bluuebunny/crossref_metadata_2025 huggingface dataset:
Intracellular pH and Electrolytes in Human Skeletal Muscle during Adrenaline and Insulin Infusions
Authors: Sahlin K. , Henriksson J. , Juhlin-Dannfelt A.
Published: August 2015

1. There is evidence that both β-adrenergic stimulation and insulin are of importance in controlling intracellular pH. Therefore we have investigated the influence of intravenous infusion of adrenaline or insulin glucose (euglycaemic clamp) on pH and electrolyte composition in resting skeletal muscle (m. quadriceps femoris) and arterial blood in six healthy subjects.

2. A decrease in the arterial potassium concentration was observed during infusion of adrenaline and is in conformity with previous studies. Both adrenaline and insulin infusions resulted in an increased lactate content of muscle and blood, indicating an enhanced glycolysis. The intracellular concentrations of K+, Na+, Mg2+ and H+, however, remained unchanged during the adrenaline infusions as well as during infusions of insulin.

3. It is concluded that increasing the plasma adrenaline and insulin concentrations to levels well above the physiological range (adrenaline) or in the upper physiological range (insulin) does not affect the concentrations of electrolytes and hydrogen ions in resting human muscle to any appreciable extent.
Relationship between Ventilation and Breathlessness during Exercise in Chronic Obstructive Airways Disease is not Altered by Prevention of Hypoxaemia
Authors: Swinburn C. R. , Wakefield J. M. , Jones P. W.
Published: August 2015

1. We have examined the hypothesis that hypoxaemia contributes to breathlessness by a mechanism distinct from its action as a ventilatory stimulant.

2. Five patients who developed arterial oxygen desaturation during incremental exercise were studied. Exercise tests were performed on a cycle-ergometer. Breathlessness was measured by using a visual analogue scale technique. All five patients had considerable previous experience of these procedures.

3. Two identical exercise tests were performed by each patient, breathing either room air or 60% oxygen in a blind randomized study.

4. Breathing air, arterial saturation at rest was 93% and fell by 7% during exercise. Breathing 60% oxygen, resting saturation was 98% and there was no fall during exercise.

5. Breathing oxygen, ventilation for a given work load was reduced and exercise duration was increased when compared with air breathing.

6. In each of the five patients the relationship between breathlessness and minute ventilation was the same whether breathing air or 60% oxygen, despite the reduction in ventilation for a given work rate.
Hypertension Produced by Chemical Renal Medullectomy: Evidence for a Renomedullary Vasodepressor Function in the Rat
Authors: Taverner D. , Bing R. F. , Fletcher A. , Russell G. , Swales J. D. , Thurston H.
Published: August 2015

1. The rat renal papilla was selectively destroyed by 2-bromoethylamine hydrobromide; increasing doses produced a graded severity of histological damage, polyuria and a reduction in urinary prostaglandin E2 excretion.

2. Destruction of at least half of the papilla caused significant hypertension, but plasma renin concentration and plasma creatinine did not change.

3. After graded medullary damage Goldblatt two-kidney, one-clip hypertension was induced. Four weeks later the severity of hypertension was similar in medulla-damaged and medulla-intact groups.

4. When Goldblatt two-kidney, one-clip hypertension was reversed by removal of the renal artery clip, the blood pressure fall was less when the inner renal papilla was ablated than when it was intact, although plasma renin concentration and sodium balance were similar. The final blood pressure was similar to that observed in normal rats treated with 2-bromoethylamine compared with their respective controls.

5. These findings are consistent with the hypothesis that the inner renal medulla produces a vasodepressor that influences blood pressure in normal rats, and also lowers blood pressure when two-kidney, one-clip hypertension is reversed surgically.
Tamm—Horsfall Glycoprotein Release from Rat Kidney Cortex Slices in Vitro
Authors: Wirdnam P. K. , Milner R. D. G.
Published: August 2015

1. Rat kidney cortex slices were incubated for 30 min at 37°C in unmodified Krebs-Henseleit buffer containing aldosterone, vasopressin, theophylline, ethacrynic acid, frusemide, spironolactone or ouabain.

2. Tamm—Horsfall glycoprotein (THG) released into the media was measured by radioimmunoassay and at the end of each experiment the slices were homogenized and assayed for THG content.

3. Incubation of kidney cortex slices in unmodified buffer resulted in a significant increase in the slice THG content when compared with pre-incubation levels. The increase was prevented by puromycin or cycloheximide.

4. Incubation in ethacrynic acid (1 mmol/l) or frusemide (10 mmol/l) resulted in a significant increase in release of THG when compared with unmodified buffer. Puromycin or cycloheximide failed to prevent the increased release.

5. THG release induced by ethacrynic acid or frusemide is probably the result of an aggregation-disaggregation reaction on the cell membrane. It is suggested that the action of the chloride inhibiting diuretics, ethacrynic acid and frusemide, is mediated in some way via THG.
Effect of Acetylsalicylic Acid and of Indomethacin on Diuresis in Man: The Role of Cyclo-Oxygenase Inhibition
Authors: Vierhapper H. , Jörg J. , Waldhäusl W.
Published: August 2015

1. The effect of acetylsalicylic acid (ASA, 3 g/day for 3 days) and of indomethacin (IND, 150 mg/day for 3 days) on diuresis and on the excretion of prostaglandin E2 (PGE2) was studied in six healthy, male volunteers. After overnight deprivation the subjects received an oral water load (20 ml/kg) and hourly urine volumes were replaced by an equivalent volume of water by mouth for 4 h.

2. Pretreatment with both ASA and IND induced a comparable suppression (P<0.05 to <0.001) in the excretion of PGE2, but only IND also reduced (P<0.05) diuresis, free water clearance and the excretion of sodium. The excretion of creatinine was uninfluenced by both ASA and IND.

