bluuebunny/crossref_metadata_2025 huggingface dataset:
The effect of long-term circulatory occlusion on pH and energy metabolism of the quadriceps muscle in man
Authors: Sjöholm H. , Gidlöf A. , Larsson J. , Sahlin K.
Published: August 2015

1. The effect of up to 2.5 h circulatory occlusion on muscle pH and energy metabolism of the quadriceps muscle was studied in 13 patients operated on for an inveterate knee injury. Muscle samples were taken by the percutaneous needle biopsy technique at different times during the arterial occlusion and after restoration of circulation.

2. Energy was provided by a complete utilization of phosphocreatine and by a low rate of glycolysis during 2 h of occlusion. The ATP level remained unchanged throughout the occlusion period.

3. Muscle pH decreased from 7.0-7.1 to about 6.8 after 2 h occlusion. Muscle pH was essentially normalized within 20 min after restoration of the blood flow.
Influence of age, sex and potassium excretion on urinary prostaglandins in children
Authors: Barden A. , Beilin L. J. , Vandongen R. , Rouse I.
Published: August 2015

1. Measurement of urinary 6-ketoprostaglandin (PG) F1α and PGE2 excretion in 83 healthy children, aged 5-15 years, revealed that supervised 4 h urine collections under mild water diuresis provided more consistent results than overnight 12 h urine collections.

2. Males had higher urinary excretion of 6-keto-PGF1α but not of PGE2 compared with females.

3. Urinary potassium was related to 6-keto-PGF1α in both 4 and 12 h urine collections and urinary sodium to 6-keto-PGFα in 4 h collections only.

4. In the sexes combined multiple regression analyses revealed age as the only significant influence on prostanoid excretion (P = 0.001).

5. Thus age and sex and dietary potassium intake need to be considered in studies of urinary prostanoids in children.
Reduced plasma noradrenaline during angiotensin II-induced acute hypertension in man
Authors: Henriksen Jens H. , Kastrup Jens , Christensen Niels Juel
Published: August 2015

1. Plasma noradrenaline and adrenaline concentrations were measured in ten subjects before, during and after intravenous infusion of angiotensin II (ANG II) in order to determine the sympathoadrenal response of ANG II challenge in man. In five subjects ganglionic blockade was additionally performed by intravenous infusion of trimethaphan.

2. During ANG II infusion mean arterial blood pressure increased by 30% (P<0.001), and plasma noradrenaline decreased by 25% (P<0.001). Plasma adrenaline decreased less.

3. During ganglionic blockade plasma noradrenaline decreased significantly (P<0.005) and similarly to the decrease obtained with ANG II infusion.

4. The results indicate that a decrease in sympathoadrenal activity occurs during ANG II-induced acute hypertension in man. This may be elicited by the arterial baroreflex, which seems to dominate any direct sympathoadrenergic facilitating effect of ANG II.
Effect of angiotensin converting-enzyme inhibition on potassium-mediated aldosterone secretion in essential hypertension
Authors: Barnes J. N. , Drew P. J. T. , Furniss S. S. , Holly J. M. P. , Knight A. R. , Skehan J. D. , Goodwin F. J.
Published: August 2015

1. Eight patients with essential hypertension were challenged with an infusion of 32 mmol of potassium chloride in saline before and after control of their blood pressure by the angiotensin converting-enzyme (ACE) inhibitor enalapril.

2. The potassium infusion was associated with similar increases in plasma aldosterone before and during enalapril treatment, although absolute aldosterone levels were lower after enalapril treatment despite higher plasma potassium levels.

3. The handling of the potassium load was altered by ACE inhibition. The area under the curve of a plot of the increase in plasma potassium above baseline against time was greater during enalapril treatment than during treatment with placebo.

4. These observations contrast with data obtained in the dog and demonstrate that in patients with essential hypertension stimulation of aldosterone secretion by potassium is not abolished by chronic suppression of plasma angiotensin II; and although plasma aldosterone remains at a lower level, the homoeostasis of plasma potassium is only mildly impaired.
Angiotensin II-induced thirst and vasopressin release in man
Authors: Phillips P. A. , Rolls B. J. , Ledingham J. G. G. , Morton J. J. , Forsling M. L.
Published: August 2015

1. The thirst and plasma vasopressin responses to single-blind controlled intravenous angiotensin II infusions (2-16 ng min−1 kg−1) were investigated in ten healthy young men.

2. Thirst and vasopressin secretion were stimulated in four out of ten subjects. These effects occurred at plasma angiotensin concentrations well above those measured under physiological conditions associated with thirst and vasopressin secretion such as water deprivation.

3. Further studies are needed to define why only certain individuals respond to intravenous angiotensin II infusions and to determine whether potentiation of angiotensin-induced thirst and vasopressin secretion by other stimuli (e.g. hypovolaemia and hypertonicity) might occur in man, in particular under pathological conditions when plasma angiotensin levels are above the physiological range.
What do antagonists tell us about α-adrenoceptors?
Authors: Drew G. M.
Published: August 2015

The early proposals that pre- and post-junctional α-adrenoceptors might be different stemmed largely from two separate observations. Firstly, the orders of potency of a series of agonists at inhibiting the response to sympathetic nerve stimulation and in increasing inotropic activity in the rabbit isolated heart were different [1, 2]. Secondly, phenoxybenzamine was more potent in inhibiting vasoconstrictor responses to sympathetic nerve stimulation than in increasing transmitter overflow from the cat spleen [3]. These experiments illustrate the most fundamental, pharmacological ways of distinguishing between receptors: namely, by comparing the relative potencies of agonists and/or antagonists in producing, or preventing, pharmacological effects.

