bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antiproteinuric Effect Predicts Renal Protection by Angiotensin-Converting Enzyme Inhibition in Rats with Established Adriamycin Nephrosis
Authors: Wapstra Frits H. , Van Goor Harry , Navis Gerjan , De Jong Paul E. , De Zeeuw Dick 
Published: August 2015

1. The mechanism of renal protection by angiotensin-converting enzyme inhibition is still the subject of debate. Inhibition of proteinuria might play a role. If so, a good antiproteinuric response to angiotensin-converting enzyme inhibition should predict subsequent protection against renal structural damage. This hypothesis has not been tested in models where treatment is started after the renal disease is well established, i.e. models that mimic the clinical situation.
2. We therefore investigated this hypothesis in 96 male Wistar rats with established adriamycin nephrosis. Reduction of proteinuria was achieved by lisinopril (0, 2, 5 and 10 mg day−1 kg−1) on two different sodium diets (03% and 0.05% NaCl). Therapy started 6 weeks after adriamycin (at stable proteinuria) and was continued for 6 weeks.
3. Lisinopril reduced blood pressure by 32 ± 4% and proteinuria by an average of 72 ± 7%, with stabilization after 2 weeks. Considerable interindividual differences in antiproteinuric response were found. Glomerulosclerosis score was reduced by 15 ± 5%. All the effects of angiotensin-converting enzyme inhibitors were enhanced by sodium depletion, but sodium depletion in itself did not affect blood pressure (124 ± 4 mmHg), proteinuria (664 ± 68 mg/day) or glomerulosclerosis score (30 ± 5%). Interestingly, the more proteinuria was reduced initially in an individual rat, the less sclerosis was found in the long term in that rat.
4. In conclusion, angiotensin-converting enzyme inhibition lowers proteinuria and prevents glomerulosclerosis in established adriamycin nephrosis. These effects are enhanced by sodium depletion. The individual short-term antiproteinuric effect predicts the protection against ultimate glomerular damage. This is consistent with the hypothesis that reduction of proteinuria is a mechanism by which angiotensin-converting enzyme inhibitors exert renoprotection.
α1-Adrenoceptors in Normal and Hyperalgesic Human Skin
Authors: Drummond Peter D. , Skipworth Shiarne , Finch Philip M. 
Published: August 2015

1. Evidence of an adrenergic component of cutaneous hyperalgesia has recently been obtained in animal models of painful peripheral neuropathy. These findings have prompted speculation that an increased density or sensitivity of peripheral α-adrenoceptors contributes to sensory abnormalities and chronic neuropathic pain in conditions such as reflex sympathetic dystrophy. However, it is not known whether α-adrenoceptors are present at the site of nociception, either in hyperalgesic or normal skin.
2. We used the selective radioligand 125I-hydroxyphenyl-ethyl-aminomethyl-tetralone (HEAT) to label α1-adrenoceptors, and quantitative autoradiography to assess the relative density of these receptors in skin samples from seven normal individuals and from the hyperalgesic and pain-free limbs of five patients with reflex sympathetic dystrophy. The distribution of autoradiographic grains over the epidermis and dermis was investigated in 10 μm serial transverse sections.
3. α1-Adrenoceptors were identified in the epidermis and dermal papillae of normal individuals, and in the hyperalgesic and pain-free skin of patients with reflex sympathetic dystrophy. The density of α1-adrenoceptors was greater in the epidermis and dermal papillae than further down in the dermis.
4. The mean density of α1-adrenoceptors was significantly greater in the hyperalgesic skin of patients than in the skin of normal individuals (35.4 grains/1000 μm2 compared with 15.5 grains/1000 μm2, P &gt; 0.01). The mean density of α1-adrenoceptors in the pain-free skin of patients (26.9 grains/1000 μm2) fell midway between receptor density in hyperalgesic skin and in the skin of normal individuals, and did not differ significantly from either.
5. Our findings indicate that α1-adrenoceptors are present in the epidermis, and suggest that their numbers may be increased in the hyperalgesic skin of patients with reflex sympathetic dystrophy. Further studies need to identify the dermal and epidermal cell types that express high densities of α1-adrenoceptors, and to investigate their normal function and role in neuropathic pain.
Effect of Methionine Loading on 5-Methyltetrahydrofolate, S-Adenosylmethionine and S-Adenosylhomocysteine in Plasma of Healthy Humans
Authors: Loehrer Franziska M. T. , Haefeli Walter E. , Angst Christian P. , Browne Garry , Frick Greta , Fowler Brian 
Published: August 2015

