bluuebunny/crossref_metadata_2025 huggingface dataset:
Differential Regulation of Cyclo-Oxygenase-1 and Cyclo-Oxygenase-2 Gene Expression by Lipopolysaccharide Treatment in vivo in the Rat
Authors: Liu Shu Fang , Newton Robert , Evans Timothy W. , Barnes Peter J.
Published: August 2015

1. Prostaglandins are important regulatory mediators of cardiovascular and pulmonary functions which may become disordered in patients with sepsis. The mechanisms controlling their synthesis and release under these circumstances remain unclear. Cyclo-oxygenase (COX, prostaglandin G/H synthase) is a key enzyme in prostaglandin synthesis and has two isoforms (COX-1 and COX-2). COX-1 is constitutively expressed and is probably responsible for prostaglandin release under physiological conditions, whereas COX-2 is expressed at high levels upon induction.

2. We investigated the effect of lipopolysaccharide treatment in vivo on differential COX-1 and COX-2 mRNA expression in the rat.

3. The 2.8 kb COX-1 message was detected in all lungs and seven hearts of eight control rats. In lipopolysaccharide-treated animals, COX-1 expression was reduced by approximately 5-fold in lungs and 2-fold in hearts as quantified by densitometry. In parallel, a marked upregulation of COX-2 mRNA expression was observed. The 4.4 kb COX-2 transcript was absent or expressed at low level in control lungs and hearts, but was increased by approximately 7- and 12-fold in lipopolysaccharide-treated lungs and hearts respectively. Neither the down-regulation of COX-1 nor the upregulation of COX-2 mRNA induced by lipopolysaccharide was significantly affected by pretreatment with dexamethasone in lung and heart, although expression of inducible nitric oxide synthase, induced by lipopolysaccharide, was markedly inhibited in the same tissues.

4. The down-regulation of COX-1 and upregulation of COX-2 may contribute to the multi-organ failure seen in sepsis.
Failure of Thrombin Inhibition to Prevent Intracoronary Thrombosis in the Dog
Authors: Belcher Philip R. , Drake-Holland Angela J. , Hynd John W. , Noble Mark I. M.
Published: August 2015

1. Recurrent occlusion after thrombolysis may be caused by thrombin receptor-mediated platelet thrombosis occurring in a residual stenosis. To test the relative importance of the platelet thrombin receptor under conditions of high shear and endothelial damage (the Folts model of intracoronary thrombosis) we used the specific thrombin inhibitor recombinant hirudin.

2. A critical coronary artery stenosis overlying an area of crushed endothelium was used in a repeated measures study of eight open-chest anaesthetized dogs. In the control period, recurrent thrombosis occurred at an average rate (± SD) of 4.4 ± 1.4 ml/min2. Infusion of recombinant hirudin at 1.6 mg h−1 kg−1 abolished recurrent thrombosis in three dogs, but the thrombosis rate averaged 4.7 ± 2.9 ml/min2 in the remaining five animals.

3. Haematological measurements demonstrated the activity of recombinant hirudin: thrombin time rose from 13 ± 3 s to>165 s universally (P<0.01), partial thromboplastin time rose from 14 ± 2 s to 29 ± 10 s (P<0.01). Bleeding time rose from 2.3 ± 0.8 min to 4.7 ± 1.8 min (P<0.05).

4. It is concluded that specific thrombin inhibition, despite affecting coagulation, is relatively ineffective in preventing intracoronary thrombosis under conditions of high shear.
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 > 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 > 0.001), S-adenosylmethionine showed a significant transient increase (from 37.9 ± 25.0 to 240.3 ± 109.2 nmol/l, P > 0.001), which correlated well with homocysteine (r2 = 0.92, P > 0.001). 5-Methyltetrahydrofolate values decreased significantly (from 23.2 ± 7.2 to 13.1 ± 2.9 nmol/l, P > 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 < 0.01) and atropine administration (median 7.1, quartile range 5.7 ms, P < 0.01) and increased by scopolamine (median 79.3, quartile range 33 ms, P < 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 < 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 < 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 < 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 < 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 < 0001), office heart rate (P = 0.03) and cardiac index (P < 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 (> 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 < 0.001, n = 35 biopsies (seven patients)] and 1.5 μmol/l [P < 0.001, n = 35 (seven patients)] respectively. The maximal effect of hydrocortisone was significantly greater than that of prednisolone (P < 0.05). Carbenoxolone, 0.17 mmol/l, also increased mucin synthesis in the left colon by 242% [P < 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 < 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.
Effect of a Physiological Insulin Infusion on the Cardiovascular Responses to a High Fat Meal: Evidence Supporting a Role for Insulin in Modulating Postprandial Cardiovascular Homoeostasis in Man
Authors: Kearney M. T. , Cowley A. J. , Stubbs T. A. , MacDonald I. A.
Published: August 2015