3. These data indicate that a mechanism other than cyclo-oxygenase inhibition is involved in the effect of IND and ASA on diuresis in man.
Effect of Two Models of Portal Hypertension on Splanchnic Organ Blood Flow in the Rat
Authors: Lebrec D. , Blanchet L.
Published: August 2015

1. Splanchnic organ blood flow and cardiac output were measured by the microsphere method in fasted rats with prehepatic portal hypertension due to portal vein stenosis, in rats with intrahepatic portal hypertension due to bile duct ligation, and in unoperated normal rats.

2. Portal venous pressure was higher in both groups of portal hypertensive rats than in normal rats. Cardiac output was significantly higher in portal hypertensive rats than in normal rats.

3. In rats with portal vein stenosis, splanchnic blood flow was higher than in controls. This increase was caused by increased perfusion of all organs drained by the portal vein, and by increased hepatic arterial blood flow. In rats with bile duct ligation, splanchnic blood flow was not significantly higher than in normal rats: haemoperfusion of all organs contributing to the portal circulation decreased, whereas hepatic arterial blood flow increased. As cardiac output rose similarly, the differences observed between the two types of portal hypertension depend mainly on the difference in distribution of flow within the splanchnic bed.
Intracellular Chloride in Essential Hypertension
Authors: Zidek W. , Losse H. , Lange-Asschenfeldt H. , Vetter H.
Published: August 2015

1. In 25 patients with untreated essential hypertension and 25 healthy controls, erythrocyte intracellular Cl− concentration and activity as well as Na+ activity were measured.

2. Intracellular Cl− concentration in essential hypertensive patients was 70.6 ± 11.3 as compared with 84.4 ± 9.5 mmol/l in the controls (P<0.001).

3. Intracellular Cl− activity was 77.5 ± 13.0 mmol/l of cell water in hypertensive patients, the control value being 100.8 ± 11.0 mmol/l of cell water (P<0.001).

4. In the hypertensive group intracellular Na+ activity was 14.3 ± 4.1 as compared with 7.1 ± 1.8 mmol/l of cell water in the normotensive group (P<0.01).

5. From these results it is suggested that in essential hypertension not only disturbances of cation metabolism, but also of anion metabolism, occur. Possibly the Cl− changes reflect a decreased Cl− inward transport due to an altered Na-K co-transport.
Cholestasis induced by Sulphated Glycolithocholic Acid in the Rat: Protection by Endogenous Bile Acids
Authors: Kuipers Folkert , Havinga Rick , Vonk Roel J.
Published: August 2015

1. Sulphated glycolithocholic acid (SGLC) causes cholestasis in experimental animals, despite its sulphated form. In the present study, the cholestatic potency and the pharmacokinetics of SGLC were investigated in rats under two conditions: (a) in the presence of an intact circulating bile acid pool and (b) after exhaustion of the bile acid pool by 24 h of bile diversion.

2. Intravenous administration of SGLC (8 μmol/ 100 g body weight) to rats with an intact bile acid pool did not cause cholestasis. However, biliary phospholipid and cholesterol concentrations were reduced by 40% and 29% respectively during the first hour after administration. When the same dose of the bile acid was injected in rats with a 24 h biliary drainage, a complete cessation of bile production was observed within 1 h. Twelve hours after the onset of cholestasis, bile production gradually increased again, showed a marked overshoot, and reached control levels after 3 days. In the recovery phase, biliary phospholipid and cholesterol concentrations were greatly reduced.

3. The absence of endogenous bile acids did not change the hepatic clearance rate of a tracer dose of radiolabelled SGLC, but markedly decreased its biliary excretion rate.

4. It was concluded that the hepatotoxic effect of SGLC is much more pronounced in rats with an exhausted bile acid pool, possibly due to a slower biliary excretion of the toxic compound. This phenomenon may have clinical implications for patients with a contracted bile acid pool.
Potentiation of Cardiac Vagal action by Cold
Authors: Potter Erica K. , Parker Pamela , Caine A. C. , Lumbers Eugenie R.
Published: August 2015

1. The effect of cold on vagal action at the heart was studied in sheep, dogs and an isolated guinea pig atrial preparation.

2. During cardiac output measurements in un-anaesthetized sheep, by the thermodilution method, bradycardia was evoked on injection of cold indicator in eight of 12 sheep studied. This bradycardia was consistently evoked when blood pressure was increased, but not at normal blood pressure levels.

3. In the guinea pig atrial preparation, which has one vagus nerve attached, bradycardia was evoked by electrical stimulation of the vagus nerve. When the preparation was cooled this bradycardia was potentiated.

4. In anaesthetized dogs, the cut peripheral end of one vagus was stimulated electrically at different frequencies. The linear relationship between pulse interval and vagal frequency was then compared at deep body temperatures of 35, 37, 39 and 41°C. This comparison showed that the vagus prolonged pulse interval more effectively when the animal was cool (35°C) than when it was warm (41°C).
Determination of the Rate of Urea Synthesis from Serial Measurements of Plasma Urea Concentration after an Alanine Load: Theoretical and Methodological Aspects
Authors: Geiseler D. , Kay J. D. S. , Oberholzer V. G. , Seakins J. W. T. , Hjelm M.
Published: August 2015

1. A method is described by which the rate of synthesis of urea can be calculated from the change of plasma concentration of urea after an alanine load.

2. The results can be expressed in terms of f, the maximum increase in the rate of urea synthesis, and t, the time at which urea synthesis reaches its maximum.

