bluuebunny/crossref_metadata_2025 huggingface dataset:
Inhibition of Acetylcholinesterase Selectively Potentiates NG-Monomethyl-l-Arginine-Resistant Actions of Acetylcholine in Human Forearm Vasculature
Authors: Chowienczyk P. J. , Cockcroft J. R. , Ritter J. M.
Published: August 2015

1. NG-monomethyl-l-arginine (l-NMMA, a nitric oxide synthase inhibitor) inhibits vasodilator responses to acetylcholine but not methacholine in human forearm vasculature. To investigate whether this difference results from the relative susceptibility of these agonists to hydrolysis by acetylcholinesterase, we studied vasodilator responses to brachial artery administration of acetylcholine alone and in the presence of the acetylcholinesterase inhibitor edrophonium.

2. Vasodilator responses to constant-rate brachial artery infusions of acetylcholine were biphasic, with an initial peak response fading over 2 min to a plateau. Fade [(peak—plateau)/peak × 100%] was dose dependent (P < 0.02), ranging from 43 ± 7% (mean ± SEM) at low dose (16 nmol/min) to 9 ± 8% at high dose (83 nmol/min).

3. Edrophonium (0.5 μmol/min intra-arterially) alone produced no change in forearm blood flow but increased blood flow responses to acetylcholine (P < 0.01), causing an approximately 10-fold reduction in the dose required to increase plateau blood flow by 10 ml min−1 100 ml−1.

4. Responses to low doses of acetylcholine alone (16 and 41 nmol/min) faded more (P < 0.01) than those to doses of acetylcholine with edrophonium chosen to produce similar plateau blood flows. Responses to acetylcholine (41 nmol/min) also faded more (P < 0.01) than those to methacholine (5 nmol/min), producing matched plateau flows.

5. Peak and plateau responses to acetylcholine (41 nmol/min) were reduced (P < 0.01) by similar amounts (47 ± 15% and 37 ± 13% respectively, P = 0.39) by coinfusion of l-NMMA (4 μmol/min). l-NMMA inhibited responses to acetylcholine more than matched responses to acetylcholine with edrophonium (P < 0.01).

6. These results suggest that the actions of acetylcholine in human forearm resistance vessels are mediated both through an l-NMMA-sensitive pathway (l-arginine/nitric oxide pathway) that exhibits biphasic characteristics and through an l-NMMA-resistant pathway. The l-NMMA-resistant pathway is selectively potentiated by edrophonium. Inhibition of acetylcholinesterase by edrophonium may increase concentrations of acetylcholine deep to the endothelium and favour NO-independent actions on smooth muscle or sensory nerve endings mediating vasodilatation.
Serum and Platelet-Derived Growth Factor-Induced Expression of Vascular Permeability Factor Mrna by Human Vascular Smooth Muscle Cells In Vitro
Authors: Williams Bryan , Quinn-Baker Anne , Gallacher Barbara
Published: August 2015

1. Endothelial dysfunction and vascular smooth muscle cell (VSMC) proliferation are key events in the pathogenesis of atherosclerosis. Vascular permeability factor (VPF), an endothelial-cell-specific multifunctional cytokine, was recently described, and has the potential to contribute to the development of endothelial dysfunction. The present study determines whether cultured human VSMCs express mRNA for VPF and whether VPF mRNA expression is influenced by human VSMC proliferation.

2. A 204 bp cDNA fragment, specific for all known variants of VPF mRNA, was cloned and used to demonstrate that human VSMCs express abundant quantities of VPF mRNA, whereas human endothelial cells do not. VPF mRNA levels were markedly diminished in non-proliferating human VSMCs. In contrast, when human VSMCs were stimulated to proliferate by exposure to serum, there was a rapid 6.6-fold increase (<P < 0.01 versus time 0 h) in VPF mRNA expression, which was maximal at 3 h and persisted beyond 24 h. The magnitude of the VPF mRNA response in human VSMCs was dependent on the serum concentration.

3. Platelet-derived growth factor also increased VPF mRNA expression by human VSMCs, thus confirming that recognized growth factors for VSMCs also potently influence the VPF gene.

4. In conclusion, VPF mRNA is expressed by human VSMCs, the magnitude of VPF expression being temporally related to the proliferation of human VSMCs and the potency of the growth-promoting stimulus. We propose that VPF produced by proliferating human VSMCs could act as a paracrine hormone to powerfully influence the permeability and growth of the overlying vascular endothelium. We thus report a novel mechanism whereby the stimulation of VSMC proliferation could potently and directly contribute to the development of endothelial dysfunction and the pathogenesis of vascular disease.
Effects of Inhaled Nebulized Morphine on Ventilation and Breathlessness during Exercise in Healthy Man
Authors: Masood A. R. , Subhan M. M. F. , Reed J. W. , Thomas S. H. L.
Published: August 2015

1. Nebulized inhaled morphine has been reported to increase exercise endurance in patients with chronic lung disease and to relieve dyspnoea in patients with malignant disease. Potential mechanisms include a central effect occurring after systemic drug absorption or a local action mediated by receptors in the lung.

2. The ventilatory effects of nebulized morphine (10 and 25 mg) were therefore compared with those of intravenous morphine (1.0 and 2.5 mg) and placebo in a double-blind study involving 12 young healthy males. Submaximal cycle ergometry with respiratory gas analysis was performed 15 min after drug administration and breathlessness assessed using a linear visual analogue scale.

3. Neither dose of inhaled morphine had statistically significant effects on spirometry, heart rate, ventilation, respiratory gases or breathlessness at any level of exercise. The slopes and intercepts of the lines relating ventilation to breathlessness were also unaffected.

4. Intravenous morphine 2.5 mg reduced breathlessness slightly at the highest equivalent workload [mean (least significant range) 33 mm (26–40 mm)] compared with placebo [41 mm (34–48 mm), P < 0.05] but had no other significant effects.