1. While the haemodynamic adjustments occurring after meal ingestion and the different effects of meals of different composition on these changes are well established, the mechanisms underlying these changes are less clear. Insulin, which has been shown to be both a positive inotrope and to stimulate vasodilatation in the skeletal muscle vascular bed, may account for the different cardiac and regional haemodynamic responses to high fat and high carbohydrate meals.

2. This study assessed the effect of an insulin infusion reproducing the plasma insulin profile seen after a high carbohydrate meal on the cardiovascular and regional haemodynamic response to a high fat meal. All measurements were carried out non-invasively in nine healthy lean subjects (mean age 24.5 ± 1.3 years).

3. The high fat meal resulted in increases in cardiac output (0.7 ± 0.321/min, P < 0.001), heart rate (7.8 ± 2.1 beats/min, P < 0.001) and insulin (25.1 ± 4.2 m-units/l, P < 0.001), and a decline in systemic vascular resistance (−1.9 ± 0.9 units, P < 0.05) and superior mesenteric artery vascular resistance (− 45 ± 9 units, P < 0.01). After the high fat meal alone, calf vascular resistance and blood pressure did not change. After the high fat meal accompanied by insulin (peak insulin 86.1 ± 10.1 m-units/l) there were greater cardiac responses [(P < 0.001); cardiac output, 1.17 ± 0.361/min, and heart rate, 13.4 ± 2.1 beats-/min], and a larger fall in systemic vascular resistance and superior mesenteric artery vascular resistance. Unlike the high fat meal alone, the high fat meal with insulin was accompanied by a fall in calf vascular resistance (8.3 ± 3.3 units) and blood pressure (3.8 ± 1.6 mmHg).

4. The results of this study support a role for insulin in modulating postprandial cardiovascular homoeostasis; in particular, by its depressor action on skeletal muscle vasculature, insulin may in part contribute to the fall in blood pressure seen in the elderly, who have an inadequate cardiac response to the fall in systemic vascular resistance occurring after meal ingestion.
Effect of Sustained Inspiratory Loading on Respiratory Sensation and Co2 Responsiveness in Normal Humans
Authors: Clague J. E. , Carter J. , Pearson M. G. , Calverley P. M. A.
Published: August 2015

1. To examine the effects of sustained resistive loading on the relationship between inspiratory effort sensation and respiratory drive (P0.1) and to determine if the change in CO2 responsiveness after sustained loading is accompanied by altered effort perception, hypercapnic responses were measured before, immediately after and 15 min after sustained resistive loading in seven subjects (six men, one woman). Sustained resistive loading was set to exceed a diaphragm tension—time index of 0.2.

2. Mean time to task failure during sustained loading was 17.7 min (range 12.5–22.5 min). The mean inspiratory effort sensation score rose from 3.4 (SEM 0.8) to 8.1 (0.8), whereas P0.1 fell from 29.5 (3.6) to 18.1 (3.6)cmH2O.

3. Immediately after loading the slopes of the ventilatory and sensory responses to CO2 fell (ventilatory response: before loading 16.7 (2.4)1 min−1 kPa−1, immediately after loading 7.88 (2.18) 1 min−1 kPa−1; sensory response: before loading 1.95 (0.38)units/kPa; immediately after loading 1.12 (0.38) units/kPa; P < 0.05. Changes reverted to preloading levels by 15 min.