3. These parameters are calculated by an algebraic curve-fitting technique which is suitable for a desk computer.

4. The method removes the need for isotopic analysis and urine collections.

5. The effect of various errors and experimental conditions on the calculated synthesis parameters is investigated.
Mechanisms of abnormalities in host defences against bacterial infection in liver disease
Authors: Rajkovic I. A. , Williams Roger
Published: August 2015

Introduction: The clinical course of chronic liver disease is frequently complicated by bacterial infection. A series of studies over the years has shown that patients with cirrhosis of the liver are particularly susceptible to bacteraemia/septicaemia, bacterial endocarditis and pneumonia [1-7]. In addition, patients with ascites have a high frequency of spontaneous bacterial peritonitis [8,9], irrespective of the aetiology of underlying liver disease [10]. Bacterial infection appears not to be so common in patients with acute viral hepatitis [5] and, indeed, there is little mention in the literature of bacterial infection in association with acute liver disease. However, in the small proportion of patients with acute viral hepatitis and drug-induced liver damage who develop the clinical syndrome of fulminant hepatic failure, severe bacterial infection is common [11-14]. In this condition, as well as in chronic liver disease, infection may be the immediate cause of death and it may also be an important factor in precipitating gastrointestinal haemorrhage, renal failure and other complications.
Dopaminergic regulation of natriuretic response to acute volume expansion in dogs
Authors: McClanahan M. , Sowers J. R. , Beck F. W. J. , Mohanty P. K. , McKenzie T.
Published: August 2015

1. Effects of carbidopa, a dopa (3,4-dihydroxy-phenylamine) decarboxylase inhibitor, on the renal, haemodynamic and hormonal responses to acute volume expansion were examined in six healthy mongrel dogs which were infused intravenously with 0.9% sodium chloride solution (saline; 30 ml h−1 kg−1) over 2 h.

2. Saline infusion studies were performed in the absence (control) and in the presence of carbidopa given by nasogastric tube in a dose of 1 mg/kg every 8 h beginning 24 h before the infusion.

3. Saline infusion resulted in an increase in renal excretion of dopamine (3,4-dihydroxy-phenylethylamine) and a decrease in renal excretion of noradrenaline.

4. Carbidopa treatment decreased urinary sodium excretion and eliminated the increase in renal production of dopamine in response to saline infusion without affecting renal or haemodynamic response to acute vascular volume expansion with saline.

5. Carbidopa treatment obliterated the suppression of aldosterone produced by saline infusion.

6. Thus, dopamine appears to play a significant role in mediating both the natriuretic and aldosterone response to acute volume expansion.
Apparent compartmentation of body nitrogen in one human subject: its consequences in measuring the rate of whole-body protein synthesis with 15N
Authors: Fern Edward B. , Garlick Peter J. , Waterlow John C.
Published: August 2015

1. The rate of protein synthesis in the whole body was measured in one fed subject with seven 15N-labelled amino acids (intravenous and oral doses) and two 15N protein mixtures (oral doses only). The rates were determined individually from the urinary excretion of ammonia and total urea over a 12 h experimental period.

2. Except with oral glycine and alanine, the synthesis rates given by ammonia and urea were appreciably different within each study when calculated on the assumption of a single pool of metabolic nitrogen in the body. In general, intravenous administration of the tracers gave higher rates with urea and the oral route gave higher rates with ammonia.

3. The differences between intravenous and oral doses of 15N could be reduced significantly by calculating synthesis rates from either the arithmetic or harmonic average of flux rates given by ammonia and urea. The averages correspond to estimates of the total flux in a two-pool model of metabolic nitrogen when it is assumed either that both pools receive an equal amount of tracer (arithmetic) or that both have the same rate of nitrogen turnover (harmonic).

4. By so reducing the effect of physical separation of nitrogen in the body, the metabolic aspects of compartmentation of the tracer could be examined. The results show that the absolute value obtained for protein synthesis depends on the source of labelled nitrogen. The data are discussed in this empirical context.
Leukaemic promyelocytes and normal bone marrow cells release a passive sodium transport modifier (inhibitin)
Authors: Morgan Kevin , Spurlock Gillian , Mir M. Afzal
Published: August 2015

1. Previous studies have shown that leukaemic immature cells, specifically promyelocytes but not mature leucocytes, contain and release an inhibitor of ouabain-insensitive sodium transport (inhibitin).

2. In the present study, medium from cultured leukaemic promyelocytes significantly reduced the ouabain-insensitive sodium efflux from erythrocytes, whereas medium from the same cell line which had been made to differentiate did not have this effect.

3. Culture medium from normal bone marrow cells (containing promyelocytes) also significantly (P < 0.001) reduced ouabain-insensitive sodium efflux.

4. These data suggest that inhibitin is secreted by primitive but not by mature leukaemic cells and normal bone marrow cells.
Neuropeptide Y: a novel renal peptide with vasoconstrictor and natriuretic activity
Authors: Allen J. M. , Raine A. E. G. , Ledingham J. G. G. , Bloom S. R.
Published: August 2015

1. A novel vasoconstrictor peptide, neuropeptide Y (NPY), has been identified in considerable quantities in the renal artery and kidney. Within the kidney, NPY was confined to the cortex and corticomedullary interface, the regions where the juxtaglomerular apparatus is most numerous.

2. In the isolated perfused rat kidney, NPY caused a prompt dose-dependent increase in perfusion pressure and reduction in flow, with only a small fall in glomerular filtration rate (GFR). In spite of the reduced renal perfusion, a dose-dependent natriuresis was observed. This response contrasts to the response of this preparation to noradrenaline, which causes sodium reabsorption.