1. Elevated plasma homocysteine concentration, either in the fasting state or after methionine loading, is an independent risk factor for vascular disease in man. Methionine loading has been used to investigate impaired methionine metabolism, especially of the trans-sulphuration pathway, but most studies have focused on changes in homocysteine.
2. We investigated the effect of methionine excess on total plasma homocysteine, 5-methyltetrahydrofolate (which is the active form of folate in the remethylation of homocysteine to methionine), S-adenosylmethionine (the first metabolite of methionine) and S-adenosylhomocysteine (the demethylated product of S-adenosylmethionine) over 24 h in 12 healthy subjects.
3. As well as the expected increase in homocysteine (from 8.0 ± 1.3 to 32.6 ± 10.3 μmol/l, mean ± SD, P &gt; 0.001), S-adenosylmethionine showed a significant transient increase (from 37.9 ± 25.0 to 240.3 ± 109.2 nmol/l, P &gt; 0.001), which correlated well with homocysteine (r2 = 0.92, P &gt; 0.001). 5-Methyltetrahydrofolate values decreased significantly (from 23.2 ± 7.2 to 13.1 ± 2.9 nmol/l, P &gt; 0.01), and gradually returned to baseline levels after 24 h. No significant change over the time of measurement was found for S-adenosylhomocysteine.
4. The sequence of metabolic changes observed in this study strongly suggests that a change in either homocysteine or S-adenosylmethionine may cause a reduction in 5-methyltetrahydrofolate. This must be considered in evaluating the relationship between folate and homocysteine in vascular disease. The metabolic relationships illustrated in this study should be evaluated in the search for pathogenetic mechanisms of mild hyperhomocysteinaemia and vascular disease.
Poincaré Plot of Heart Rate Variability Allows Quantitative Display of Parasympathetic Nervous Activity in Humans
Authors: Kamen Peter Walter , Krum Henry , Tonkin Andrew Maxwell 
Published: August 2015

1. Time domain summary statistics and frequency domain parameters can be used to measure heart rate variability. More recently, qualitative methods including the Poincaré plot have been used to evaluate heart rate variability. The aim of this study was to validate a novel method of quantitative analysis of the Poincaré plot using conventional statistical techniques.
2. Beat-to-beat heart rate variability was measured over a relatively short period of time (10–20 min) in 12 healthy subjects aged between 20 and 40 years (mean 30 ± 7 years) during (i) supine rest, (ii) head-up tilt (sympathetic activation, parasympathetic nervous system activity withdrawal), (iii) intravenous infusion of atropine (parasympathetic nervous system activity withdrawal), and (iv) after overnight administration of low-dose transdermal scopolamine (parasympathetic nervous system augmentation).
3. The ‘width’ of the Poincaré plot, as quantified by SD delta R—R (the difference between successive R—R intervals), was determined at rest (median 48.9, quartile range 20 ms) and found to be significantly reduced during tilt (median 19.1, quartile range 13.7 ms, P &lt; 0.01) and atropine administration (median 7.1, quartile range 5.7 ms, P &lt; 0.01) and increased by scopolamine (median 79.3, quartile range 33 ms, P &lt; 0.01). Furthermore, log variance of delta R—R intervals correlated almost perfectly with log high-frequency (0.15–0.4 Hz) power (r = 0.99, P &lt; 0.01).
4. These findings strongly suggest that the ‘width’ of the Poincaré plot is a measure of parasympathetic nervous system activity. The Poincaré plot is therefore a quantitative visual tool which can be applied to the analysis of R—R interval data gathered over relatively short time periods.
Experimental Iron Deficiency in Rats: Mechanical and Electrophysiological Alterations in the Cardiac Muscle
Authors: Goldstein Dalit , Felzen Bella , Youdim Moussa , Lotan Rachel , Binah Ofer 
Published: August 2015