4. Sustained loading can lead to a dissociation between respiratory drive, as reflected by P0.1, and inspiratory effort sensation, and this disturbance can persist once the load is removed. Impaired sensory perception may be the primary determinant of the change in CO2 responsiveness seen after sustained resistive loading.
Normal Insulin Release during Sustained Hyperglycaemia in Hypokalaemic Periodic Paralysis: Role of the Potassium Channel Opener Pinacidil in Impaired Muscle Strength
Authors: Ligtenberg J. J. M. , Van Haeften T. W. , Van Der Kolk L. E. , Smit A. J. , Sluiter W. J. , Reitsma W. D. , Links T. P.
Published: August 2015

1. Hypokalaemic periodic paralysis is characterized by attacks of muscle weakness. Glucose, insulin and an abnormal regulation of ATP-sensitive potassium channels may be involved in these attacks. We studied the effect of hyperglycaemia and of the potassium channel opener pinacidil on insulin release and muscle strength in patients with hypokalaemic periodic paralysis.

2. Insulin release was assessed on two occasions in four patients with hypokalaemic periodic paralysis and in eight matched control subjects, with and without treatment with 25 mg pinacidil orally, during a hyperglycaemic glucose clamp at a blood glucose level of 10 mmol/l, in a placebo-controlled, double-blind study. Muscle strength was measured in the hypokalaemic periodic paralysis patients before and during hyperglycaemia using a handheld dynamometer.

3. During the clamp, the mean glucose concentration (10–180 min) in control subjects was 9.9 ± 0.07 and 10.0 ± 0.03 mmol/l with and without pinacidil respectively, and in patients with hypokalaemic periodic paralysis was 10.0 ± 0.04 and 10.1 ± 0.06 mmol/l respectively (not significantly different). In both groups, the areas under the insulin curve from 0 to 10 min (first-phase insulin release) and from 30 to 180 min (second phase) were not different on the pinacidil study day compared with on the placebo day. The areas under the insulin curve of the first and second phases also did not differ between control subjects and patients with hypokalaemic periodic paralysis (with or without pinacidil). The M/I ratio, a measure of insulin sensitivity, was not different in the two groups. On the placebo day, baseline muscle strength in patients with hypokalaemic periodic paralysis was 165 ± 16 N for the hip abductors and 168 ± 19 N for the knee flexors. During the period of hyperglycaemia on the placebo day, muscle strength did not decrease in either muscle group. On the pinacidil study day, an increase in muscle strength was found only in the two hypokalaemic periodic paralysis patients with the lowest mean muscle strength (<150 N) on the placebo day. The two hypokalaemic periodic paralysis patients with a mean muscle strength on the placebo day >150N showed no increase in muscle strength with pinacidil.

4. Insulin secretion and sensitivity were normal in patients with hypokalaemic periodic paralysis. Hyperglycaemia during hyperglycaemic clamping did not provoke paralytic attacks and did not result in a decrease in muscle strength. The potassium channel opener pinacidil had no effect on insulin secretion in hypokalaemic periodic paralysis patients or in normal subjects. Pinacidil may enhance muscle strength in those hypokalaemic periodic paralysis patients who suffer partial paralytic attacks.
Plasma and Urinary 8-iso-Prostane as An Indicator of Lipid Peroxidation in Pre-Eclampsia and Normal Pregnancy
Authors: Barden Anne , Beilin Lawrence J. , Ritchie Jackie , Croft Kevin D. , Walters Barry N. , Michael Constantine A.
Published: August 2015

1. This study was designed to seek evidence for excessive lipid peroxidation in pre-eclamptic women using 8-iso-prostane as a novel bioactive marker of lipid peroxidation in vivo. Plasma free, total and urinary 8-iso-prostane were measured in 20 women with proteinuric pre-eclampsia, and compared with 18 age- and gestation-matched pregnant control subjects, before delivery and at 6 weeks postpartum.

2. Plasma free 8-iso-prostane was significantly elevated in the pre-eclamptic women compared with control subjects before delivery, and fell to control levels post-partum. Conversely, levels in women with normal pregnancy rose post-partum

3. Total plasma 8-iso-prostane levels were not significantly elevated in pre-eclamptic women compared with control subjects during pregnancy, but fell significantly in the pre-eclamptic women postpartum, suggesting that they had relatively higher levels compared with their non-pregnant state.

