulation: A New Drug Principle for Regulation of Smooth Muscle Contractility. Studies on Isolated Airways and Arteries
Author: Nielsen-Kudsk, J. E.; (Date: Dec, 1996)
Journal: Dan Med Bull; V. 43; Issue: 5; Pages: 429-47

Abstract: K+ channels play a key role in regulation of membrane potential and cell excitability. Several different types of K+ channels have been identified and the presence, characteristics and functions of these channels vary among different tissues. The 3 most important K+ channels in smooth muscle are the KATP (activated by a fall in intracellular ATP and a rise in nucleotide diphosphates and blocked by glibenclamide), BKCa (activated by a rise in intracellular Ca2+) and Kv (activated by depolarization). Cromakalim, pinacidil and nicorandil are members of a rapidly increasing group of novel drugs which open K+ channels. Opening of such channels leads to K+ efflux, membrane hyperpolarization, reduced excitability and smooth muscle relaxation. The purpose of the studies included in this thesis was to investigate this novel drug principle of K+ channel modulation on smooth muscle contractility of isolated airways and arteries and on neuroeffector transmission in airways. Smooth muscle contractility was measured in airway and vascular ring preparations suspended in isometric myographs. Neurotransmitter release was elicited by transmural electrical field stimulation. The major findings were: 1) Membrane depolarization by high extracellular K+ concentrations induced contraction of airway smooth muscle that was easily relaxed by Ca2+ antagonists and abolished in a Ca2+ free medium indicating that K+ contraction is triggered by Ca2+ influx through voltage-operated Ca2+ channels. Indomethacin was required to obtain reproducible responses upon repeated exposure to K+ suggesting that endogenous prostaglandins are released by K+ and interferes with its contractile effect. K+ depolarization was shown to be a valuable pharmacological tool for detection of drugs acting by K+ channel opening. The prototype K+ channel opener cromakalim relaxed contractions induced by 20-30 mM K+ but had no effect against contraction induced by 124 mM K+. This was a unique profile of action not shared by other types of airway and vascular smooth muscle relaxants. As the extracellular K+ concentration is raised the outward directed electrochemical gradient for K+ is reduced and at high K+ concentrations the effect of K+ channel opening is negligible. Although the K+ channel opener pinacidil had a higher relaxant potency against contraction induced by 30 mM K+ than by 124 mM K+, it still relaxed the latter contraction indicating an additional K+ channel independent mechanism of action of the drug. When K+ depolarization is used as a pharmacological tool, it is essential to maintain osmolarity. Addition of KCI directly to the tissue bath solution, which previously was a commonly applied technique, produced confounding and unwanted effects due to hyperosmolarity per se. 2) Pinacidil and cromakalim relaxed guinea-pig trachea either tone was spontaneous or induced by a range of airway spasmogens (histamine, PGF2 alpha, LTC4/LTD4 or carbachol) of relevance as asthma mediators. The relaxant effectiveness of the drugs was reduced when tone was elicited by carbachol. The airway smooth muscle relaxation produced by pinacidil and cromakalim was selectively blocked by the antidiabetic sulfonylureas glibenclamide, glipizide and glibornuride and also by phentolamine. These drugs are blockers of KATP which therefore indicates that this channel is the target for cromakalim and pinacidil in airway smooth muscle. Additional to the antagonistic action against K+ channel openers the sulfonylurea KATP blockers and phentolamine at higher concentrations relaxed airway smooth muscle by yet unknown mechanisms that seemed unrelated to KATP. 3) Cromakalim and pinacidil inhibited nerve-mediated e-NANC contractile responses in guinea-pig bronchi. Such responses are due to release of SP and related tachykinins from sensory nerve endings. These neuropeptides cause bronchoconstriction and airway inflammation and may possibly play an important role in the pathophysiology of asthma.
Notes: Journal Article
Author Address: Institute of Pharmacology, University of Aarhus, Sweden.

Title: Methacholine Airway Responsiveness and 24-Hour Urine Excretion of Sodium and Potassium. The Normative Aging Study
Author: Sparrow, D.; O’Connor, G. T.; Rosner, B.; Weiss, S. T.; (Date: Sep, 1991)
Journal: Am Rev Respir Dis; V. 144; Issue: 3 Pt 1; Pages: 722-5

Abstract: Prior studies have suggested a direct relationship between dietary sodium intake and nonspecific airway responsiveness. The relationship of dietary sodium and potassium intake to methacholine airway responsiveness was examined among 273 male participants of the Normative Aging Study (age range 44 to 82 yr) using 24-h urinary excretion of these cations as a surrogate for intake. Methacholine airway responsiveness was analyzed as dose-response slope, a continuous measure of responsiveness that represents the slope of a line connecting the origin to the last point of the dose-response plot. Greater airway responsiveness to methacholine was associated with greater potassium excretion. A significant relationship between methacholine dose-response slope and potassium excretion (p = 0.014) was observed in multivariate analysis that took into account other covariates, including age, percentage of predicted FEV1, cigarette smoking, and skin test reactivity. In contrast, methacholine airway responsiveness did not appear related to urinary sodium excretion. These data suggest that dietary potassium may have an influence on airway responsiveness of middle-aged and older men.
Notes: Journal Article
Author Address: Normative Aging Study, Department of Veterans Affairs Outpatient Clinic, Boston, MA 02114.

Title: Dietary Sodium Intake, Airway Responsiveness, and Cellular Sodium Transport
Author: Tribe, R. M.; Barton, J. R.; Poston, L.; Burney, P. G.; (Date: Jun, 1994)
Journal: Am J Respir Crit Care Med; V. 149; Issue: 6; Pages: 1426-33

Abstract: Both epidemiologic and experimental evidence suggest that a high dietary sodium intake may increase airway responsiveness, but no adequate explanation exists of how changes in sodium intake might lead to increased responsiveness. This investigation was carried out to study dietary sodium intake and airway response to methacholine in relation to cellular sodium transport in 52 young men. Airway response to methacholine was associated with urinary sodium excretion when subjects were on normal sodium intake. Airway responsiveness in patients with mild asthma correlated with the furosemide-insensitive influx of sodium into peripheral leukocytes stimulated by autologous serum, but there was no relation between this influx and 24-h urinary sodium excretion. In a separate investigation, serum from subjects with increased airway responsiveness caused an increase in the sodium influx and sodium content of leukocytes from nonatopic subjects. The magnitude of the furosemide-insensitive, serum stimulated influx was related to the degree of airway responsiveness of the serum donor, as was the increase in intracellular sodium content. Neither was related to the 24-h urinary sodium excretion of the donor. Patients with airway hyperresponsiveness have an increased sodium influx into cells stimulated by a serum-borne factor. This is independent of the effect of added dietary sodium on airway responsiveness.
Notes: Journal Article
Author Address: Department of Public Health Medicine and Renal Laboratory, United Medical School, Guy’s Hospital, London, United Kingdom.

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