There are, however, difficulties in using agonists to classify receptors because their ability to generate a response depends not only upon their intrinsic properties of affinity for, and efficacy at, the receptors but also upon the capacity of the tissue to translate the stimulus into a response. Thus agonists with a relatively low intrinsic efficacy may produce a small response, or no response at all, in a tissue in which the efficiency of the stimulus-response coupling mechanism is low. The importance of this phenomenon in influencing tissue responses to agonists with low efficacy has been demonstrated for the α-adrenoceptor agonist prenalterol [4] and for the α-adrenoceptor agonist oxymetazoline [5].
Attempts to uncover subtypes of α-adrenoceptors and associated mechanisms by using sequential administration of blocking drugs
Authors: Grant T. L. , Flavahan N. A. , Greig J. , McGrath J. C. , McKean C. E. , Reid J. L.
Published: August 2015

1. By the sequential administration of α1- and α2-blockers it can be shown, in the pithed rabbit, that the dose/pressor response curve to noradrenaline consists of two separate curves, one for each receptor. α2-mediated responses predominate at low doses and α1-mediated responses predominate at high doses. Pressor responses to sympathetic nerve stimulation have, similarly, an α2 component at low frequencies and a dominant α1-mediated response at high frequencies: a residual response is resistant to combined α1- plus α2-blockade.

2. This α-blocker-resistant pressor nerve response was further analysed in the pithed rat and was found to be partly susceptible to α,β-methylene ATP, which densitizes purinergic responses. However, reserpine pretreatment produced a greater reduction of nerve-mediated pressor responses than did α-blockade, suggesting that part of the ‘α-blocker resistant’ response might be adrenergic.

3. It is concluded that sympathetic vasopressor nerve transmission is mediated for the greater part by α1- and α2-adrenoceptors but that there is evidence for contributions from non-α-adrenergic and ‘purinergic’ elements. An even greater proportion of the responses to circulating catecholamines is attributable to the α-receptors with a relatively small but significant ‘resistant’ component.
α-Adrenoceptor-effector coupling: affinity states or heterogeneity of the α2-adrenoceptor?
Authors: Nahorski S. R. , Barnett D. B. , Cheung Y.-D.
Published: August 2015

Receptor-effector coupling

At the present time there is substantial evidence supporting the concept of at least two major groups of α-adrenoceptors, which have been termed α1 and α2 [1]. Whereas α1 and β2 adrenoceptors are linked positively to adenylate cyclase, it seems likely that α1- and α2-adrenoceptors possess different mechanisms for signal transduction.
Ca2+ sources mobilized by α1-receptor activation in vascular smooth muscle
Authors: Leijten P. , Cauvin C. , Lodge N. , Saida K. , Breemen C. Van
Published: August 2015

1. We propose the following model of Ca2+ mobilization by noradrenaline in vascular smooth muscle. Upon receptor occupation Ca2+ from a labile small intracellular store on the inner plasmalemma is released. This Ca2+ does not function as activator Ca2+ but triggers Ca2+ release from the sarcoplasmic reticulum (Ca2+-induced Ca2+ release).

2. Simultaneously Ca2+ from an extracellularly bound store (on the external surface of the plasmalemma) is dislodged, which enters the cell through receptor linked channels.

3. These processes are responsible for the early ‘phasic’ component of the noradrenaline contraction. In addition, Ca2+ from the free extracellular Ca2+ pool enters through receptor operated channels, supporting the maintained tension development.
α-Adrenoceptor agonists and the Ca2+-dependence of smooth muscle contraction: evidence for subtypes of receptors or for agonist-dependent differences in the agonist-receptor interaction?
Authors: McGrath John C.
Published: August 2015

1. The effects of varying [Ca2+]o on the contraction of smooth muscle by different α-adrenoceptor agonists were examined on rat isolated anococcygeus muscle. Agonists were tested in the presence of various [Ca2+]o or ‘Ca2+-re-addition curves’ were constructed. In some experiments the [Ca2+]free was buffered with EGTA and nitrilotriacetic acid. The components of the response which were revealed were further analysed by using drugs which modify Ca2+ mobilization.

2. Three separate elements in the contractile response were identified: (i) an initial transient contraction, due to intracellular Ca2+ release could be isolated with [Ca2+]o between 1 nmol/l and 3 μmol/l (this could be obtained only with noradrenaline, phenylephrine and amidephrine); (ii) a nifedipine-sensitive response requiring [Ca2+]o of 3 μmol/l or more; (iii) a nifedipine-resistant response requiring [Ca2+]o of 100 μmol/l or more. Presumably (ii) and (iii) involve the entry of Ca2+o: they could be obtained with all agonists tested, including these above, methoxamine, indanidine and xylazine.

3. The results are discussed in relation to the possibility of distinct types of response and their relationship to subgroups of receptors or agonists. It is concluded that there is a continuous spectrum of activity across the agonist range and that this is likely to correlate with ‘efficacy’ at a single α1 receptor type.
Evidence for ATP and noradrenaline as cotransmitters in sympathetic nerves
Authors: Burnstock G. , Sneddon P.
Published: August 2015