4. Urinary 8-iso-prostane excretion was significantly lower in the pre-eclamptic women compared with control subjects during pregnancy, suggesting that renal clearance of 8-iso-prostane is impaired in pre-eclampsia.

5. Increased levels of plasma free 8-iso-prostane in pre-eclampsia could be due to an increase in lipid peroxidation, an increase in phospholipase A2 activity or a reduction in renal clearance of 8-iso-prostane, or a combination of all three. The potent direct and indirect vasoconstrictor actions of 8-iso-prostane may contribute to the pathogenesis of pre-eclampsia.
Vascular Hyporesponsiveness in Aortic Rings from Cirrhotic Rats: Role of Nitric Oxide and Endothelium
Authors: Oriíz M. Clara , Fortepiani Lourdes A. , Martínez Concha , Atucha Noemí M. , García-Estañ Joaquín
Published: August 2015

1. The role of nitric oxide as mediator of the vascular alterations present in different models of experimental liver cirrhosis is controversial. In the present study, we evaluated the role of nitric oxide and that of the endothelium in the response to phenylephrine and acetylcholine of isolated aortic rings from chronic bile duct-ligated (29 days) rats and their corresponding controls. Experiments were performed in rings with or without endothelium, in rings pretreated with N-ω-nitro-l-arginine methyl ester (10−4 mol/l) to inhibit nitric oxide synthesis and in rings pretreated with aminoguanidine (10−4 mol/l) to inhibit inducible nitric oxide synthesis.

2. Under basal conditions, the maximum absolute tension developed in response to cumulative addition of phenylephrine was significantly decreased in rings from bile duct-ligated animals (1.62 ± 0.06 g) compared with the control rings (2.15 ± 0.099). This hyporesponsiveness to phenylephrine of rings from bile duct-ligated animals was corrected after treatment with N-ω-nitro-l-arginine methyl ester and reduced, but not completely eliminated, in rings without endothelium. In contrast, aminoguanidine did not modify the lower response to phenylephrine rings from bile duct-ligated animals. ED50 values were not different between groups under any experimental conditions.

3. The endothelium-dependent vasodilatation to acetylcholine in phenylephrine-constricted rings was similar in both groups of animals, control and bile duct ligated, under all experimental conditions. N-ω-nitro-l-arginine methyl ester pretreatment and removal of the endothelium completely abolished the response to acetylcholine in cirrhotic and control rings.

4. These results demonstrate that in aortic rings from cirrhotic, bile duct-ligated rats, increased production of nitric oxide, mainly of endothelial origin, is responsible for the lower contractile response to phenylephrine. Our data, however, do not support the involvement of the inducible nitric oxide synthase isoform in this alteration. In contrast, endothelial vasodilatory response to acetylcholine is not altered in this model of cirrhosis, which indicates that not all mechanisms of nitric oxide release are abnormal.
Elevated Plasma Levels of Human Adrenomedullin in Cardiovascular, Respiratory, Hepatic and Renal Disorders
Authors: Cheung Bernard , Leung Raymond
Published: August 2015

1. Adrenomedullin is a potent vasodilating peptide first isolated from phaeochromocytoma and adrenal medulla but also found in the heart, lungs and kidneys. It may also be a paracrine factor because endothelial and smooth muscle cells synthesize adrenomedullin as well as express the receptors. Adrenomedullin induces vasorelaxation by activating adenylate cyclase and also by stimulating the release of nitric oxide.

2. We have developed a specific radioimmunoassay and measured the immunoreactivity of human adrenomedullin in the plasma of 58 male subjects: eight with essential hypertension, 12 with heart failure, 10 with ascites due to cirrhosis, 12 with chronic renal failure, four with hypoxia due to chronic obstructive pulmonary disease and 12 control subjects.

3. Plasma levels (mean ± SEM) in patients with essential hypertension (16.3 ± 1.9 pmol/l), congestive heart failure (17.5 ± 2.8 pmol/l) and renal failure (17.7 ± 2.5 pmol/l) were raised compared with control subjects (7.8 ± 1.4 pmol/l, P < 0.05), confirming previous reports.

4. In addition, we observed that plasma levels of adrenomedullin were significantly raised in patients with ascites due to liver cirrhosis (15.5 ± 1.9 pmol/l) and chronic obstructive pulmonary disease with hypoxia (20.0 ± 1.5 pmol/l).