5. These results do not support the hypothesis that intrapulmonary opiate receptors modulate the sensation of breathlessness in healthy man. The possibility that inhaled morphine may affect breathlessness caused by other factors, such as disease, has not been excluded.
Effects of Sodium Status on the Venous Response to Noradrenaline Infusion in Pre-Ascitic Cirrhosis
Authors: Wong Florence , Bomzon Arieh , Logan Alexander , Blendis Laurence
Published: August 2015

1. This study assesses the effects of sodium status on venous responsiveness to noradrenaline and the neurohumoral profile in pre-ascitic cirrhotic patients. Eight cirrhotic patients and ten control subjects were studied after both a low (20 mmol/day) and a high (200 mmol/day) sodium diet. Venous responsiveness to increasing doses of noradrenaline in a dorsal hand vein and various plasma hormone levels were measured. Maximal response (Rmax.) and the dose of noradrenaline that yielded 50% of Rmax (ED50) were then calculated.

2. A significantly smaller dorsal hand vein diameter was observed in the control subjects on a low sodium (2.23 ± 0.14 mm) compared with a high sodium (2.57 ± 0.15 mm; P = 0.04) diet, but not in the cirrhotic patients. Rmax. was not significantly different in either group on both diets. With low sodium intake, ED50 was similar in the two groups. However, on high sodium intake, control subjects had a significantly higher ED50 (34.4 ± 7.4 ng/min) than the cirrhotic patients (5.03 ± 0.86 ng/min; P < 0.003). Plasma noradrenaline in the control subjects fell significantly with the change from a low (1.29 ± 0.11 nmol/l) to a high (0.68 ± 0.09 nmol/l; P < 0.001) sodium diet, but remained elevated in the cirrhotic patients. Cirrhotic patients had significantly higher atrial natriuretic factor levels and lower plasma renin activity than the control subjects on both diets.

3. In conclusion, pre-ascitic cirrhotic patients show no evidence of venodilatation. Their sympathetic nervous activity is not suppressible by volume expansion. Relative hyper-responsiveness of the peripheral venous circulation to adrenergic stimulation with high sodium intake is present.
Effect of Blockade of Nitric Oxide Synthesis on the Renin Secretory Response to Frusemide in Conscious Rabbits
Authors: Reid Ian A. , Chou Lance
Published: August 2015

1. The enzyme nitric oxide synthase is present in the macula densa and may participate in the control of renin secretion by the adjacent juxtaglomerular cells. In the present study, we investigated the effect of inhibiting nitric oxide synthase on the renin secretory response to frusemide, which stimulates renin secretion by blocking Na+-K+-2Cl− co-transport in the macula densa.

2. Injection of frusemide in 12 conscious rabbits elicited a transient increase in mean arterial pressure from 84 ± 2 to 92 ± 3 mmHg at 5 min (P < 0.01) and a sustained increase in heart rate from 246 ± 6 to 281 ± 10 beats/min at 45 min (P < 0.01). Plasma renin activity increased from 8.0 ± 1.2 to 14.3 ± 1.8, 12.4 ± 1.6 and 11.6 ± 1.5 pmol 2 h−1 ml−1 at 15, 30 and 45 min respectively (P < 0.01). There were no changes in plasma sodium and potassium concentrations or osmolality.

3. Inhibition of nitric oxide synthase with NG-nitro-l-arginine methyl ester increased mean arterial pressure by 9 mmHg, decreased heart rate and plasma renin activity, and markedly suppressed the renin response to frusemide (from 4.6 ± 0.7 to 7.6 ± 1.7, 4.7 ± 1.0 and 4.6 ± 0.7 pmol 2 h−1 ml−1 at 15, 30 and 45 min respectively). By contrast, infusion of an equipressor dose of phenylephrine did not suppress the renin response to frusemide.

4. Histochemical studies with the NADPH diaphorase technique confirmed the presence of nitric oxide synthase in the macula densa, and suggested that enzyme activity is increased by treatment with frusemide.

5. These results are consistent with a role for the l-arginine—nitric oxide pathway in the modulation of renin secretion by the macula densa.
Intracranial Pressure at High Altitude and Acute Mountain Sickness
Authors: Wright A. D. , Imray C. H. E. , Morrissey M. S. C. , Marchbanks R. J. , Bradwell A. R.
Published: August 2015

1. Raised intracranial pressure has been noted in severe forms of acute mountain sickness and high-altitude cerebral oedema, but the role of intracranial pressure in the pathogenesis of mild to moderate acute mountain sickness is unknown.

2. Serial measurements of intracranial pressure were made indirectly by assessing changes in tympanic membrane displacement in 24 healthy subjects on rapid ascent to 5200 m.

3. Acute hypoxia at 3440 m was associated with a rise in intracranial pressure, but no difference was found in pressure changes at 4120 or 5200 m in subjects with or without symptoms of acute mountain sickness.

4. Raised intracranial pressure, though temporarily associated with acute hypoxia, is not a feature of acute mountain sickness with mild or moderate symptoms.
Effects of Endopeptidase 24.11 Inhibition on Plasma and Tissue Concentrations of Vasoactive Intestinal Peptide
Authors: Duggan K. A. , Jones D. M. , Ye V. Z. C. , Davis R. E. , MacDonald G. J.
Published: August 2015

1. In this study, we sought to determine the effect of endopeptidase 24.11 inhibition on the rate of metabolism of vasoactive intestinal peptide. The effect of such inhibition on the concentration of vasoactive intestinal peptide in two tissues was also investigated.