1. Our aim was to investigate the effect of experimental iron deficiency on cardiac functional properties. We recorded ventricular isometric twitch, action potentials and the L-type Ca2+ current in isolated ventricular myocytes from iron-deficient rats and control rats.
2. Twitch tension and maximal rates of tension activation and relaxation were reduced in iron-deficient compared with control rats, whereas twitch duration was prolonged. Isoproterenol (10−6 mol/l) augmented tension in iron-deficient rats (P &lt; 0.05), but only moderately affected control rats. In contrast, maximal rates of tension activation and relaxation were increased equally by isoproterenol in the two groups.
3. To determine the mechanism(s) responsible for the reduced mechanical function in iron-deficient rats, action potentials and the L-type Ca2+ current (with or without isoproterenol) were recorded in both groups.
4. The L-type Ca2+ current was smaller in ventricular myocytes from control rats than in those from iron-deficient rats; at a membrane potential of 0 mV, L-type Ca2+ current amplitudes were −1.44 ± 0.18 and −0.97 ± 0.07 nA in myocytes from control and iron-deficient rats respectively (P &lt; 0.05).
5. Action potential duration was markedly shortened in myocytes from iron-deficient compared with control rats; action potential duration at 50% repolarization was 12.0 ± 1.6 and 7.2 ± 1.4 ms in myocytes from control and iron-deficient rats respectively (P &lt; 0.01). These iron deficiency-induced electrophysiological alterations most probably contribute to the depressed mechanical function in iron-deficient rats.
6. The L-type Ca2+ current was augmented equally by isoproterenol in the two groups, suggesting that the enhanced inotropic responsiveness in iron-deficient rats was not due to an increased response of the L-type Ca2+ current.
7. These results may have an important implication for anaemic (iron-deficient) patients; the attenuation of their cardiac mechanical performance may be compensated by an increased reactivity to β-adrenergic stimulation.
Endothelin Peptides and Receptors in Human Kidney
Authors: Karet Fiona E. 
Published: August 2015

1. Animal kidneys are exquisitely sensitive to the vasoconstrictor and antinatriuretic effects of the endogenous vascular peptide endothelin. Animal studies have implicated endothelin in cyclosporin A and ischaemia-mediated renal damage.
2. In man, endothelin levels are raised in various disorders. Orally active endothelin antagonists are now being developed, but little was known of endothelin's role as a renal peptide in humans. These studies therefore aimed to characterize endothelin peptides and receptors ETA and ETB in human kidney, to direct potential therapeutic endeavours.
3. Ligand binding, immunocytochemical, radioimmunoassay and molecular biological studies were used to establish endothelin as a renal peptide in man.
4. The identification of species differences between man and rat directed further development of quantitative molecular biological methodology to permit analysis of endothelin receptors in human renal biopsies, and demonstrated perturbation of the system in the context of cyclosporin A therapy in renal transplantation.
Supernormal Left Ventricular Performance in Young Subjects with Mild Hypertension: An Alerting Response to the Echocardiographic Procedure?
Authors: Palatini Paolo , Visentin Pieralberto , Nicolosi Gianluigi , Mione Vincenzo , Stritoni Paolo , Canali Cristina , Mormino Paolo , Pessina Achille C. 
Published: August 2015

1. To assess the clinical significance of supernormal left ventricular systolic function in the initial phase of hypertension, 635 never-treated 18–45-year-old borderline to mild hypertensive subjects (477 males, 158 females) were studied. All subjects underwent echocardiography, 24 h ambulatory blood pressure monitoring and 24 h urine collection for catecholamine dosage.
2. Subjects whose left ventricular shortening-stress relationship was above the 95% confidence intervals of 50 normotensive subjects of similar age and sex distribution were defined as having supernormal function.
3. Age, duration of hypertension and left ventricular mass were similar in the hypertensive subjects with normal (85%) and supernormal (15%) ejective performance. Subjects with supernormal function showed higher office systolic blood pressure (P &lt; 0001), office heart rate (P = 0.03) and cardiac index (P &lt; 0001). Conversely, 24 h systolic blood pressure, 24 h heart rate and 24 h catecholamine output did not differ according to left ventricular function.
4. In conclusion, the greater white-coat effect and the normal baseline sympathetic tone exhibited by the patients with increased performance suggest that supernormal left ventricular pump function is only a marker of the alerting reaction elicited by the echocardiographic examination.
Neutral Endopeptidase Inhibition: Augmented Atrial and Brain Natriuretic Peptide, Haemodynamic and Natriuretic Responses in Ovine Heart Failure
Authors: Rademaker Miriam Tessa , Charles Christopher John , Espiner Eric Arnold , Nicholls Michael Gary , Richards Arthur Mark , Kosoglou Teddy 
Published: August 2015