Sympathetically innervated smooth muscles, including those in some arteries, arterioles, cat nictitating membrane and vas deferens, have α1-adrenoceptors which respond to exogenously applied noradrenaline (NA) by producing contractions which can be abolished by α1-adrenoceptor antagonists such as prazosin. Stimulation of the sympathetic nerves innervating these muscles causes release of NA and a contractile response. However, this contraction is (at least partly) resistant to specific α1-adrenoceptor antagonists. This apparent contradiction could be explained by a variety of ad hoc explanations (such as high transmitter concentrations within the nerve-muscle junction, or prejunctional enhancement of transmitter release by the antagonist due to prejunctional α2-adrenoceptor blockade etc.) but recently two hypotheses have been advanced which may have more fundamental implications for sympathetic neurotransmission. First, Hirst and Neild and their colleagues suggested that the electrical and mechanical responses of some smooth muscles were resistant to α-adrenoceptor antagonists because neuronally released NA was acting not only on α-adrenoceptors but also on a new class of adrenoceptors which they designated γ-receptors, located near the nerve-muscle junction. The crucial experiments in support of this hypothesis were originally performed on the arterioles of the guinea-pig submucosa [1], but the idea has been extended to include many other sympathetically innervated smooth muscles [2], including guinea-pig vas deferens, which was also the smooth muscle preparation in which the experimental evidence for an alternative hypothesis was obtained by Fedan et al. [3]. They proposed that the α-blocker-resistant portion of the contractile response to sympathetic nerve stimulation was mediated by ATP, acting as a cotransmitter with NA. Full details of the early development of the concept of cotransmission in sympathetic nerves have been reviewed previously [4, 6, 7].

The experimental evidence relating to the co-transmission hypothesis is outlined below, drawing mainly on results obtained in guinea-pig vas deferens, where most of the more recent experiments have been performed.
Functional consequences of contrasting properties of α1/α2 systems
Authors: Timmermans Pieter B. M. W. M. , Thoolen Martin J. M. C. , Jonge Adriaan De , Wilffert Bob , Zwieten Pieter A. Van
Published: August 2015

Ample experimental evidence supports the existence of two distinct types of vasoconstrictor α-adrenoceptors in vascular smooth muscle at postjunctional sites, showing similarities with α1 and α2-adrenoceptors. Especially in vivo, the characterization of an α2-adrenoceptor mediating an increase in diastolic pressure has been most successful. In this respect the model of the pithed rat has been employed most frequently (for reviews see [1, 2]).

At present, the agents cirazoline, (−) phenylephrine, (±)-erythro-methoxamine, (−)-amidephrine, SKF89748, St587 and Sgd 101/75 fulfil the criteria for selective α1-adrenoceptor agonists; their log dose-vasopressor effect curves are virtually unaffected by previous treatment with yohimbine or rauwolscine (selective dose in pithed rats: 1 mg/kg), whereas prazosin (selective dose in pithed rats: 0.1 mg/kg) causes an appreciable parallel rightward displacement. The reverse holds true for the stimulants B-HT 920, B-HT 933, B-HT 958, UK-14304, xylazine, TL-99, M-7 and DP-6,7-ADTN, which all have been classified as preferential agonists of vascular postjunctional α-adrenoceptors.
Evidence for the involvement of α1-adrenoceptors in negative feedback regulation of noradrenergic transmitter release in rat atria
Authors: Story D. F. , Standford-Starr C. A. , Rand M. J.
Published: August 2015

1. Experiments were undertaken to determine if prejunctional α1-adrenoceptors are involved in autoinhibitory regulation of transmitter noradrenaline release in rat atria.

2. The noradrenergic transmitter stores in rat isolated atria were radiolabeled with [3H]noradrenaline and transmitter release was deduced from the efflux of the radiolabel evoked by field stimulation of the atrial intramural sympathetic nerves.

3. Phentolamine (3 μmol/l) and prazosin (0.1 and 3 μmol/l) enhanced the release of radiolabel evoked by stimulation with trains of 4, 8 and 16 pulses, whereas idazoxan (10 μmol/l) enhanced release evoked by stimulation with 8 and 16 pulses. Idazoxan and prazosin were about equieffective in enhancing the evoked release but phentolamine produced much greater enhancement than either idazoxan or prazosin.

4. Combination of idazoxan (10 μmol/l) and prazosin enhanced the stimulation-evoked release with 4, 8 and 16 pulses to the same extent as phentolamine (3 μmol/l).

5. The selective α1-adrenoceptor agonist methoxamine (10 μmol/l) inhibited stimulation-evoked release and this effect was blocked by the α1-adrenoceptor antagonist prazosin (0.1 μmol/l).

6. The findings indicate that α1-adrenoceptors may contribute to autoinhibitory feedback regulation of transmitter release in rat atria.
Metabolic and haemodynamic effects of α2-adrenoceptor stimulation and antagonism in man
Authors: Brown M. J. , Struthers A. D. , Silvio L. Di , Yeo T. , Ghatei M. , Burrin J. M.
Published: August 2015

1. Six healthy volunteers received a 60 min infusion of guanfacine (α2-agonist) on two occasions, preceded by either idazoxan (α2-antagonist) or vehicle.

2. Idazoxan elevated blood pressure by 8/7 mmHg, but there was no change on either day during guanfacine infusion.

3. Guanfacine reduced plasma noradrenaline by approximately 30%, and this was not antagonized by idazoxan. By contrast, the 30-fold increase in plasma growth hormone caused by guanfacine was almost completely blocked by idazoxan.

4. Guanfacine caused a two- to three-fold increase in plasma glucagon and a similar reduction in plasma insulin. Only the latter was antagonized by idazoxan. No consistent changes in plasma ACTH were observed after either idazoxan or guanfacine.

5. Idazoxan itself elevated plasma noradrenaline up to twice baseline values, but did not affect the other metabolic measurements.

6. α2-Adrenoceptor stimulation plays a minor role in control of hormone release but has a greater physiological role in regulating release of the neurotransmitter, noradrenaline.
Extracellular Elastolytic Activity in Human Lung Lavage: A Comparative study between Smokers and Non-Smokers
Authors: Smith S. F. , Guz A. , Cooke N. T. , Burton G. H. , Tetley T. D.
Published: August 2015

1. Unrestrained proteolysis in the lung is believed to initiate emphysema, a disease common among tobacco smokers. However, few studies have found extracellular protease activity in human lung lavage.