2. Male Sprague—Dawley rats were given the endopeptidase 24.11 blocker UK77,568 (10 mg/kg) or vehicle as a single intravenous injection or as a daily injection for 4 days. Two hours after the final or single injection, the rats were anaesthetized and blood was sampled to determine plasma concentrations of vasoactive intestinal peptide and angiotensin II. The hearts and kidneys were harvested and snap-frozen in liquid nitrogen. The plasma and tissue concentrations of vasoactive intestinal peptide and the plasma concentration of angiotensin II were determined by radioimmunoassay. In a separate group of experiments, male Sprague—Dawley rats were anaesthetized and carotid and jugular catheters were inserted. One hour after intravenous administration of UK77,568 or vehicle, an infusion of vasoactive intestinal peptide (10 pmol min−1 kg−1) was commenced via the jugular catheter. Blood was sampled to determine the vasoactive intestinal peptide concentration 1 h after commencing the vasoactive intestinal peptide infusion to calculate the metabolic clearance rate.

3. Plasma vasoactive intestinal peptide increased after acute (P < 0.05) but not chronic administration of UK77,568, while the concentration of vasoactive intestinal peptide in the heart increased after chronic administration (P < 0.0005). The concentration of vasoactive intestinal peptide in the kidney was unchanged after both acute and chronic endopeptidase 24.11 blockade. Plasma angiotensin II decreased significantly in the chronic group (P < 0.05). The metabolic clearance rate of vasoactive intestinal peptide decreased significantly after UK77,568 administration (P < 0.05).

4. These studies add to the existing indirect evidence that endopeptidase 24.11 may metabolize vasoactive intestinal peptide in addition to a number of other hormones.
Whole-Body Protein Turnover and Hepatic Protein Synthesis Are Increased by Vaccination in Man
Authors: Cayol M. , Tauveron I. , Rambourdin F. , Prugnaud J. , Gachon P. , Thieblot P. , Grizard J. , Obled C.
Published: August 2015

1. The ability of diphtheria—tetanus—poliomyelitis—typhoid vaccination to induce modifications in protein metabolism was investigated in post-absorptive healthy humans.

2. Seven subjects were studied before and 2 days after vaccination. They underwent an intravenous primed constant infusion of l-[1-13C]leucine for 4 h. Plasma protein concentrations, whole-body amino acid fluxes and acute-phase protein synthesis were determined.

3. Plasma concentrations of fibrinogen, α1-acid glycoprotein, haptoglobin and α1-antitrypsin were significantly elevated 2 days after vaccination (P < 0.05). Leucine oxidation was unaffected but whole-body protein synthesis and breakdown were both increased (P < 0.05), by 25 and 16% respectively, in subjects who had an elevated body temperature (n = 5). Albumin synthesis was unchanged, but hepatic synthesis of fibrinogen was 56% higher after vaccination.

4. The present investigation indicates that diphtheria—tetanus—poliomyelitis—typhoid vaccination could induce a sustained acute-phase reaction. Moreover, protein metabolism appeared to be extremely sensitive to a mild stress since leucine kinetics and fibrinogen synthesis were affected. Therefore, diphtheria—tetanus—poliomyelitis—typhoid vaccination might represent an attractive model for studying the inflammatory process in humans.
Effects of Weight Reduction on the Regulation of Lipolysis in Adipocytes of Women with Upper-Body Obesity
Authors: Reynisdottir Signy , Langin Dominique , Carlström Kjell , Holm Cecilia , Rössner Stephan , Arner Peter
Published: August 2015

1. The regulation of lipolysis was studied in 14 upper-body obese women aged 26–55 years. Isolated subcutaneous adipocytes from the abdominal region were examined before and after an 8 to 12-week-long weight reduction programme, during which the mean body mass index (kg/m2) of the group was reduced from 36.4 ± 0.9 to 30.3 ± 1.0.

2. Fat cell volume was reduced from 891 ± 39 to 655 ± 45 pl. The sensitivity to noradrenaline stimulation of lipolysis in vitro increased fivefold after weight reduction. A corresponding increase in sensitivity was found with the β2-selective adrenoceptor agonist terbutaline. However, the number of β2-adrenoceptor binding sites as assessed by radioligand binding with 125I-labelled cyanopindolol was not changed. No changes were observed when dobutamine (a β1-selective adrenoceptor agonist) and clonidine (an α2-adrenoceptor agonist) were used.

3. The basal lipolysis rates decreased by about 50% after weight reduction and the maximum enzyme activity of hormone-sensitive lipase was also reduced by almost 50%.

4. Plasma concentrations of insulin, noradrenaline and total testosterone decreased and sex hormone-binding globulin increased after weight reduction. Calculated apparent free testosterone levels decreased by more than 40% after weight reduction.

5. In conclusion, weight reduction leads to increased efficiency of adipocyte lipolysis with decreased resting lipolysis rate but increased sensitivity to stimulation by catecholamines, which may be attributed to a decreased activity of hormone-sensitive lipase and an increased sensitivity of β2-adrenoceptors. Changes in circulating levels of catecholamines, insulin and testosterone may play a role in these modifications of adipocyte function. The increased lipolytic efficiency may be of importance for amelioration of the metabolic complications of obesity that are observed after weight reduction.
Calcitonin Gene-Related Peptide as An Endogenous Vasodilator: Immunoblockade Studies in Vivo with an Anti-Calcitonin Gene-Related Peptide Monoclonal Antibody and Its Fab′ Fragment
Authors: Tan Keith K. C. , Brown Morris J. , Hargreaves Richard J. , Shepheard Sara L. , Cook Deborah A. , Hill Raymond G.
Published: August 2015

1. Calcitonin gene-related peptide (CGRP) is localized in perivascular sensory neurons and is a potent vasodilator. We investigated the utility of immunoblockade as an in vivo technique for probing the role of CGRP as an endogenous vasodilator.

2. The effects of an anti-CGRP monoclonal antibody (MAb; coded C4.19) and its Fab′ fragment on CGRP-induced changes in blood pressure and skin blood flow were studied in pentobarbitone-anaesthetized rats. Antidromic skin vasodilatation in the rat hind paw was measured by laser Doppler fluxmetry.