5. We concluded that the plasma level of adrenomedullin is raised in a variety of diseases.
Comparative Bioactivity of Atrial and Brain Natriuretic Peptides in An Ovine Model of Heart Failure
Authors: Rademaker Miriam Tessa , Charles Christopher John , Espiner Eric Arnold , Frampton Christopher Miles , Nicholls Michael Gary , Richards Arthur Mark
Published: August 2015

1. Whereas many studies have detailed the effects of exogenous atrial natriuretic peptide (ANP) infusions in heart failure, and a limited number have examined the effects of brain natriuretic peptide (BNP), none have directly compared the bioactivity of similar doses of ANP and BNP under standard conditions of impaired cardiac function. We compared the hormonal, haemodynamic and renal effects of 3 h infusions of ANP, BNP and a vehicle control in eight sheep with pacing-induced heart failure (225 beats/min for 8–12 days).

2. Infusion of ANP and BNP increased plasma ANP (P < 0.001) (276 ± 27 versus control 142 ± 26 pmol/l) and BNP (P < 0.001) (257 ± 34 versus control 45 ± 5 pmol/l) respectively, in association with increased cyclic 3′,5′-guanosine monophosphate [control, 40 ± 6; ANP, 53 ± 6 (P < 0.05); BNP, 57 ± 7 nmol/l (P < 0.001)]. Metabolic clearance rate and half-life were similar for both peptides. Infusion of ANP and BNP similarly reduced mean arterial pressure [control, 73.0 ± 1.6; ANP, 67.6 ± 1.2 (P < 0.01); BNP, 65.7 ± 1.7 mmHg (P < 0.001)], left atrial pressure (both P < 0.05) (control, 22.0 ± 0.7; ANP, 19.9 ± 1.0; BNP, 19.8 ± 0.9 mmHg) and peripheral resistance [control, 50.3 ± 4.1 mmHg l−1 min−1; ANP, 46.0 ± 2.8 (P < 0.05); BNP, 43.8 ± 4.5 (P < 0.01)], and increased urine volume (2-3-fold, both P < 0.05), sodium excretion (> 10-fold, both P < 0.01) and haematocrit levels relative to control (both P < 0.05). Infused BNP tended to raise plasma ANP levels (by 28 pmol/l), while ANP increased plasma BNP (by 18 pmol/l). Plasma aldosterone was reduced by approximately 40% by both peptides (both P < 0.05).

3. In conclusion, ANP and BNP are both powerfully natriuretic, similarly suppress aldosterone and appear equipotent in reducing preload and after-load in this model of pacing-induced heart failure.
Evidence that Nitric Oxide Inhibits Steroidogenesis in Cultured Rat Granulosa Cells
Authors: Dave Shilpa , Farrance David P. , Whitehead Saffron A.
Published: August 2015

1. A few studies have shown that nitric oxide may exert cytotoxic and/or steroidogenic effects on cultured ovarian cells but the source of this factor within the ovary remains equivocal.

2. In this study we have investigated the effects of nitric oxide on progesterone secretion, cell viability and cell morphology of cultured rat granulosa/ lutein cells and examined whether granulosa cells are an important source of nitric oxide.

3. Only very low or undetectable levels of nitrites were measured in granulosa/lutein-cell-only cultures, although there was a small but significant increase in nitrite release observed in granulosa/lutein cells obtained from oestrous rats compared with those obtained from proestrous rats.

4. There was a concentration-dependent inhibition of progesterone synthesis in the presence of the nitric oxide donors sodium nitroprusside and S-nitroso-N-acetyl-penicillamine which corresponded with an increased concentration of nitrite accumulation in the culture medium.

5. High concentrations of nitrites were measured in the medium of granulosa/lutein cells co-cultured with peritoneal macrophages and progesterone synthesis was inhibited. This effect of the macrophages was partially reversed by inhibitors of nitric oxide synthesis, aminoguanidine, NG-methyl-l-arginine and NG-l-arginine-methyl-ester, and the reversal of inhibition was inversely proportional to the concentration of nitrites measured in the medium. Dose—response curves for the three drugs on the inhibition of nitrite accumulation in macrophage cultures were obtained.