2. In this investigation, elastase and serine protease activities were measured in broncho-alveolar lavage supernatants (BAL) from patients undergoing routine investigations. Significantly more elastolytic activity (against insoluble [3H]-elastin) was recovered in the lavage of smokers than that of non-smokers. However, no significant difference was found when the levels of serine proteolytic activity (against N-succinyl-L-trialanyl-p-nitroanilide) were compared.

3. The elastolytic component of the protease activity rose from 5% in non-smokers’ BAL to over 30% in that of smokers, suggesting that elastase activity is selectively enhanced by smoking. In lavages from most smokers, 80% or more of the elastase activity was serine-dependent, whereas lavages from non-smokers contained variable proportions of serine elastase.

4. Both α1-proteinase inhibitor (α1-PI) and a low molecular weight antiprotease, bronchial mucus proteinase inhibitor (BMPI) were detectable in the lavage samples, the latter contributing up to 76% of the total antiprotease quantified in the lavage. Functional antiprotease was detected in 85% of the lavages.

5. Since there were no differences in either antiprotease levels or functional inhibitory capacities between lavages from smokers and controls, it is concluded that the imbalance in the protease/antiprotease profile of the smokers’ lung results from an enhancement of proteases, specifically of elastolytic activity, rather than a reduction in inhibitory capacity.
The effect of Pyridoxine on Oxalate Dynamics in three Cases of Primary Hyperoxaluria (with Glycollic Aciduria)
Authors: Watts R. W. E. , Veall N. , Purkiss P. , Mansell M. A. , Haywood E. F.
Published: August 2015

1. We have measured glomerular filtration rate (GFR), extracellular fluid volume (ECF), oxalate distribution volume (OxDV), plasma oxalate concentration (POx.), plasma total clearance of oxalate (PCOx.), oxalate metabolic pool size [(OxDV) × (POx.)], renal clearance of oxalate (RCOx.), oxalate excretion, tissue clearance of oxalate (TCOx.) and tissue oxalate accumulation rate [(TOx.A) = (TCOx.) × (POx.)] in three patients with type I primary hyperoxaluria (hyperoxaluria with hypergrycollic aciduria) when they were taking pyridoxine and after discontinuation of the vitamin.

2. Seven days after stopping pyridoxine the plasma oxalate concentration, oxalate metabolic pool size and the urinary excretion of oxalate had all increased between seven- and eight-fold in two of the patients. The third patient showed no changes on stopping pyridoxine.

3. These results support the view that pyridoxine acts by reducing oxalate biosynthesis in some patients with type I primary hyperoxaluria.

4. The possible biochemical basis for this effect is discussed.
Urinary Adenosine Cyclic 3',5'-Monophosphate in Idiopathic Calcium Stone-Formers
Authors: Baghurst P. A.
Published: August 2015

Walker & Sutton in Clinical Science (1984, 66, 193-199) [1] have compared changes in urinary cyclic AMP excretion in response to an oral calcium load given to normal subjects with corresponding changes in idiopathic calcium stone-formers.
Leg Metabolism of Amino Acids and Ammonia in Patients with Chronic Renal Failure
Authors: Deferrari Giacomo , Garibotto Giacomo , Robaudo Cristina , Canepa Alberto , Bagnasco Serena , Tizianello Alberto
Published: August 2015

1. Leg metabolism of amino acids and ammonia in the postabsorptive state was evaluated in 10 patients with chronic renal failure (CRF) and in 10 patients with normal renal function (controls) by measuring the arterial-femoral venous (A-FV) differences for free amino acids and ammonia.

2. Total amino acid release from the leg and alanine and glutamine release, which accounts for the greatest amount of the total amino acid release, are similar in patients and controls. Total amino acid uptake from the arterial blood and glutamate uptake, which is the amino acid extracted at the highest rate, are comparable in both groups. Taken together these data, in addition to the similarity of A-FV differences for proteolytic markers, namely tyrosine, phenylalanine and histidine, suggest that protein breakdown in peripheral tissues is not increased in patients with CRF.

3. In CRF selective metabolic abnormalities for some amino acids are evident. Whilst only the A-FV differences for valine, leucine and isoleucine are decreased, additional alterations are observed by relating the A-FV difference for each amino acid to that of proteolytic markers. Such a procedure demonstrates that in CRF histidine release relative to that of proteolytic markers is reduced, whereas proline and arginine release is increased.

4. In CRF the reduced release of some amino acids, mainly branched-chain amino acids, by the leg probably affects the pattern of circulating amino acids.

5. Finally, both in patients and in controls a significant uptake of ammonia is observed; the ammonia uptake is related to arterial levels of this metabolite, confirming the role of peripheral tissues in removing ammonia from circulation.
Alcohol Withdrawal and Hypertension: Evidence for a Kidney Abnormality
Authors: Marchi Sergio De , Cecchin Emanuela
Published: August 2015

We are very interested to read the paper by Bannan et al. [1] about the effect of alcohol withdrawal on blood pressure, plasma renin activity, aldosterone, cortisol and dopamine β-hydroxylase. It has been known for several years that alcoholic patients admitted to hospital for detoxification have a high prevalence of hypertension [2]. Their blood pressures return to normal after alcohol withdrawal symptoms have abated and they remain normal if they continue to abstain. Patients who resume drinking sustain a rise in blood pressure to their former high levels.
Effect of indomethacin on urine concentration and dilution in the rat
Authors: Ray C. , Carney S. L. , Gillies A. H. B.
Published: August 2015

1. The precise role of prostaglandins in modulating urine concentration and dilution is unclear. Evidence in vitro has recently cast doubt on the accepted theory that renal prostaglandins inhibit the hydro-osmotic effect of vasopressin.