3. The dose—response relationship for the hypotensive effect of intravenous rat αCGRP (rαCGRP) was similarly shifted rightward by MAb C4.19 IgG (1 mg/rat; intravenously) and Fab′ fragment (2 mg/rat; intravenously). The C-terminal fragment of human αCGRP (hαCGRP8–37) also blocked the hypotensive effect of rαCGRP.

4. MAb C4.19 Fab′ fragment (2 mg/rat; intravenously) and hαCGRP8–37 (100 nmol/kg; intravenously), but not MAb C4.19 IgG (up to 3 mg/rat; intravenously) or normal mouse Fab′ fragment (2 mg/rat; intravenously), blocked the increased skin blood flow response to antidromic stimulation of the saphenous nerve.

5. The mean percentage changes in skin blood flow parameters due to MAb C4.19 Fab′ fragment were significantly different from those due to normal mouse Fab′ fragment (unpaired t-test; P < 0.05) but not from those due to hαCGRP8–37.

6. The results demonstrate the pharmacokinetic advantage of Fab′ fragment over IgG for immunoblockade studies in vivo and support the role of CGRP in mediating skin vasodilatation.
Differential Effects of a Novel Non-Peptide Endothelin Receptor Antagonist (Bosentan) in Rat Liver and Vasculature
Authors: Phillips Paddy A. , Risvanis John , Aldred Kathryn , Burrell Louise M. , Bartholomeusz Briony
Published: August 2015

1. We studied the effects of the non-selective, non-peptide, orally active endothelin (ET) receptor antagonist bosentan (Ro 47–0203) on rat hepatic and mesenteric vascular membrane 125I-ET-1 binding characteristics in vitro and ex vivo (after bosentan by gavage in vivo).

2. Bosentan caused a concentration-dependent competitive inhibition of 125I-ET-1 binding to female rat mesenteric vascular (predominantly ETA receptors) and hepatic (predominantly ETB receptors) membranes in vitro and ex viva

3. The time course of the inhibition of binding ex vivo after administration of bosentan in vivo was 1–4 h for mesenteric vascular (predominantly ETA receptors) binding and 1–16 h for hepatic (predominantly ETB receptors) binding.

4. The time course of displacement of 125I-ET-1 binding from mesenteric vascular and hepatic membranes by bosentan in vitro was similar.

5. Since bosentan is significantly excreted by the liver, the prolonged hepatic 125I-ET-1 binding by bosentan presumably represents hepatic accumulation of bosentan, which may have implications for bosentan antagonizing the actions of ET in the liver.
Intravenous Magnesium Sulphate Relieves Migraine Attacks in Patients with Low Serum Ionized Magnesium Levels: A Pilot Study
Authors: Mauskop Alexander , Altura Bella T. , Cracco Roger Q. , Altura Burton M.
Published: August 2015

1. We tested the hypothesis that patients with an acute attack of migraine headache and low serum levels (< 0.54 mmol/l) of ionized magnesium are more likely to respond to an intravenous infusion of magnesium sulphate (MgSO4) than patients with higher serum ionized magnesium levels.

2. Serum ionized magnesium levels were drawn immediately before infusion of 1 g of MgSO4 in 40 consecutive patients with an acute migraine headache.

3. Pain reduction of 50% or more as measured on a headache intensity verbal scale of 1 to 10, occurred within 15 min of infusion in 35 patients. In 21 patients, at least this degree of improvement or complete relief persisted for 24 h or more. Pain relief lasted at least 24 h in 18 of 21 patients (86%) with serum ionized magnesium levels below 0.54 mmol/l, and in 3 of 19 patients (16%) with ionized magnesium levels at or above 0.54 mmol/l (P < 0.001). Mean ionized magnesium levels in patients with relief lasting for at least 24 h were significantly lower than in patients with no relief or brief relief (P < 0.01).

4. Measurement of serum ionized magnesium levels may be useful in identifying patients with migraine headaches who may respond to an intravenous infusion of MgSO4.
Characteristics of the Sodium/Hydrogen Exchange in Non-Insulin-Dependent Diabetic Patients with Microalbuminuria and Hypertension
Authors: Zaidi K. Fatima , Yudkin John S.
Published: August 2015

1. An association has been described between increased sodium/hydrogen (Na+/H+) exchange rates in various cells and microalbuminuria in type 1 diabetic patients. However, no data are available on the Na+/H+ exchange rate in type 2 diabetes and its association with urinary albumin excretion rates.

2. We have estimated platelet sodium-activated proton efflux (Na+/H+ exchange rate), based on a fluorimetric method, in 43 type 2 diabetic patients, of whom 29 were normoalbuminuric and 14 microalbuminuric, and in 10 non-diabetic control subjects. The factors measured were: buffering power, Km for external Na+ and Vmax. of the exchange rate.

3. There were no differences in Km and Vmax. for the Na+/H+ exchange between the subject groups. However, the 14 patients with microalbuminuria showed a significantly lower buffering capacity [17.2 (4.6) mmol l−1 pH unit−1] [mean (SD)] compared with non-diabetic control subjects [21.1 (1.9) mmol l−1 pH unit−1] (P = 0.020).

4. Among the 43 diabetic patients, 16 were hypertensive. These patients had similar characteristics of Na+/H+ exchange to the 27 normotensive diabetic patients and the control subjects.

5. There was no correlation between exchange rate variables of type 2 diabetic patients and fasting concentrations of insulin or albumin excretion rate.