1. Atrial and brain natriuretic peptide are both circulating hormones subject to degradation by neutral endopeptidase 24.11. Whereas endogenous levels of atrial natriuretic peptide are increased by neutral endopeptidase inhibition in most pathophysiological states, the effect on brain natriuretic peptide and the influence of cardiac status is less clear. To further evaluate the role of neutral endopeptidase 24.11, we directly compared the responses of atrial and brain natriuretic peptide, together with the effects on other vasoactive hormones, haemodynamics and renal indices, to a neutral endopeptidase inhibitor, SCH32615, and a vehicle control in eight conscious sheep before and during pacing-induced heart failure.
2. In normal animals, SCH32615 significantly increased concentrations of plasma atrial natriuretic peptide (22±5 pmol/l compared with 14±2 pmol/l in control, 1.6-fold increase) and brain natriuretic peptide (6.5±1.2 pmol/l compared with 4.1±0.7 pmol/l in control, 1.6-fold increase), whereas in heart failure, plasma levels of atrial natriuretic peptide (306±38 pmol/l compared with 187±25 pmol/l in control, 1.6-fold increase) and brain natriuretic peptide (93±11 pmol/l compared with 55 ± 9 pmol/l in control, 1.7-fold increase) were elevated to a significantly greater absolute, but proportionately similar, extent. In both normal and heart-failed animals, SCH32615 induced reductions in mean arterial pressure and left atrial pressure and increases in haematocrit, plasma cGMP and endogenous creatinine clearance. However, only in heart failure did neutral endopeptidase inhibition induce a significant and marked natriuresis (&gt; 10-fold increase) and diuresis (4-fold increase), together with suppression of renin activity and haemodynamic effects including decreased peripheral resistance and raised cardiac output.
3. In conclusion, neutral endopeptidase inhibition increases plasma concentrations of atrial and brain natriuretic peptide to a proportionately similar extent in both normal and heart-failed sheep. The striking natriuresis and diuresis and additional haemodynamic effects demonstrated in sheep with heart failure, where natriuretic peptide levels are elevated compared with normal sheep, supports the concept that neutral endopeptidase inhibition augments endogenous atrial and brain natriuretic peptide.
Effects of Mineral Composition of Drinking Water on Risk for Stone Formation and Bone Metabolism in Idiopathic Calcium Nephrolithiasis
Authors: Marangella Martino , Vitale Corrado , Petrarulo Michele , Rovera Lidia , Dutto Franca 
Published: August 2015

1. To assess whether the mineral content of drinking water influences both risk of stone formation and bone metabolism in idiopathic calcium nephrolithiasis, 21 patients were switched from their usual home diets to a 10 mmol calcium, low-oxalate, protein-controlled diet, supplemented with 21 of three different types of mineral water. Drinking water added 1, 6 and 20 mmol of calcium and 0.5, 10 and 50 mmol of bicarbonate respectively to the controlled diet.
2. The three controlled study periods lasted 1 month each and were separated by a 20 day washout interval. Blood and urine chemistries, including intact parathyroid hormone, calcitriol and two markers of bone resorption, were performed at the end of each study period. The stone-forming risk was assessed by calculating urine saturation with calcium oxalate (βCaOx), calcium phosphate (βbsh) and uric acid (βUA).
3. The addition of any mineral water produced the expected increase in urine output and was associated with similar decreases in βCaOx and βUA, whereas βbsh varied marginally. These equal decreases in βCaOx, however, resulted from peculiar changes in calcium, oxalate and citrate excretion during each study period. The increase in overall calcium intake due to different drinking water induced modest increases in calcium excretion, whereas oxalate excretion tended to decrease. The changes in oxalate excretion during any one study period compared with another were significantly related to those in calcium intake. Citrate excretion was significantly higher with the high-calcium, alkaline water.
4. Parathyroid hormone, calcitriol and markers of bone resorption increased when patients were changed from the high-calcium, alkaline to the low-calcium drinking water.
5. We suggest that overall calcium intake may be tailored by supplying calcium in drinking water. Adverse effects on bone turnover with low-calcium diets can be prevented by giving high-calcium, alkaline drinking water, and the stone-forming risk can be decreased as effectively as with low-calcium drinking water.
Phenotypic and Quantitative Changes in Mast Cells after Syngeneic Unilateral Lung Transplantation in the Rat
Authors: Buvry Annick , Garbarg Monique , Dimitriadou Violetta , Rouleau Agnès , Newlands George F. J. , Tavakoli Reza , Poaty Virginie , Lockhart Alain , Schwartz Jean-Charles , Frossard Nelly 
Published: August 2015