3. The presence of a potent vasoconstrictor and natriuretic peptide within the rat renovascular system suggests that it may play a significant role in the control of renal function.
Maternal zinc and intrauterine growth retardation
Authors: Simmer Karen , Thompson R. P. H.
Published: August 2015

1. The levels of zinc in plasma, erythrocytes, polymorphonuclear (PMN) and mononuclear (MN) white cells were measured after delivery in women giving birth to appropriate-for-gestational-age (AGA) babies (group I mothers), or small-for-gestational-age (SGA) babies (group II mothers) and in non-pregnant controls.

2. Mean maternal plasma zinc and albumin levels 24-48 h after delivery were lower than in controls, but PMN and MN zinc levels were unchanged. PMN zinc levels were lower than those of MN cells.

3. PMN and MN zinc levels were significantly lower in group II mothers than in group I, irrespective of smoking habits. There were no racial differences in peripheral white cell zinc levels.

4. PMN, and to a lesser degree MN, zinc levels were lower in smoking than in non-smoking mothers.

5. Erythrocyte zinc did not correlate with other zinc measurements nor with the size of the babies. Fetal erythrocyte zinc levels were one-third of maternal levels.

6. A combination of smoking and/or low PMN zinc levels selects 85% of mothers having small-for-gestational-age babies.
The human eccrine sweat gland adenylate cyclase system: response to agonists
Authors: Khullar A. K. , Schwarz V. , Wilson P. D.
Published: August 2015

1. Cyclic AMP accumulation has been measured in whole human sweat glands. The mean rate in glands from 19 subjects was 0.519 ± 0.316 pmol of cyclic AMP formed 5 min−1 μg−1 of DNA, which is comparable with that reported for other tissues.

2. Cyclic AMP accumulation in the sweat gland is stimulated fourfold by prostaglandin (PG) E1 and fivefold by PGE2 (0.1 mmol/l), in accord with stimulation in renal tubules and medullary membranes.

3. Bradykinin (10 μg/ml) increases the rate threefold and this is substantially prevented by indomethacin (1.5 × 10−5 mol/l), as also is a five-fold stimulation by cyclic GMP (10−5 mol/l).

4. Mecholyl (10−2 mol/l) and isoprenaline (6 × 10−6 mol/l) increase the rate five- and four-fold respectively, and these agonist effects are largely abolished by atropine and propranolol.

5. The stimulation and inhibition pattern suggests a direct action of PGE, enhancement of prostaglandin synthetase by cyclic GMP and stimulation of guanylate cyclase by mecholyl and bradykinin. Isoprenaline presumably stimulates adenylate cyclase directly.

6. This complex chain of events, from cholinergic stimulation to an enhancement of adenylate cyclase, demonstrated in vitro, constitutes a potential for flexible and fine control of sweat gland function.
Changes in plasma catecholamines in response to reflex modulation of sympathetic vasoconstrictor tone by cardiopulmonary receptors
Authors: Grassi Guido , Gavazzi Cecilia , Cesura Andrea M. , Picotti Giovanni B. , Mancia Giuseppe
Published: August 2015

1. The effects of selective deactivation and stimulation of cardiopulmonary receptors on plasma noradrenaline (radioenzymatic method) were studied in nine normotensive subjects by reducing and increasing central venous pressure for 20 min via lower body suction and leg-raising manoeuvres that did not alter arterial blood pressure and heart rate.

2. Deactivation of cardiopulmonary receptors was accompanied by a rise in plasma noradrenaline that achieved a peak within 5 min (91.8 ± 22%, mean ± se) and was then sustained. Stimulation of cardiopulmonary receptors was accompanied by a fall in plasma noradrenaline (−16.6 ± 3.4%) that levelled off at the second minute and was then sustained.

3. On average the increase and the reduction in plasma noradrenaline had a time course and a magnitude similar to the increase (80.5 ± 10.5%) and the reduction (−28.4 ± 5%) in forearm vascular resistance (derived from plethysmographic flow measurement) concomitantly caused by cardiopulmonary receptors. Furthermore, analysis of individual data showed that changes in plasma noradrenaline and forearm vascular resistance were linked by a positive relationship (r = 0.64).

4. Thus the cardiopulmonary receptor reflex can produce rapid, marked and sustained changes in both plasma noradrenaline and forearm vasomotor tone. This is in sharp contrast with the previously observed inability of the carotid baroreflex to alter both these humoral and haemodynamic variables. Taken together these findings support the hypothesis that sympathetic tone to skeletal muscle is an important determinant of the concentration of plasma noradrenaline in blood.
The retention of cobalamin by the liver in the cobalamin-deficient rat
Authors: Owens Julie A. , Scott J. S. D. , Cooksley W. G. E.
Published: August 2015

1. The effect of cobalamin deficiency on whole body cobalamin content and its turnover was examined in the rat. Quantitative and qualitative changes in hepatic cobalamin were also followed and the effect of deficiency on the turnover of this cobalamin was determined in the isolated perfused liver.

2. As cobalamin deficiency developed after total gastrectomy, whole body cobalamin content declined at a constant rate, indicating no attempt to conserve total body cobalamin stores even when depleted (5% of normal).

3. In contrast, the cobalamin concentration of liver declined more slowly, indicating conservation of hepatic cobalamin. Furthermore, the methylcobalamin (Me Cbl) content of liver was maintained or even increased.

4. Measurement of the rate of release of cobalamin by the isolated perfused liver at varying times after gastrectomy showed that as depletion of whole body and hepatic cobalamin stores proceeded, the rates of release of hepatic cobalamin into plasma and bile decreased. Regression analysis showed that the fractional rates of release of hepatic cobalamin into plasma (r = 0.9, P < 0.001, n = 15) and bile (r = 0.65, P<0.01, n = 15) were significantly correlated with hepatic cobalamin content.