6. We conclude that the platelets of microalbuminuric diabetic patients manifest a significantly lower buffering capacity. This lower buffering capacity may be due to abnormalities of other ion transport systems or to abnormalities in intermediary metabolism.
Effect of Angiotensin-Converting Enzyme Inhibitors on Resistance Artery Structure and Endothelium-Dependent Relaxation in Two-Kidney, One-Clip Goldblatt Hypertensive and Sham-Operated Rats
Authors: Bennett Michael A. , Thurston Herbert
Published: August 2015

1. This study was designed to examine the effect of angiotensin-converting enzyme inhibitors on resistance artery structure and endothelium-dependent relaxation in Goldblatt two-kidney, one-clip hypertensive rats. Four weeks after clipping, hypertensive and sham rats were treated with either perindopril (1 mg day−1 kg−1) or quinapril (3 or 30mg day−1 kg−1). After 6 weeks mesenteric resistance arteries were mounted in a myograph for measurements of vascular structure. The endothelium-dependent relaxation response to acetylcholine and bradykinin and the response to the nitric oxide donor sodium nitroprusside were recorded.

2. All treatment regimes lowered the blood pressure and reversed both cardiac and resistance artery hypertrophy. Two-kidney, one-clip rats treated with quinapril showed a dose-dependent reduction in media cross-sectional area and media to lumen ratio.

3. Hypertension of 10 weeks' duration was associated with an impaired endothelium-dependent relaxation response to acetylcholine and bradykinin. Treatment with perindopril and either dose of quinapril prevented the development of impaired endothelium-dependent relaxation but had no effect on the response to sodium nitroprusside. Treatment had no effect on endothelium-dependent relaxation in sham rats.

4. Angiotensin-converting enzyme inhibitor treatment is effective in normalizing blood pressure and cardiovascular structural changes. Angiotensin-converting enzyme inhibitor treatment prevented the development of impaired endothelium-dependent relaxation to both acetylcholine and bradykinin. The ability of angiotensin-converting enzyme inhibitors to reverse cardiovascular structural changes and prevent the development of abnormal endothelium-dependent relaxation may contribute to the overall effect of this type of antihypertensive drug.
Bed Rest Decreases Whole-Body Protein Turnover in Post-Absorptive Man
Authors: Bettany G. E. A. , Ang B. C. , Georgiannos S. N. , Halliday D. , Powell-Tuck J.
Published: August 2015

1. Whole-body protein turnover was measured using the [15N]glycine tracer technique in 10 post-absorptive healthy volunteers during normal daily activities and a period of bed rest.

2. Bed rest reduced whole-body protein turnover (25%), synthesis (26%) and breakdown (25%), but short-term urinary nitrogen excretion remained unchanged.
Unique Response of Human Arteries to Endothelin B Receptor Agonist and Antagonist
Authors: Liu James J. , Chen Joan R. , Buxton Brian F.
Published: August 2015

1. The role of the ETB receptor in human arteries has not been well studied because of the lack of specific ETB receptor antagonists. In the present studies the specific ETB receptor antagonist BQ-788 and the specific ETB agonist IRL-1620 were used to characterize the function of the ETB receptor in human radial arteries and internal mammary arteries.

2. The results showed that the ETB antagonist BQ-788 significantly inhibited endothelin-1-induced contraction in internal mammary arteries, but not in radial arteries. In internal mammary arteries, BQ-788 at a concentration of 10 μmol/l shifted the endothelin-1-induced concentration-dependent curve to the right by one order. By comparison, the ETA receptor antagonist BQ-610 at 1 μmol/l produced a much more potent inhibitory effect (three-order shifting) on endothelin-1-induced contraction in internal mammary arteries, and also potently inhibited the contraction in radial arteries.

3. The ETB agonist IRL-1620 caused a contraction in internal mammary arteries, but not in radial arteries, although the response of radial arteries to endothelin-1 was very strong. The contraction induced by IRL-1620 was weaker than that induced by endothelin-1; however, the maximal contraction to IRL-1620 was obtained at 3 nmol/l, which was lower than that with endothelin-1 (maximal contraction at 10 nmol/l).

4. In internal mammary arteries the contraction to endothelin-1 and IRL-1620 gradually changed to relaxation with high concentrations of endothelin-1 (from 30 nmol/l) and IRL-1620 (from 3 nmol/l), whereas it did not in radial arteries; suggesting that the ETB receptor on human arterial smooth muscle cells may mediate contraction at low agonist concentrations and relaxation at high agonist concentrations.

5. The ETB agonist IRL-1620, endothelin-1 and endothelin-3 did not cause endothelium-dependent relaxation in either precontracted radial arteries or internal mammary arteries, although endothelium-dependent relaxation was fully induced by acetylcholine in these two arterial preparations.

6. In conclusion, the present studies demonstrate that the responses of internal mammary arteries and radial arteries to an ETB antagonist and an ETB agonist are significantly different from those of animal vascular vessels, and also from each other. The ETB receptor may play only a minor role in endothelium-dependent relaxation of these human arteries. Endothelin-1-induced contraction is mediated by both the ETA (major) and the ETB (minor) receptors in internal mammary arteries, but only by the ETA receptor in radial arteries. These studies may help to determine therapeutic strategy.
Implications of Urinary Basic Fibroblast Growth Factor Excretion in Patients with Urothelial Carcinoma
Authors: Chow Nan-Haw , Chang Chih-Jen , Yeh Trai-Ming , Chan Shih-Huang , Tzai Tzong-Shin , Lin Johnny Shinn-Nan
Published: August 2015

1. Angiogenesis occurs in response to wounding, and is of vital importance for tumour growth and metastasis. Basic fibroblast growth factor, a well-known angiogenic factor, has been suggested to be a urine marker for urothelial carcinoma. However, the relevance of its detection has not been evaluated in a large number of patients.

2. Immunoassay of basic fibroblast growth factor was performed on urine samples from different aetiologies of urothelial disorder. Expression of basic fibroblast growth factor in the corresponding tumour was correlated with the urine level.