2. Urine clearance studies were performed on indomethacin treated (prostaglandin deficient) and control anaesthetized water diuretic rats both before and during the addition of vasopressin in maximal (10 m-units) and supramaximal (100 m-units) concentrations.

3. Before the addition of vasopressin, indomethacin treatment inhibited the excretion of a water load by 48.7%. The mean papillary sodium concentration was also greater in this group of rats.

4. Vasopressin (10 m-units) increased the urine osmolality in control and indomethacin treated rats; however, the mean urine osmolality was greater in the indomethacin group (1521 ± 103 compared with 1120 ± 98 mosmol/kg; P < 0.01), as was the papillary sodium concentration. A tenfold increase in vasopressin depressed the papillary sodium concentration to a level similar to that in the control group and produced a marked natriuresis. Consequently, the mean urine osmolalities and urine flows were similar in control and indomethacin treated rats.

5. These experiments suggest that a major function of renal prostaglandins is to increase the ability of the kidney to excrete a water load. Renal prostaglandins do not interfere with the vasopressin induced increase in distal nephron water permeability.
A family with mild hereditary xerocytosis showing high membrane cation permeability at low temperatures
Authors: Stewart G. W. , Ellory J. C.
Published: August 2015

1. Radioisotopic cation transport studies are described in a family whose erythrocytes had previously been found to show an abnormal net efflux of potassium when cooled to room temperature. This net efflux effect, which was inherited as an autosomal dominant trait, was associated with a few target cells on the blood film and a mild compensated haemolytic state.

2. Measurements of intracellular electrolyte concentrations, cell water and of Na+ and K+ transport rates across the membrane at 37°C were consistent with a diagnosis of mild hereditary xerocytosis.

3. Studies of cation transport in the temperature range 20–37°C revealed that the fluxes attributable to the Na+-K+ pump showed a temperature dependence comparable with that in normal cells, but that the ouabain plus loop-diuretic insensitive fluxes of K+, which probably represent the ‘passive diffusional leak’ to K+, were less sensitive to temperature than normal over the range 20–37°C. These findings were held to account for the net efflux effect previously reported.
A circadian rhythm of proteinuria in patients with a nephrotic syndrome
Authors: Koopman M. G. , Krediet R. T. , Zuyderhoudt F. J. M. , De Moor E. A. M. , Arisz L.
Published: August 2015

1. Circadian variations in proteinuria were studied in 17 patients with different types of glomerulopathies. During 3–4 successive days urine was collected over periods of 3 h under standardized conditions.

2. Thirteen of the 17 patients showed a circadian rhythm of their proteinuria with a maximum excretion in daytime around 16.00 hours and a minimum excretion at night around 03.00 hours.

3. In the majority of patients the urinary excretory rhythms of albumin, transferrin and immunoglobulin G were ‘in phase’ with each other and with the circadian rhythm of total protein excretion.

4. Nine patients had a larger degree of rhythmicity for immunoglobulin G than for transferrin excretion. In eight of them a circadian rhythm of the selectivity index of proteinuria was seen with the lowest index at night.

5. No relation was observed between the circadian rhythm of proteinuria and the type of glomerulopathy.
The porphyrogenic effects of calcium channel blocking drugs
Authors: Schoenfeld N. , Aelion J. , Beigel Y. , Epstein O. , Atsmon A.
Published: August 2015

1. Treatment of monolayers of chick embryo hepatocytes with the calcium channel blocking drugs nifedipine and verapamil resulted in a decrease in the activity of uroporphyrinogen decarboxylase, an increase in the activity of δ-aminolaevulinate synthase and accumulation of porphyrins with uroporphyrin and heptacarboxylic porphyrin predominating.

2. Diltiazem, another calcium channel blocking drug, did not affect uroporphyrinogen decarboxylase activity and had a slight effect only on the accumulation of porphyrins.

3. Experiments with nifedipine and verapamil in the presence of various concentrations of calcium indicate that the porphyrogenic effect is apparently not related to blocking of calcium channels.
The calmodulin content of the epidermis in psoriasis
Authors: Mac Neil S. , Tucker W. F. G. , Dawson R. A. , Bleehen S. S. , Tomlinson S.
Published: August 2015

1. The calmodulin content of epidermis was determined by assay of biologically active and radioimmunoassayable calmodulin in epidermal biopsy samples of 16 normal control subjects and 36 patients with psoriasis.

2. Calmodulin levels in the involved epidermis of patients with psoriasis were significantly greater than in epidermis of control subjects, with both methods of calmodulin measurement. Levels of calmodulin in the uninvolved epidermis were also elevated but to a lesser degree, achieving statistical significance only when measured by radioimmunoassay. However, the degree of correlation between the two measurements of calmodulin was poor for the patient samples, suggesting that each may measure a different form of calmodulin.

3. The specificity of the elevated calmodulin in psoriatic epidermis was investigated by measuring calmodulin in another unrelated tissue. Calmodulin activity in circulating peripheral blood lymphocytes of seven patients with psoriasis was similar to that found in the lymphocytes of ten normal volunteers.

4. The relationship between calmodulin and the hyperproliferative state of the psoriatic epidermis was investigated. No significant increase in calmodulin activity was found after mitogen stimulation of lymphocyte proliferation or after Sellotape-stripping of the epidermis by a protocol which has been shown to cause hyperproliferation of the epidermis.