5. It is concluded that conservation of hepatic cobalamin in deficiency is achieved, at least in part, by a specific decrease in the rate of release of hepatic cobalamin.
Human jejunal transglutaminase: demonstration of activity, enzyme kinetics and substrate specificity with special relation to gliadin and coeliac disease
Authors: Bruce S. E. , Bjarnason I. , Peters T. J.
Published: August 2015

1. By use of a radiometric assay transglutaminase activity was demonstrated for the first time in human jejunal mucosa. The activity is similar to that in other tissues, with a pH optimum of 9.0, an absolute requirement for Ca2+ and an apparent Km for putrescine of 0.15 mmol/l.

2. Assay of jejunal transglutaminase activity with a variety of dietary proteins as acceptors showed high activity with gliadin, comparable with that of the standard substrate, dimethylcasein. Deamidation of the gliadin markedly reduced its acceptor activity. Collagen, ovalbumin, elastin and zein exhibited very low acceptor activities.

3. Increased transglutaminase activity was demonstrated in jejunal biopsies from four patients with untreated coeliac disease compared with 14 control subjects and eight patients with inflammatory bowel disease. Eight patients with coeliac disease in remission, with normal levels of brush border α-glucosidase, showed elevated transglutaminase activities compared with those of controls.

4. It is postulated that intestinal transglutaminase activity may be important in gliadin binding to tissues and thus in the pathogenesis of coeliac disease.
Interactions between neural mechanisms, the renin-angiotensin system and vasopressin in the maintenance of blood pressure during water deprivation: studies in Long Evans and Brattleboro rats
Authors: Gardiner S. M. , Bennett T.
Published: August 2015

1. Plasma volumes and cardiovascular status were assessed in rats with a congenital deficiency in hypothalamic vasopressin (Brattleboro strain) and in the parent strain (Long Evans), in water-replete and water-deprived states.

2. Water-replete Brattleboro rats were not hypovolaemic; water deprivation (14 h in Brattleboro rats, 53 h in Long Evans rats) produced similar percentage reductions in plasma volumes in the two groups.

3. In the water-replete state, cardiovascular variables were similar in Long Evans and Brattleboro rats. Inhibition of ganglionic transmission (with pentolinium) or of the renin-angiotensin system (with captopril), separately, did not have a greater effect on blood pressure in Brattleboro rats than in Long Evans rats. Recovery from hypotension caused by pentolinium was characterized by large swings in blood pressure in both groups of rats. These pressor episodes were abolished by administration of captopril to Brattleboro rats. After administration of pentolinium and captopril to Long Evans rats there was a substantial, although intermittent, recovery in blood pressure that was abolished by an antagonist of the cardiovascular actions of vasopressin.

4. In the water-deprived state, blood pressures were similar in Long Evans and Brattleboro rats; both groups showed an elevation in diastolic blood pressure relative to the water-replete state. After administration of pentolinium, there was a more marked recovery in blood pressure than was seen in the water-replete state. Administration of Captopril alone had a slightly greater effect on blood pressure in Long Evans rats in the water-deprived, compared with the water-replete, state. However, in the former condition, Brattleboro rats showed a profound and progressive hypotension in response to captopril, indicating an indispensable role for the renin-angiotensin system in the maintenance of blood pressure in these animals during water deprivation.

5. Only when the renin-angiotensin system and neural activity were inhibited did vasopressin express its full, independent, pressor potential in Long Evans rats. However, evidence was obtained that vasopressin may exert important effects on cardiovascular regulation via neural mechanisms and through interactions with the renin-angiotensin system.
The implication of bilitranslocase function in the impaired rifamycin SV metabolism in Gilbert's syndrome
Authors: Gentile Sandro , Persico Marcello , Baldini Giulia , Lunazzi Giancarlo , Tiribelli Claudio , Sottocasa Gian Luigi
Published: August 2015

1. The plasma disappearance rate and the increment in plasma unconjugated bilirubin after intravenous administration of 5.9 μmol of rifamycin SV (RSV)/kg body wt. were investigated in 51 subjects with Gilbert's syndrome and 35 control subjects of both sexes.

2. Both the plasma disappearance rate and the unconjugated hyperbilirubinaemia after RSV administration were higher (P<0.001) in Gilbert's syndrome. Females, both normal and with the syndrome, showed a significantly shorter t1/2 and a lower hyperbilirubinaemic response as compared with males. A linear correlation (P<0.001) was present between RSV plasma half-life and the hyperbilirubinaemic response.

3. In vitro, RSV was shown to inhibit sulphobromophthalein (BSP) uptake in rat liver plasma-membrane vesicles with a Ki of 20 μmol/l. Evidence that this effect was due to competition for bilitranslocase was sought on preparations of the purified protein. Under these experimental conditions, RSV inhibited BSP binding with a Ki of 17 μmol/l.

4. Since RSV competes with BSP for binding to bilitranslocase in vitro, the data are interpreted as suggesting that reduced bilitranslocase function might underlie the delayed RSV plasma clearance and the exacerbated unconjugated hyperbilirubinaemia present in Gilbert's syndrome.
Dexamethasone effect on prostanoid formation in healthy man
Authors: Rosenkrantz Bernd , Náray-Fejes-Tóth Aniko , Fejes-Tóth Geza , Fischer Christine , Sawada Masafumi , Frölich Jürgen C.
Published: August 2015

1. Dexamethasone was administered to six healthy female volunteers for 4 days, resulting in plasma levels of 4.8 ± 1.4 × 10−8 mol/l. Urinary excretions of six prostanoids as well as collagen-induced platelet thromboxane formation and aggregation were determined before, during and 1 month after administration of dexamethasone.