3. The excretion of basic fibroblast growth factor (ng/g creatinine) was significantly elevated in both inflammatory and neoplastic urological diseases compared with normal individuals (P < 0.05), while it was normalized in tumour-free subjects (P < 0.01). Receiver operating characteristic plotting revealed a sensitivity of 40% for tumour diagnosis at the cut-off point of 3.29 ng/g creatinine. The sensitivity of the test in predicting tumour recurrence was only 14%. The basic fibroblast growth factor level in urine showed a positive association with increasing age of cancer patients (P = 0.02) and with tumour grading (P = 0.05). However, no important relationship was observed regarding tumour stage, size, number, shape or degree of local inflammatory reaction (P > 0.01). Pairwise analysis of the basic fibroblast growth factor level in urine and its expression in corresponding tumours did not reveal a conspicuous correlation (r = −0.097, P = 0.43).

4. Our results suggested that estimation of urinary basic fibroblast growth factor cannot be satisfactory as a tumour marker. The measurement may represent one of the tissue responses to injury or the host—tumour interactions. A longitudinal study is required to elucidate the role of basic fibroblast growth factor in order to select the appropriate treatment strategy for urothelial carcinoma.
Effect of Hyperglycaemia on Arterial Pressure, Plasma Renin Activity and Renal Function in Early Diabetes
Authors: Miller Judith A. , Floras John S. , Zinman Bernard , Skorecki Karl L. , Logan Alexander G.
Published: August 2015

1. In insulin-dependent diabetes mellitus, hyperglycaemia has a profound effect on renal and systemic haemodynamic function. The mechanism for this is unknown.

2. We conducted a study in 11 males with insulin-dependent diabetes mellitus, within 6 years of diagnosis. We examined the neurohumoral, haemodynamic and renal variables during euglycaemia (4.0–6.0 mmol/l) and after a 12 h period of hyperglycaemia (8.5–10.5 mmol/l). Subjects were examined in a sodium-replete state during supine rest and during simulated orthostatic stress induced by lower body negative pressure at –15 mmHg.

3. Variations in glycaemia markedly influenced plasma renin activity, which was increased at baseline during hyperglycaemia (3.82 ± 0.66 pmol of angiotensin I h−1 ml−1 compared with 2.13 ± 033 pmol of angiotensin I h−1 ml−1 during euglycaemia, P = 0.009), and rose further during simulated orthostatic stress. Mean arterial pressure was also elevated during hyperglycaemia (89 ± 2 mmHg compared with 81 ± 3 mmHg during euglycaemia, P = 0.03), both at rest and during orthostatic stress.

4. The renal haemodynamic effects of hyperglycaemia included maintenance of glomerular filtration rate in the face of significant declines in renal blood flow, and a probable increase in filtration fraction (0.21 ± 0.01 compared with 0.18 ± 0.01 during euglycaemia, P = 0.06). The responses of mean arterial pressure and renal blood flow to simulated orthostatic stress were not affected by hyperglycaemia, but the forearm vascular response was significantly augmented.

5. These data suggest that sustained hyperglycaemia activates the renin—angiotensin system, thereby increasing systemic and renal vasomotor tone. Over time such changes may have deleterious microvascular consequences.
Plasma Lathosterol as a Screening Test for Bile Acid Malabsorption Due to Ileal Resection: Correlation with 75SeHCAT Test and Faecal Bile Acid Excretion
Authors: Färkkilä M. A. , Kairemo K. J. , Taavitsainen M. J. , Strandberg T. A. , Miettinen T. A.
Published: August 2015

1. Plasma lathosterol concentration, known to reflect cholesterol and bile acid synthesis, was evaluated as a screening test for bile acid malabsorption, comparing it with faecal bile acid measurements, SeHCAT test and Schilling test in 22 subjects of whom six were healthy controls and 16 had Crohn's disease with ileal resections of varying length.

2. Plasma lathosterols and other non-cholesterol sterols were determined by GLC. Faecal bile acids were measured by GLC, and SeHCAT retention times by gamma camera. The study subjects were divided into two groups according to the degree of bile acid malabsorption: controls (faecal bile acids<10 mg day−1 kg−1, n = 9) and bile acid malabsorption (faecal bile acids > 10 mg day−1 kg−1, n = 13).

3. Faecal bile acid excretion was 5.9 ± 1.0 mg day−1 kg−1 in control subjects and 45.7 ± 6.1 mg day−1 kg−1 in the bile acid malabsorption group. The biological half-life of 75SeHCAT (T½) was 95.6 ± 16.3 h and 14.1 ± 4.1 h, respectively. Plasma lathosterol levels were significantly elevated in patients with bile acid malabsorption (742 ± 84 μg/ml compared with 400 ± 59 μg/ml in control subjects) and correlated closely with faecal bile acid levels (r = 0.779, P<0.001), with 75SeHCAT T½ (r = −0.524, P<0.05) and with Schilling test (r = −0.591, P<0.05). Significant correlations were also obtained for Δ8-cholestenol with faecal bile acids (r = 0.784, P<0.001) and 75SeHCAT (r = −0.505, P<0.05). The biological half-life of SeHCAT correlated with faecal bile acid excretion (r = −0.702, P<0.01). Using mean + 2 SD of lathosterol (In μg/ml cholesterol) as a cut-off value and 10 mg day−1 kg−1 as the upper limit for faecal bile acid excretion, the test gives 100% sensitivity and 82% specificity for plasma lathosterol determination to detect bile acid malabsorption.

4. The results indicate that both the 75SeHCAT test and plasma lathosterol detect bile acid malabsorption in patients with ileal resections for Crohn's disease. However, plasma lathosterol is a simpler and less expensive method.
Spiral Laminar Flow in Vivo
Authors: Stonebridge P. A. , Hoskins P. R. , Allan P.L. , Belch J. F. F.
Published: August 2015

1. Blood flow patterns are poorly understood despite their impact on arterial disease. There have been few measurements in vivo of the three-dimensional blood flow patterns; we present the results of such studies using a new non-invasive in-vivo method of examining biplanar arterial blood flow patterns.

2. Multiple colour Doppler ultrasound directional velocity images were obtained at two different beam target angles from the artery in the plane perpendicular to its axis. Ensemble average images were constructed; the absolute velocity and direction were calculated by compounding the left and right averaged images. Simple directional, non-directional velocity and vector maps were constructed.