5. Elevated calmodulin in psoriatic epidermis therefore appears to be a localized phenomenon of the disease and does not appear to be a consequence of the hyperproliferative state of the epidermis.
Effects of an intravenous saline load on erythrocyte sodium transport in normal human subjects
Authors: Boero Roberto , Quarello Francesco , Guarena Cesare , Rosati Clelia , Piccoli Giuseppe
Published: August 2015

1. The effects of a 2 litre intravenous infusion of saline (0.9% NaCl solution) over 3 h on erythrocyte transmembrane sodium transport were studied in 12 normal human subjects.

2. After saline infusion a significant (P < 0.01) reduction of both outward Na+, K+ pump- and Na+, K+ cotransport-mediated Na+ effluxes was observed. The Na+, Li+ countertransport rate and the passive Na+ permeability did not change.

3. The incubation of the subjects' erythrocytes, obtained on a separate occasion, with their own plasma taken after the saline infusion, induced an inhibition of both Na+, K+ pump and Na+, K+ cotransport outward sodium fluxes. The percentage decrease after incubation was closely correlated with the percentage reduction induced by the saline infusion in vivo (r = 0.93 for the pump and r = 0.96 for cotransport; P < 0.01).

4. These data suggest that extracellular fluid volume expansion affects the release of circulating factors modulating sodium transport by the Na+, K+ pump and by Na+, K+ cotransport.
Short-term effects of β-adrenoceptor blocking drugs with and without cardioselectivity and intrinsic sympathomimetic activity on lipoprotein metabolism in hypertriglyceridaemic patients and in normal men
Authors: Durrington P. N. , Brownlee W. C. , Large D. M.
Published: August 2015

1. In six patients with hypertriglyceridaemia presenting whilst receiving treatment with β-adrenoreceptor blocking drugs (mean serum triglycerides 31.2 mmol/l) the half-life (t1/2) of an intravenously administered triglyceride emulsion was 32.8 ± 7.9 min (mean ± sem) on β-blocker and 22.8 ± 4.8 min after stopping β-blocker treatment.

2. In three of these patients subsequent administration of a β-blocker with intrinsic sympathomimetic activity had no effect on t1/2.

3. In a cross-over trial of placebo, atenolol (β1-blocker), propranolol (β1- and β2-blocker) and pindolol (β1- and β2-blocker with intrinsic sympathomimetic activity) in 11 normal men t1/2 was 11.8±0.9, 12.6±1.1, 14.3±1.7 and 12.4±1.1 min respectively. None of the apparent differences achieved statistical significance, but in two men marked increases in t1/2 occurred on propranolol.

4. The concentrations of serum triglycerides and very low density lipoprotein cholesterol in the normal men were, however, increased by β-blockade, most markedly by pindolol.

5. Serum high density lipoprotein (HDL) cholesterol concentration decreased in normal men on β-blockers, most clearly on atenolol and propranolol. This decrease was due to a reduction in cholesterol in the HDL2 subfraction.

6. No statistically significant effects on serum low density lipoprotein cholesterol or apolipoprotein B concentrations occurred in the normal men.

7. The doses of atenolol and propranolol used in this study were equipotent as judged by the heart rate response to exercise.
Partial characterization of abnormal salivary proteins associated with rheumatoid arthritis
Authors: Mairs Robert J. , Beeley Josie A.
Published: August 2015

1. Isoelectric focusing of parotid saliva from 33 patients with rheumatoid arthritis but without clinical evidence of salivary gland involvement revealed multiple abnormal proteins of pI 3.95–4.25 in all cases, whereas only two out of 16 samples from normal healthy individuals exhibited any similar bands.

2. Although rheumatoid factors of abnormally low isoelectric point and restricted heterogeneity were detected in this pI region in five of the diseased samples, these could not account for all of the bands even in these cases. The abnormal proteins did not otherwise cross-react with antisera to immunoglobulin (Ig) G, IgA or albumin.

3. Analysis of rheumatoid arthritis parotid saliva by a method involving adsorption of rheumatoid factors to immobilized rabbit immunoglobulin revealed the presence of salivary rheumatoid factors (in seven patients) of all the major immunoglobulin classes, including secretory-IgA in two patients.

4. Although these abnormal proteins are as yet uncharacterized, their presence could form the basis of a non-invasive procedure in the diagnosis of salivary gland and connective tissue disorders.
Iron uptake and ferritin synthesis in human erythroblasts
Authors: Hodgetts J. , Hoy T. G. , Jacobs A.
Published: August 2015

1. The erythroblasts from four normal bone marrows were enriched by using an anti-myeloid monoclonal antibody (TG-1), and a polyclonal antibody against mononuclear cells to effect complement mediated lysis of unwanted cells.

2. The erythroblasts were cultured for 2h in medium containing [59Fe]transferrin and [3H]-leucine, then fractionated on Percoll gradients according to their density.

3. Whole cell iron uptake by early erythroblasts was greater than in the dense late erythroblasts. In all marrows, iron uptake into ferritin was highest in fractions containing the earliest erythroblasts and decreased with increasing erythroblast maturity. In three of the four marrows this paralleled the pattern of ferritin synthesis.

4. It seems likely that apoferritin is synthesized in response to the amount of iron taken into the cell and this iron is incorporated within the protein shell to form ferritin.
Age-related differences in granulocyte Chemotaxis and degranulation
Authors: McLaughlin B. , O'Malley K. , Cotter T. G.
Published: August 2015

1. In the present study we have demonstrated that human peripheral blood granulocytes from elderly subjects exhibit reduced chemotaxis and degranulation in response to stimulation with fMet-Leu-Phe.

2. Cyclic AMP levels in non-stimulated cells were not significantly different (mean ± sem): 4.8 ± 0.6 and 3.9 ± 0.4 pmol/107 cells for young and elderly respectively. Stimulation with fMet-Leu-Phe (5 × 10−7 mol/l) for 30 s induced the production of cyclic AMP: 8.4 ± 0.5 and 6.7 ± 0.3 pmol/107 cells for young and elderly.