2. Dexamethasone had no effect on urinary thromboxane B2 (77 ± 22 ng/day vs 63 ± 16 ng/day during dexamethasone), dinor-thromboxane B2, the major urinary metabolite of thromboxane B2 (406 ± 84 ng/day vs 380 ± 90 ng/day), dinor-6-keto-prostaglandin F1α, the major urinary metabolite of prostacyclin (199 ± 41 ng/day vs 237 ± 53 ng/day), tetranor-5,1 l-diketo-7α-hydroxy-prostane-1,16-dioic acid, the major urinary metabolite of prostaglandins E1 and E2 (7712 ± 1677 ng/day vs 7886 ± 2565 ng/day) and tetranor-11-keto-5α, 7α-dihydroxy-prostane-1,16-dioic acid, the major urinary metabolite of prostaglandins F1α and F2α (14 394 ± 2053 ng/day vs 18288 ± 2251 ng/day). Prostaglandin E2 excretion slightly but significantly increased from 217 ± 48 ng/day to 294 ± 55 ng/day. Collagen-induced platelet thromboxane formation and aggregation were not altered.

3. These results suggest that glucocorticoids do not regulate renal, platelet or total body prostanoid formation in healthy man.
The biliary excretion of 25-hydroxy-[3H] vitamin D3 in the Gunn rat
Authors: Gascon-Barré Marielle
Published: August 2015

1. The biliary excretion of 25-hydroxy-[3H]-vitamin D3 (25-(OH)-[3H]D3)-derived materials after the intravenous administration of 25-(OH)-[3H]D3 (1.25 nmol/100 g body weight) was studied during a period of 3 h in homozygous (icteric) and heterozygous (anicteric) Gunn rats.

2. The heterozygous rats excreted significantly more 25-(OH)-[3H]D3-derived materials than the homozygous Gunn rats (7.2 ± 1.5% vs 3.1 ± 0.5% of the administered dose, P<0.025).

3. The lower biliary excretion of 25-(OH)-[3H]-D3-derived material in homozygous compared with heterozygous Gunn rats was not due to differences in the plasma 25-(OH)-[3H]D3 concentrations nor was it due to differences in the uptake of 25-(OH)-[3H]D3 by the liver since similar liver/plasma concentration ratios were observed in both groups of animals; it seemed, however, to be due to differences in the biliary transfer of 25-(OH)-[3H]-D3, as indicated by a lower bile/liver concentration ratio in homozygous than in heterozygous rats (1.39 ± 0.23 vs 0.49 ± 0.06, P<0.05).

4. Moreover, samples of bile obtained from homozygous rats contained no β-glucuronidase-sensitive 25-(OH)-[3H]D3-derived materials but contained significantly more intact 25-(OH)-[3H]-D3 than samples obtained from heterozygous Gunn rats (P<0.05). After hydrolysis of bile obtained from homozygous and heterozygous Gunn rats with the enzyme β-glucuronidase, the total amount of intact 25-(OH)-[3H]D3 recovered was found to be similar in the two groups of rats.

5. The results of the present experiments indicate that conjugation of 25-(OH)D3 with glucuronic acid is one of the metabolic pathways involved in its biliary transfer; they also illustrate that the homozygous Gunn rats constitute a good model to study the importance and biological significance of the glucuronidation pathway in the biliary excretion of vitamin D sterols.
Studies of α2-adrenoceptor antagonist potency in vitro: comparisons in tissues from rats, rabbits, dogs and humans
Authors: Waterfall J. F. , Rhodes K. F. , Lattimer N.
Published: August 2015

1. The potencies of a number of selective α2-adrenoceptor antagonists have been measured in preparations from four species.

2. In the rat vas deferens, the newer synthetic antagonists Wy 25309, Wy 26392, Wy 26703 and RX 781094 were more potent than the alkaloid yohimbine in blocking a clonidine-induced inhibition of an electrically evoked twitch response.

3. In the rabbit vas deferens yohimbine was substantially more potent than the synthetic antagonists in reversing the action of clonidine.

4. Yohimbine was also more potent than the synthetic antagonists in blocking the B-HT 933-induced contractile responses of the dog saphenous vein and preventing adrenaline-induced aggregation of human platelets.

5. Together with previously published data derived from tritium overflow studies on rabbit pulmonary arteries and displacement of [3H]-rauwolscine binding from rat cerebral cortex and human platelets, the results suggest that the adrenoceptor currently labelled α2 may not be a single entity.
Inositol lipid breakdown as a step in α-adrenergic stimulus-response coupling
Authors: Michell Robert H.
Published: August 2015

1. A widespread, and maybe universal, response to stimulation of α-adrenoceptors is inositol lipid hydrolysis: the receptor-coupled event is probably hydrolysis of phosphatidylinositol 4,5-bisphosphate. This reaction generates two second messenger molecules.

2. Inositol 1,4,5-trisphosphate may be responsible for the intracellular mobilization of Ca2+ that has long been recognized as a major mediator of the effects of α-receptor activation. In addition, the released 1,2-diacylglycerol probably contributes to control of cell function through activation of protein kinase C.
Vascular α2-adrenoceptors can mediate nerve stimulation-evoked contractions
Authors: Docherty James R. , Hyland Lisa
Published: August 2015

1. It is now established that α2-adrenoceptors can be present on vascular smooth muscle as targets for exogenous agonists, but some controversy exists as to whether these vascular α2-receptors may also be the target for neurally released noradrenaline.

2. In human saphenous vein we have found evidence that the α2-antagonist yohimbine in low concentrations (0.01 μmol/l) can significantly inhibit stimulation-evoked contractions, whereas the α1-antagonist prazosin is more than ten times less potent.