1. Lung transplantation causes a total interruption of the innervation and vascularization within the transplanted organ, followed by repair processes. This is frequently associated with bronchial hyper-responsiveness. A common feature of tissue repair is an increase in the number of mast cells. Three phenotypically distinct mast cell subsets, with respect to their protease content, have been identified in rat lung, and it is probable that mast cells of differing protease phenotype fulfil different functions.
2. We have compared the number, protease phenotype and distribution of mast cells in left lung from transplanted and control Lewis rats 1 month after syngeneic unilateral left lung transplantation, without interference of inflammation, graft rejection or of any treatment. Connective and mucosal-type mast cell phenotypes were characterized using antibodies directed against their specific rat mast cell proteases, RMCPI and RMCPII, respectively.
3. After transplantation, RMCPI and RMCPII tissue concentrations increased by 172% and 239%, respectively, compared with controls (13.1 ± 1.2 and 5.6±1.0 μg/g).
4. Localization of mast cell phenotypes was studied by immunohistochemistry after double immunostaining. The number of mast cells increased after transplantation: the increase in the number of RMCPI-immunoreactive mast cells (RMCPI+) was significant around bronchioles and arterioles, around large vessels and in the pleura. The number of RMCPII+ mast cells also significantly increased around bronchioles and arterioles, as well as in the smooth muscle layer of large airways. Some mast cells stained for the presence of both RMCPI and RMCPII, supporting the existence of co-expressing phenotype in rat lung. The number of mast cells of the RMCPI+ /H+ phenotype significantly increased around bronchioles and arterioles and in the pleura. Moreover, the distribution of the mast cell phenotypes was modified in the different areas after transplantation.
5. This indicates a local differentiation/maturation of mast cells after transplantation.
Stimulation of Colonic Mucin Synthesis by Corticosteroids and Nicotine
Authors: Finnie Ian A. , Campbell Barry J. , Taylor Barry A. , Milton Jeremy D. , Sadek Sherif K. , Yu Lu-Gang , Rhodes Jonathan M. 
Published: August 2015

1. We speculated that corticosteroids might cause beneficial stimulation of mucus synthesis, since this is a known action of carbenoxolone, itself a corticosteroid, and has also been proposed as a possible mechanism for the protective effect of smoking on ulcerative colitis. We have therefore compared the effects of corticosteroids including carbenoxolone, and nicotine on mucin synthesis, assessed by incorporation of N-[3H]acetylglucosamine into mucin by colonic epithelial biopsies in culture.
2. In histologically normal biopsies from the left colon, hydrocortisone and prednisolone caused a very marked concentration-dependent increase in mucin synthesis, with maximal effect (580 and 300% of control values respectively) at 6 μmol/l [P &lt; 0.001, n = 35 biopsies (seven patients)] and 1.5 μmol/l [P &lt; 0.001, n = 35 (seven patients)] respectively. The maximal effect of hydrocortisone was significantly greater than that of prednisolone (P &lt; 0.05). Carbenoxolone, 0.17 mmol/l, also increased mucin synthesis in the left colon by 242% [P &lt; 0.05, n =15 (three patients)]. In contrast, these corticosteroids caused only a small, non-significant increase in mucin synthesis in the histologically normal right colon; fludrocortisone, 2 and 20 μmol/l, and aldosterone, 0.1–10 μmol/l, had no effect. Nicotine significantly increased mucin synthesis (180–220% of control values) between 62.5 nmol/l and 6.25 μmol/l (P &lt; 0.05 at all concentrations) in both the right and left colon. In biopsies from the relatively uninvolved right colon of patients with ulcerative colitis, corticosteroids and nicotine caused relatively smaller increases in mucin synthesis.
3. The marked stimulation of mucin synthesis by corticosteroids suggests that this may account, at least in part, for their therapeutic effect in ulcerative colitis.