3. These findings, together with those previously published by us, suggest that cyclic AMP production and cellular functions which this molecule participates in are reduced in cells from elderly individuals.
Inhibition by omeprazole of adrenocortical response to ACTH: Clinical studies and experiments on bovine adrenal cortex in vitro
Authors: Howden C. W. , Kenyon C. J. , Beastall G. H. , Reid J. L.
Published: August 2015

1. Omeprazole, a substituted benzimidazole, is a potent inhibitor of gastric acid secretion which is currently being evaluated in patients with peptic ulcer and Zollinger-Ellison syndrome.

2. Drugs which possess an imidazole nucleus have previously been shown to inhibit cortisol release from the adrenal cortex, secondary to inhibition of mitochondrial cytochrome P-450 dependent hydroxylation reactions.

3. In a double-blind placebo-controlled crossover study in healthy male volunteers, omeprazole (60 mg daily for 7 days) did not alter basal cortisol levels. The peak cortisol response to ACTH stimulation was significantly reduced. Cortisol levels 60 min after ACTH were 824 ± 27 nmol/l on omeprazole (mean ± sem), and 929 ± 35 on placebo (P < 0.005).

4. In vitro, omeprazole caused a concentration-dependent inhibition of ACTH-stimulated cortisol release from isolated bovine adrenal cells (ED50 = 20 μg/ml). This was associated with a decrease in deoxycortisol synthesis. Therefore, unlike some other imidazole-containing drugs, the inhibitory effects of omeprazole are not entirely due to steroid 11 β-hydroxylase inhibition.

5. Substantial inhibition occurred at omeprazole concentrations which are higher than plasma levels normally achieved in clinical use. However, impairment of adrenocortical function may occur in patients on long-term high dose omeprazole treatment for Zollinger-Ellison syndrome.
The influence of streptozotocin-induced diabetes mellitus on fluid and electrolyte handling in rats
Authors: Hebden R. A. , Gardiner S. M. , Bennett T. , MacDonald I. A.
Published: August 2015

1. Intakes and urine outputs of fluid and electrolytes were measured daily in rats before, and for 3 weeks after, induction of diabetes by intraperitoneal injection of streptozotocin (STZ; 60 mg/kg); control animals received saline.

2. Water intakes and urine outputs were increased on and after the first day after injection with STZ; after a transient period of negative water balance, fluid intakes and urine outputs increased in parallel.

3. Food intake was reduced for the first 3 days after injection of STZ but thereafter there was a steady increase. On the final experimental day, the food intake of the diabetic group was 60% greater than that of the control group.

4. Urinary electrolyte excretion was increased after injection of STZ; at the end of the experiment, the increase in urinary sodium excretion was similar to the increase in intake but the increase in urinary potassium excretion was less.

5. On day 21 after injection of STZ plasma sodium concentration and packed cell volume were significantly reduced in the diabetic group but plasma potassium concentration was not.

6. There was a difference between the measured osmolality and the calculated osmolarity of the plasma of the diabetic animals which was not seen in the controls. This difference was not due to pseudohyponatraemia, but was probably due to the presence of unidentified solutes, since there was a significant gap between the urinary osmolal and osmolar excretion in the diabetic animals that was not present in the control animals.
Tissue specific modulation of β-adrenoceptor number in rats with chronic hypoxia with an attenuated response to down-regulation by salbutamol
Authors: Winter R. J. D. , Dickinson K. E. J. , Rudd R. M. , Sever P. S.
Published: August 2015

1. The number of β-adrenoceptors and their affinity for the radioligand 125I-labelled cyanopindolol (125I-CYP) were measured in crude membrane preparations of left ventricle, spleen and lung from Wistar rats exposed to 28 days continuous hypoxia.

2. β-Adrenoceptor density in the left ventricle was not significantly altered after exposure to chronic hypoxia (binding site maxima, Bmax: normoxic control 36 sem 5, hypoxic 24.8 sem 2 fmol/mg of protein). There was no change in β-adrenoceptor number in the spleen in response to chronic hypoxia (Bmax: normoxic control 76 sem 19 fmol/mg of protein, hypoxic 80 sem 15 fmol/mg of protein).

3. Chronic hypoxia resulted in a significant increase in β-adrenoceptor number in lung tissue (binding site maxima, Bmax.: normoxic control 406 (sem 31) fmol/mg of protein; hypoxic 535 (sem 30) fmol/mg of protein, P < 0.01 without change in the dissociation constant (KD) of the radioligand.

4. β-Adrenoceptor subtypes in lung homogenates were studied by establishing displacement curves for 125I-CYP by ICI 118551 (a selective β2-antagonist). A significant difference was seen in the proportion of β1-/β2-adrenoceptor subtypes after hypoxia (normoxic control 66 sem 2.5%, hypoxic 79 sem 2.4% β2-adrenoceptors, P < 0.01).

5. α1-Adrenoceptor number in lung membranes was measured with 125I-labelled 2-[β-(4-hydroxyphenyl)ethylaminomethyl]tetralone (125I-HEAT). No difference was seen in the number of α1-receptors in normoxia and in chronic hypoxia [Bmax.: normoxic control 48 (sem 3), hypoxic 48 (sem 5) fmol/mg of protein].