3. It is concluded that, at least in some tissues, neuro-effector transmission can be mediated by vascular α2-adrenoceptors.
Human vascular smooth muscle responses mediated by α2 mechanisms in vivo and in vitro
Authors: Thom S. , Calvete J. , Hayes R. , Martin G. , Sever P.
Published: August 2015

1. The effects of compounds with α2-agonist and α2-antagonist properties on human forearm blood flow and on isolated human arterial segments have been studied.

2. The findings from these studies in vivo and in vitro did not provide evidence in support of the hypothesis that postsynaptic α2-receptors mediate smooth muscle contraction in the tissues under investigation.

3. The constriction of the forearm vascular bed in response to low intra-arterial doses of idazoxan (RX 781094), an α2-antagonist, provides evidence for a physiological role for a presynaptic α2 autoregulatory mechanism.

4. The variability of the forearm vascular responses to higher doses of idazoxan highlights the pitfalls that may have misled previous authors in their interpretation of the results of similar studies. A U-shaped dose-response curve to compounds with mixed α2-and α1-antagonist properties may be constructed, which emphasizes the importance of the dose-dependent selectivity of these antagonists at α2- and α1-receptors.

5. The effect of idazoxan on the responses of arterial segments in vitro to exogenous catecholamines was dependent on the integrity of the endothelium, and provides evidence that α2-receptors may mediate release of the endothelium-derived relaxing factor.
The Distribution of Catecholamines between Platelets and Plasma in Normal Human Subjects
Authors: Smith C. C. T. , Curtis L. D. , Delamothe A. P. , Prichard B. N. C. , Betteridge D. J.
Published: August 2015

1. We have used high-performance liquid chromatography with electrochemical detection to measure content of adrenaline and noradrenaline in platelets in 13 normal subjects at rest.

2. Subjects were exercised to raise plasma catecholamine levels and promote the platelet release reaction.

3. There was a significant positive correlation between plasma noradrenaline concentrations and platelet noradrenaline content.

4. Platelet/plasma concentration ratios were 1855 for noradrenaline and 268 for adrenaline at rest and 473 and 152 respectively after exercise.

5. Plasma noradrenaline levels positively correlated with age.

6. Determination of platelet factors released to the plasma showed increases of β-thromboglobulin and platelet factor 4 with exercise, whereas thromboxane B2 remained unchanged. No change in platelet catecholamine levels occurred with exercise and no correlations were observed between platelet catecholamines and released platelet factors.

7. These data suggest that plasma catecholamine levels influence platelet content and that noradrenaline and adrenaline are concentrated in platelets.
The Measurement of Breathlessness Induced in Normal Subjects: Validity of two Scaling Techniques
Authors: Adams L. , Chronos N. , Lane R. , Guz A.
Published: August 2015

1. The intensity of breathlessness induced by ventilatory stimulation resulting from hypercapnia, hypoxia or exercise has been quantified in normals by using the two different sensory scaling techniques of linear visual analogue scaling and ratio magnitude estimation.

2. In naive individuals both techniques show good face validity.

3. When related to ventilation, quantification of breathlessness is moderately reproducible with both methods, even when subjects are kept in ignorance of the pattern of ventilatory stimulation.

4. There is a small within- and large between-subject variability with both scaling techniques; possible factors responsible are discussed.

5. The reproducibility of visual analogue scaling when related to ventilation is independent of the nature of the ventilatory stimulus and is maintained over intervals as long as 1 week when memory for the score given is unlikely to be an important factor.

6. The difficulties of interpreting subjective estimates of perceived breathlessness are discussed, together with the relative merits of the two scaling techniques.
Measurement of Blood Cortisol and Acid Output in Patients with Duodenal Ulceration and Normal Subjects During Insulin Hypoglycaemia
Authors: Athow Anna C. , Sewerniak Anna T. , Barton Tina P. , Clark C. G. , Lewin M. R.
Published: August 2015

1. The blood cortisol and gastric acid responses to insulin hypoglycaemia were investigated in 18 healthy control subjects and 14 patients with endoscopically proven duodenal ulceration.

2. In both controls and patients, insulin hypoglycaemia caused blood cortisol and acid output to rise and peak simultaneously, the rises being significantly greater in patients with duodenal ulcer than in control subjects.

3. The peak acid output and the base to peak cortisol increments were also found to be significantly greater in patients with duodenal ulcer than in control subjects (P < 0.001 and P < 0.005 respectively).

4. We conclude that insulin hypoglycaemia causes stimulation of the sympathetic and parasympathetic nervous systems and of the hypothalamo-pituitary-adrenal axis, resulting in the simultaneous elevation of gastric juice acidity and blood cortisol levels. We have shown that synchronous rises in gastric acid and blood cortisol occur during insulin hypoglycaemia and that these rises are greater in patients with duodenal ulcer.
Sulphasalazine and Derivatives, Natural Killer Activity and Ulcerative Colitis
Authors: Gibson P. R. , Jewell D. P.
Published: August 2015

1. The effects of sulphasalazine, 5-aminosalicylic acid (5-ASA), sulphapyridine and azodisalicylic acid (ADS) in vitro on the natural killer (NK) activity of peripheral blood mononuclear cells (MNC) have been examined and compared with those of the lipoxygenase inhibitor, nordihydroguaiaretic acid (NDGA) and the cyclooxygenase inhibitor, indomethacin.

2. Sulphasalazine, sulphapyridine and ADS inhibited NK activity with 50% inhibitory concentrations (IC50) of 0.7, 2.5 and 4.0 mmol/l respectively. The effect was rapidly reversible. In contrast, 5-ASA minimally inhibited NK activity at 50 mmol/l only.