3. Flow patterns were sampled in 11 healthy male volunteers at four points of the pulse cycle; peak systole, systolic downswing, diastolic reverse flow and diastolic forward flow and at three sites; the right common and distal superficial femoral and the left common femoral arteries.

4. Stable rotational flow was observed in all subjects, the direction of rotation varying between sides and individuals.

5. There are theoretical advantages to spiral laminar blood flow; the forward-directed, rotationally induced stability and reduction of laterally directed forces may reduce turbulence in the tapering branching arterial tree and at stenoses and have a beneficial effect on mechanisms of endothelial damage and repair.
Assessment of Gentamicin—Induced Nephrotoxicity in Rats Treated with Low Doses of Ibuprofen and Diclofenac Sodium
Authors: Farag M. M. , Mikhail M. , Shehata R. , Abdel-Meguid E. , Abdel-Tawab S.
Published: August 2015

1. The effects of two non-steroidal anti-inflammatory drugs, ibuprofen (20 mg day−1 kg−1) and diclofenac sodium (2.5 mg day−1 kg−1), on the severity of gentamicin-induced nephrotoxicity were evaluated in rats.

2. Administration of gentamicin (100 mg day−1 kg−1) for 5 days resulted in a significant increase in renal cortical total phospholipids accompanied by a significant decrease in cortical Na+, K+-ATPase activity. These changes were associated with a significant decrease in body weight and increases in kidney weight, serum creatinine and urea nitrogen.

3. In rats treated simultaneously with both gentamicin and either ibuprofen or diclofenac sodium for 5 days, all the measured parameters of renal dysfunction were similar in magnitude to those observed in rats treated with gentamicin alone.

4. In contrast, rats treated with either ibuprofen or diclofenac sodium for 27 days and injected concurrently with gentamicin during the last 5 days of the treatment period had significantly higher kidney weight, lower renal cortical Na+, K+-ATPase activity and higher cortical phospholipid content, serum creatinine and urea nitrogen than did rats treated with gentamicin alone. A 27-day treatment with ibuprofen or diclofenac sodium alone resulted in no change in renal function.

5. These results demonstrate that gentamicin nephrotoxicity was potentiated after the long (27 days) but not after the short (5 days) period of treatment with ibuprofen and diclofenac sodium. Thus, prolonged administration of non-steroidal anti-inflammatory drugs should be considered as a risk factor that may increase the nephrotoxic potential of gentamicin.
Finger Arterial versus Intrabrachial Pressure and Continuous Cardiac output during Head-up Tilt Testing in Healthy Subjects
Authors: Jellema Wilbert T. , Imholz Ben P. M. , Van Goudoever Jeroen , Wesseling Karel H. , Van Lieshout Johannes J.
Published: August 2015

1. The aims of this study were to determine the clinical feasibility of continuous, non-invasive Finapres recordings as a replacement for intrabrachial pressure during a 30 min head-up tilt, and the reliability of continuous cardiac output computation by pulse contour analysis from the finger arterial versus the brachial waveform.

2. In eight healthy subjects a 30 min 70° passive head-up tilt was performed. Finger arterial (FINAP) and intrabrachial (IAP) pressures were measured simultaneously. Beat-to-beat changes in stroke volume were computed using a pulse contour algorithm.

3. Accuracy (the group-averaged FINAP—IAP difference) and precision (the SD of the difference) of Finapres measurements were 4 and 9 mmHg for systolic blood pressure, −5 and 9 mmHg for mean blood pressure and −5 and 9 mmHg for diastolic blood pressure.

4. The time course of the FINAP—IAP differences during head-up tilt showed a linear trend (P < 0.001 for all pressure levels). Averaged for the group, the difference increased 7 mmHg for mean blood pressure. The difference in stroke volume computed from FINAP and IAP was 0.3 ± 5% (mean ± SD), and independent of the duration of the tilt (P > 0.05). This difference did not change at low blood pressure levels (0.5 ± 6%).

5. The qualitative performance of the Finapres allows it to be used in the clinical setting as a monitor of sudden changes in blood pressure induced by a 30 min head-up tilt. Relative changes in stroke volume, as obtained by pulse contour analysis of the finger arterial waveform, closely follow intrabrachial values during long-duration head-up tilt and associated arterial hypotension.
Effects of Inhaled Nitric Oxide Compared with Aspirin on Platelet Function in Vivo in Healthy Subjects
Authors: Albert Johanna , Wallén N. Håkan , Bröijersén Anders , Frostell Claes , Hjemdahl Paul
Published: August 2015

1. Nitric oxide has platelet-stabilizing effects. Inhaled nitric oxide is used to treat pulmonary disorders, and may prolong bleeding times, suggesting that it has effects on haemostasis. We therefore examined if inhaled nitric oxide influences platelet function in vivo in healthy subjects.

2. Platelet aggregability (filtragometry ex vivo, which reflects aggregability in vivo), bleeding time and platelet secretion products and cGMP in plasma were studied during inhalation of two different doses of nitric oxide (30 and 80 p.p.m.; 15 min at each dose level; n = 19) and during prolonged (55 min; n = 18) inhalation of 30p.p.m. nitric oxide. For comparison, studies were also performed before and after ingestion of 640 mg aspirin in 13 of the healthy subjects.

3. Plasma cGMP increased dose dependently during nitric oxide inhalation, suggesting guanylate cyclase activation in vivo. Platelet aggregability was, however, little affected and platelet secretion was not attenuated by nitric oxide inhalation. Bleeding time tended to increase (by 16–33%), but was significantly increased only after prolonged inhalation of nitric oxide at 30 p.p.m.

4. Aspirin (640 mg orally) caused pronounced and significant prolongations of filtragometry readings and bleeding time. Thus, the methods used were able to reveal platelet stabilization.