6. Treatment with salbutamol (2.5 mg/kg twice daily subcutaneously) did not reduce the number of β-adrenceptors in lung either during normoxia or in hypoxia. In spleen β-adrenoceptor number was decreased by 80% after chronic salbutamol treatment of rats in normoxia [Bmax.: normoxic control 76 (sem 19) fmol/mg of protein, treated 14 (sem 7) fmol/mg of protein, P < 0.01]. After treatment during hypoxia, however, there was no significant reduction in β-adrenoceptor number in spleen [Bmax.: hypoxic control 80 (sem 15) fmol/mg of protein, treated 77 (sem 13) fmol/mg of protein].

7. These data suggest that there is a tissue specific modulation in β-adrenoceptor numbers in response to chronic hypoxia and that their capacity for down-regulation is reduced.
Haemodynamic effects of vasopressin in man are related to posture
Authors: Simpson H. C. R. , Zubillaga J. E. , Collier J. G. , Bennett E. D. , Ang V. T. Y. , Mehta N. , Jenkins J. S.
Published: August 2015

1. Ten healthy volunteers received intravenous infusions of arginine vasopressin (AVP) at 0.1 m-unit min−1 kg−1 and 5% d-glucose on separate days. AVP caused a small fall in forearm blood flow and small rises in mean arterial pressure and systemic vascular resistance. Cardiac output was unaffected.

2. When subjects were tilted to 50° the fall in forearm blood flow was much greater, mean fall being 44.8% with AVP compared with 18.2% with d-glucose. Cardiac output also fell significantly more with AVP, and diastolic pressure, mean arterial pressure and systemic vascular resistance rose significantly more on tilting during AVP infusion than with d-glucose.

3. Six of the same volunteers were given sequential infusions of ‘low dose’ (0.0125 m-unit min−1 kg−1) and ‘high dose’ (0.3 m-unit min−1 kg−1) AVP on a third occasion. Tilting still produced a mean fall in forearm blood flow of 41.2% during low dose infusion, despite a mean plasma AVP level of only 1.9 pg/ml, which is well within the physiological range. When the AVP concentration was increased 24-fold to the high dose, forearm blood flow fell only a further 8.8%. The low dose infusion was also associated with a marked fall in cardiac output on tilting and a rise in systemic vascular resistance.

4. We conclude that AVP has profound haemodynamic effects in man at physiological concentrations. Although these effects are modest in the supine position, they become marked on tilting, suggesting a possible role for AVP in the postural control of blood pressure.
Age-dependent blood pressure response to increased salt intake in rats influenced by a transient renal ischaemia
Authors: Kuneš J. , Jelínek J. , Zicha J.
Published: August 2015

1. The influence of renal dysfunction (induced by ischaemic injury) on the development of salt hypertension was studied in rats which were exposed to 60 min of renal ischaemia when either immature or adult. Saline-drinking age-matched animals served as controls. The blood pressure, plasma urea concentration, extracellular fluid volume (ECFV) and renal mass were measured 21 and 50 days after renal ischaemia.

2. Increments of plasma urea concentration and ECFV were considered to be indicators of renal dysfunction. Increased renal mass was used as an estimate of the degree of renal injury.

3. In adult rats, both plasma urea concentration and ECFV were increased 3 weeks after renal ischaemia. This correlated with a pronounced increase of renal mass. A similar relation of renal mass to ECFV was still present 50 days after renal ischaemia.

4. In rats treated when immature the increment of plasma urea concentration was much smaller and ECFV did not differ significantly from the control volumes.

5. A mild salt hypertension developed only in those rats which were treated when immature. On the other hand, the blood pressure tended to decrease in animals treated when adult.

6. It is concluded that mild renal dysfunction facilitates the development of salt hypertension in immature rats. This is in contrast with the reversed effects of extensive renal dysfunction in adult animals.

7. It is suggested that the age of animals is more important for the induction of salt hypertension than the degree of renal dysfunction.
Activation of human muscle pyruvate dehydrogenase with activity and immobilization
Authors: Ward G. R. , Macdougall J. D. , Sutton J. R. , Toews C. J. , Jones N. L.
Published: August 2015

1. The activity of pyruvate dehydrogenase (PDH) was measured in samples of triceps muscle obtained in 15 males, before and after immobilization for 5 weeks and 5 months of strength training carried out in random order with cross-over of treatment.

2. Although the total PDH activity was unchanged at 300 nmol min−1 g−1, the proportion in the active form increased after strength training (62 ± 10.1%) and decreased after immobilization (12 ± 2.3%) compared with control (36 ± 3.4%).

3. In six subjects measurements were repeated after 10 min maximal exercise (arm ergometer). The proportion of PDH in the active form increased least after immobilization (to 52 ± 13.6%), compared with control (95 ± 11.7%) and post-training (98 ± 6.6%).

4. After exercise muscle glycogen fell to the greatest extent and lactate rose the least in the post-training state, with opposite findings post-immobilization, suggesting that PDH activation contributes to the control of lactate formation in muscle during heavy exercise, and that the effects of training and immobilization are mediated at least in part through changes in the activation of this regulatory enzyme.
Dentine is biochemically abnormal in osteogenesis imperfecta
Authors: Gage John P. , Francis Martin J. O. , Whitaker Gill E. , Smith Roger
Published: August 2015

1. In osteogenesis imperfecta the bones are brittle but the teeth, whose dentine contains the same genetic collagen as bone (type I), may be clinically normal.

2. To investigate this paradox we have measured the amino acid composition of insoluble dentine collagen from 16 deciduous and 18 permanent teeth in control subjects and in 59 patients with different forms of osteogenesis imperfecta.

3. In 55 of the patient samples significant differences from normal were found, especially in the number of lysine residues, and in the relative amounts of hydroxylysine to lysine.

4. These results demonstrate the high frequency of biochemical abnormalities in osteogenesis imperfecta. They also suggest that classifications of this disorder based on the presence or absence of clinical dentiogenesis imperfecta are likely to be unsound.