3. NDGA potently inhibited NK activity (IC50 27 μmol/l) but this was only partly reversible in short term incubations. Indomethacin had no effect at concentrations less than those inhibiting cyclo-oxygenase activity (1-10 μmol/l) but potently and reversibly inhibited NK activity at or above 25 μmol/l.

4. The inhibitory effects observed were unlikely to be due to direct toxicity of effector cells as 5-ASA, sulphapyridine and ADS had no effect on the viability of peripheral blood MNC, whereas NDGA and indomethacin lysed MNC only at maximal concentrations tested. Though sulphasalazine produced MNC lysis at and above 1 mmol/l, the rapid reversibility of the inhibition of NK activity at 1 mmol/l suggested that lysis of NK cells contributed little to the suppressive effect at this concentration.

5. The disparity of the therapeutic efficacy and effects on NK activity of sulphasalazine and its derivatives in vitro may suggest that NK activity is not a major pathogenic mechanism in ulcerative colitis. Any inhibitory effect on cellular immune function of indomethacin does not necessarily reflect an effect of cyclo-oxygenase inhibition.
γ-l-Glutamyl-l-Dopa is a Dopamine Pro-Drug, Relatively Specific for the Kidney in Normal Subjects
Authors: Worth D. P. , Harvey J. N. , Brown J. , Lee M. R.
Published: August 2015

1. γ-l-Glutamyl-l-dopa was given by intravenous infusion to eight normal subjects at doses of 12.5 and 100 μg min−1 kg−1.

2. Both doses of the dipeptide resulted in an increase in mean urinary sodium excretion.

3. Mean effective renal plasma flow rose at both doses, but mean glomerular filtration rate increased only at the lower dose.

4. There was a fall in mean plasma renin activity after the infusion of both 12.5 and 100 μg min−1kg−1.

5. Mean urine free dopamine excretion increased by 280- and 2500-fold at infusion rates of 12.5 and 100 μg min−1 kg−1 respectively.

6. Mean plasma free dopamine rose at both doses but the increase at 12.5 μg min−1 kg−1 was not to a level previously associated with systemic effects of the catecholamine.

7. On administration of the dipeptide at 12.5 μg min−1 kg−1 there were no changes in blood pressure or heart rate, but at the higher dose there was a fall in diastolic blood pressure.

8. At a dose of 12.5 μg min−1 kg−1 in man, there is kidney specific conversion of gludopa to dopamine.
Cytosolic free Calcium and Intracellular Calcium Stores in Neutrophils from Hypertensive Subjects
Authors: Lew P. Daniel , Favre Laurent , Waldvogel Francis A. , Vallotton Michel B.
Published: August 2015

1. Alterations in intracellular calcium have been implicated in the pathogenesis of essential hypertension. To see whether this is a generalized phenomenon we assessed cytosolic free calcium and intracellular calcium stores in neutrophils from normo- and hyper-tensive subjects, by trapping the fluorescent calcium indicator quin2 in intact cells.

2. Ten patients with untreated essential hypertension were compared with 10 age- and sex-matched normotensive subjects. The levels of cytosolic free calcium and intracellular calcium stores releasable by the calcium ionophore ionomycin did not differ. No significant relationship was found between blood pressure and the calcium parameters in all 20 subjects studied.

3. The results indicate that essential hypertension is not associated with a membrane defect in calcium handling of all human cell systems, leading to generalized increases in resting values of cytosolic free calcium.

4. Neutrophils do not appear to be a good model for intracellular calcium handling in vascular smooth muscle.
Influence of the parasympathetic and sympathetic nervous system on nocturnal bronchial obstruction
Authors: Postma D. S. , Keyzer J. J. , Koëuter G. H. , Sluiter H. J. , De Vries K.
Published: August 2015

1. To determine whether an autonomic nervous system imbalance might underlie the nocturnal dyspnoea in patients with chronic airflow obstruction (CAO), we determined FEV1, sinus arrhythmia gap (SA gap), heart rate and urinary adrenaline and noradrenaline excretion every 4 h over 24 h. Measurements were performed in eight non-allergic patients with CAO and eight age- and sex-matched normal controls.

2. The amplitude of the circadian changes in FEV1 in patients and controls was 27 ± 2% and 7 ± 1% respectively (P < 0.001).

3. Both an increased SA gap and a decreased heart rate are features of increased vagal activity. This vagal activity was significantly increased in patients, compared with normal controls (difference P < 0.01), the difference being maximal at night. This increased activity might contribute to a bronchial obstruction in these patients.

4. Urinary adrenaline excretion was significantly higher by day than by night in both patients and normal controls (P < 0.01). The urinary levels of adrenaline in the patients were significantly decreased at all hours of observation as compared with levels in normal controls (P < 0.05).

5. Urinary noradrenaline levels were significantly lower in patients as compared with normal subjects (P < 0.01), and lower by night than by day.

6. Urinary histamine and Nτ-methylhistamine excretion were in the normal range in each individual. Urinary levels, however, were significantly higher in patients at all hours of observation (P < 0.05). No circadian rhythm was shown. Plasma cortisol levels showed a normal circadian variation, similar in patients and normal subjects.

7. Bronchial constriction in patients with CAO may be explained by an autonomic nervous system imbalance. Arguments favouring this hypothesis were the findings that CAO patients, in contrast with normal controls, showed lower urinary adrenaline and noradrenaline excretion throughout with a fall at night, and a higher vagal tone with an increase at night. Moreover, a higher histamine and Nτ-methylhistamine excretion both day and night existed in the patient group. A combination of these factors may lead to the nocturnal dyspnoea in patients with CAO.