5. We conclude that nitric oxide inhalation causes only mild, if any, attenuation of platelet function in healthy subjects with a normal endogenous nitric oxide production. The effects may be different in disease states.
Mechanism of the Impaired Natriuretic Response to Frusemide during Sodium Depletion: A Micropuncture Study in Rats
Authors: Shirley D. G. , Walter S. J. , Unwin R. J.
Published: August 2015

1. The nephron sites involved in the blunted natriuretic response to frusemide during sodium depletion were investigated using micropuncture techniques in anaesthetized rats.

2. Glomerular filtration rate was lower, and fractional sodium reabsorption in the proximal convoluted tubule higher, in sodium-depleted than in sodium-replete rats. Consequently, sodium delivery to the loop of Henle was reduced (by approximately 35%) in the sodium-depleted animals. Intravenous frusemide (2.5 mg h−1 kg−1; urinary water and electrolyte losses replaced) had no effect on glomerular filtration rate or proximal tubular sodium reabsorption in either group.

3. The inhibitory effect of intravenous frusemide on fractional sodium reabsorption in the nephron segments constituting the loop of Henle (measured by free-flow micropuncture) was attenuated during sodium depletion. However, when loops of Henle were microperfused at identical rates with artificial late proximal tubular fluid, no difference in the responses of sodium-depleted and sodium-replete rats to intraluminal frusemide (10−5 mol/l) could be detected.

4. In sodium-replete animals, the increased load of sodium delivered from the loop of Henle during frusemide administration resulted in a lowering of fractional sodium reabsorption in the distal tubule. In contrast, in sodium-depleted rats given frusemide, fractional distal sodium reabsorption tended to increase, so that values in the two groups of frusemide-treated animals were markedly different (0.30 ±0.04 versus 0.51 ±0.03).

5. It is concluded that the blunted natriuretic response to frusemide during sodium depletion results from at least three factors: a reduced sodium delivery to the loop of Henle; a reduced inhibitory effect of frusemide on fractional sodium reabsorption in the loop of Henle, which may be a consequence of the reduced sodium load; and enhanced fractional reabsorption of sodium in the distal tubule, which partially buffers the diuretic-induced increase in sodium delivery from the loop.
Relationship between Granulocyte Activation, Pulmonary Granulocyte Kinetics and Alveolar Permeability in Extrapulmonary Inflammatory Disease
Authors: Ussov W. Yu , Peters A. M. , Savill J. , Pusey C. D. , Gaskin G. , Hodgson H. J. , Goldman J. M. , Hughes J. M. B.
Published: August 2015

1. The aim of the study was to examine the relationship between granulocyte activation, pulmonary intravascular granulocyte transit, pulmonary extravascular granulocyte migration and lung injury in patients with systemic conditions (bone marrow transplant recipients, inflammatory bowel disease and systemic vasculitis) in which abnormalities of pulmonary granulocyte traffic have previously been reported.

2. A double 111In-99mTc granulocyte labelling technique was used for quantification of granulocyte kinetics in 23 patients, of whom five were control patients. The pulmonary vascular granulocyte pool was measured from dynamic data centred on the 99mTc signal and expressed as a percentage of the total blood granulocyte pool. Granulocyte migration was quantified on 24 h images using the 111In signal. Granulocyte activation was measured as the percentage of cells showing a change in shape. The clearance rate of an inhaled aerosol of 99mTc-diethylenetriaminepenta-acetic acid (DTPA) was used as a marker of lung injury.

3. Pulmonary granulocyte pool, migration, activation and aerosol clearance, although highly variable in the patient groups, were, in general, elevated compared with the controls.

4. Granulocyte activation correlated with pulmonary granulocyte pool (Rs = 0.72, n = 22, P <0.01), while the t1/2 of DTPA clearance correlated with migration (Rs = −0.84, n = 17, P < 0.01). Fifteen patients had an expanded pulmonary granulocyte pool, of whom six with no evidence of migration, had a normal DTPA clearance, while nine, who had an abnormal migration signal, had an accelerated DTPA clearance. The pulmonary granulocyte pool in these nine was significantly higher than in the six without a migration signal.

5. Activation of granulocytes results in delayed transit through the lung vasculature. With increasing margination, granulocytes migrate into the lung interstitium and injure the lung. An increased intravascular pool does not by itself lead to lung injury.
Effect of Almitrine on Ventilation and on Diaphragm and Geniohyoid Muscle Activity in the Rat
Authors: O'halloran Ken D. , Curran Aidan K. , Bradford Aidan
Published: August 2015

1. Ventilation was measured during normoxia, hypoxia and hypercapnia before and after administration of almitrine in conscious, unrestrained, tracheostomized rats with the superior laryngeal nerves intact or cut. In superior laryngeal nerve-intact animals breathing air, almitrine increased minute ventilation due to an increase in respiratory frequency with no change in tidal volume. In superior laryngeal nerve-sectioned animals, the minute ventilatory response to almitrine was reduced due to a reduced tidal volume component of the response. Almitrine increased the ventilatory response to hypercapnia in superior laryngeal nerve-intact but not in sectioned animals.

2. In anaesthetized, vagotomized rats breathing spontaneously through a low-cervical tracheostomy, diaphragm and geniohyoid electromyographic activities were recorded. Arterial blood pressure and rectal temperature were continuously monitored. A single dose of almitrine was administered intravenously. In all animals, the geniohyoid muscle had phasic inspiratory activity which slightly preceded diaphragm activity. Almitrine had no effect on respiratory frequency or inspiratory and expiratory duration but increased mean peak integrated diaphragm (+29.3 ±13.6%) and geniohyoid (+ 132.0 ±21.3%) muscle activity.

3. These results show that almitrine exerts part of its ventilatory effects through superior laryngeal nerve afferents. Almitrine preferentially excites upper airway compared with diaphragm muscle activity, suggesting a potential role in the alleviation of obstructive apnoea.