6. The nitric oxide scavenger c-PTIO [2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide.potassium salt] partially reversed the effects of S-nitroso-N-acetyl-penicillamine and macrophages on progesterone synthesis in granulosa/ lutein cells.

7. With the exception of the high dose of sodium nitroprusside, there was no evidence that any of the drugs reduced cellular viability, as assessed by measurement of cellular dehydrogenases and Trypan Blue exclusion, although high concentrations of nitrite in the culture medium derived either from the nitric oxide donors or macrophages were associated with a loss of morphological luteinization. 8. Based on the available evidence, we suggest that nitric oxide can inhibit steroidogenesis and that in vivo the source of nitric oxide may be from macrophages, which invade the ovary during the periovulatory period, and/or from endothelial cells of ovarian blood vessels.
Could the A2A11 Human Leucocyte Antigen Locus Correlate with Maximal Aerobic Power?
Authors: Rodas GIL , Ercilla Guadalupe , Javierre Casimiro , Garrido Eduardo , Calvo MAR , Segura Ramon , Ventura Josep Li.
Published: August 2015

1. The power of the aerobic metabolic pathway correlates well with successful physical performance in endurance sports events. The ability to alter the pathway through training presents well-known limitations, and consequently a good genetic endowment is essential to participate in elite sporting activities.

2. In 32 subjects (16 healthy pairs of male twin sportsmen, 8 monozygotic and 8 dizygotic) zygosity was determined by means of the genetic analysis of human leucocyte antigen (HLA) system specificities at class I and II loci and other genetic variants. The subjects performed a progressive exercise test on a treadmill to ascertain the maximal oxygen uptake (V̇O2max), measured by an automatic breath-by-breath analyser. We have considered the relationship between the A, B and C loci of the HLA system and V̇O2max.

3. We found a high correlation between the presence of both HLA A2 and All and V̇O2max. In the A2A11 group (n = 6) we found a V̇O2max (mean ± SD) equal to 71 ± 4 ml min−1 kg−1. The group without this pair of alleles (n = 26) showed a much lower aerobic power (58 ±5 ml min−1 kg−1). Differences between the two groups were found to be largely significant (P < 0.001). It is noteworthy that in two pairs of dizygotic twins, the higher V̇O2max value corresponded to the twin with the A2A11 allele.

4. The very marked concordance between the presence of the A2A11 locus of the HLA system and the V̇O2max could be of great interest for the identification of outstanding performers.
Complementary and Non-Coincident Increases in Heart Rate Variability and Irregularity during Fetal Development
Authors: Fleisher Lee A. , Dipietro Janet A. , Johnson Timothy R. B. , Pincus Steven
Published: August 2015

1. Two distinct notions of variability have been defined to assess heart rate: deviation from a constant output (SD) and irregularity. One statistical measure of irregularity is approximate entropy, with greater irregularity corresponding to larger approximate entropy values. The specific aims of this investigation were to determine the manner in which SD and irregularity evolve during fetal development and whether this evolution is coincident or distinct.

2. Fetal heart rate was computed in 14 males and 17 females for 15 min of undisturbed recording using a fetal actocardiograph at 4 week intervals from 20 to 36 weeks gestation.

3. Mean heart rate decreased significantly with gestational ages (P < 0.05). SD increased significantly from 4.4+0.3 ms (SEM) at 20 weeks to 7.7±0.4 ms at 36 weeks (P < 0.05) and was similar between male and female fetuses (P = 0.57). Fixed approximate entropy increased significantly from 0.47 ±0.04 to 0.78 ±0.03, paralleling the change in SD (P < 0.01). Notably, normalized approximate entropy, which decorrelates SD from regularity, increased significantly with gestational age (P < 0.01) for males, while it remained relatively constant for females (P = 0.68). Approximate entropy was significantly lower at 20 weeks in males than females (P < 0.05); however, the values were similar by 28 weeks gestation.

4. Our results demonstrate that variability increases, and that irregularity increases, independently in male fetuses but not female fetuses, consistent with an increase in the coupling of emerging networks with gestational age. The present study demonstrates the complementary information obtained by analyses of both measures of variability and regularity. This reinforces a difference in gender-based development as noted in the separate context of fetal lung maturation.