bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of the Japanese herbal medicine ‘Inchinko-to’ (TJ-135) on concanavalin A-induced hepatitis in mice
Authors: YAMASHIKI Masayoshi , MASE Akihito , ARAI Ichiro , HUANG Xian-Xi , NOBORI Tsutomu , NISHIMURA Akira , SAKAGUCHI Seigo , INOUE Kyoichi
Published: August 2015

Inchinko-to (TJ-135) is a herbal medicine consisting of three kinds of crude drugs, and in Japan it is administered mainly to patients with cholestasis. The present study evaluated the effects of TJ-135 on concanavalin A (con A)-induced hepatitis in mice in vivo and con A-induced cytokine production in vitro. When mice were pretreated with oral TJ-135 for 1 week before intravenous con A injection, the activities of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) were significantly decreased 8 h after con A administration (-82%, -96% and -66% respectively). In histological investigations, sub-massive hepatic necrosis accompanying inflammatory cell infiltration was not observed in mice pretreated with TJ-135. Serum levels of interleukin-12 (IL-12), interferon-γ (IFN-γ) and IL-2 were significantly lower in mice pretreated with TJ-135 compared with controls, while IL-10 levels were higher in these mice. Intrasplenic IL-12 levels were significantly lower in mice pretreated with TJ-135, while intrasplenic IL-10 levels were higher in these mice. In vitro, IL-10 production by splenocytes was increased by the addition of TJ-135 to the culture medium, whereas the production of IL-12 and IFN-γ was inhibited. These results suggest that con A-induced hepatitis was ameliorated by pretreatment with TJ-135. With regard to the mechanism of these effects of TJ-135, we speculate that TJ-135 inhibits the production of inflammatory cytokine and enhances the production of anti-inflammatory cytokines. Therefore administration of TJ-135 may be useful in patients with severe acute hepatitis accompanying cholestasis or in those with autoimmune hepatitis.
Pharmacokinetics of retinyl palmitate and retinol after intramuscular retinyl palmitate administration in severe malaria
Authors: DAVIS Timothy M. E. , BINH Tran Quang , THU Le The Anh , ROSSI Ric , DANH Phan Thi , BARRETT P. Hugh R. , BEILBY John
Published: August 2015

Retinol (vitamin A alcohol) is an accepted adjunctive treatment in infections such as measles. There is also indirect evidence from in vitro, animal and human studies that retinol supplementation may be beneficial in severe malaria. There have, however, been no studies that have examined the pharmacokinetics of acute retinol supplementation in severe illness. To establish whether mobilization of intramuscular retinyl palmitate (RP) and its availability as retinol are adequate in complicated falciparum malaria, we administered a single dose of 400000 i.u. of RP to six Vietnamese adults with severe malaria. Another 28 patients were not given RP. All patients had blood samples taken over 96 h for RP and retinol assay using HPLC, and received conventional anti-malarial and supportive therapy. Admission serum retinol concentrations were below the lower limit of the reference range (< 1.0 µmol/l) in 74% of the 34 patients. In supplemented patients, analysis of serum RP between 0 and 96 h using a multi-compartmental model revealed a median (range) delay in mobilization of 6.9 h (0.7–15.1 h), a bioavailability of 55% (19–100%) and an elimination half-life of 13.5 h (4.2–23.7 h). The area under the serum retinol curve expressed as an absolute or percentage change from baseline was greater in supplemented than in unsupplemented patients (P < 0.05). The separation in median serum retinol concentrations in the two groups was maximal at 48 h. The model-derived retinol half-life [1.5 (0.7–15.8) h] suggested rapid uptake, metabolism and/or excretion. In conclusion, there is variable RP bioavailability in severe malaria, but a significant if delayed increase in serum retinol over that associated with recovery from the infection. In severe infections, RP supplementation appears simple, well tolerated and of potential benefit once anti-microbial and supportive therapy have been established.
Plasma bradykinin levels in human chronic congestive heart failure
Authors: CUGNO Massimo , AGOSTONI Piergiuseppe , BRUNNER Hans R. , GARDINALI Marco , AGOSTONI Angelo , NUSSBERGER Jürg
Published: August 2015

Induction of congestive heart failure by high-frequency pacing has been reported to increase plasma levels of immunoreactive kinins in dogs. In the present study, we evaluated plasma bradykinin levels in human heart failure. Utilizing a recently developed method, we specifically measured plasma levels of bradykinin-(1–9) nonapeptide in 21 patients with chronic congestive heart failure [New York Heart Association (NYHA) stages III and IV). At the same time, we measured plasma atrial natriuretic peptide levels and plasma renin activity, and, as a marker of inflammation, plasma levels of tumour necrosis factor. In addition, 18 healthy subjects matched for gender and age served as normal controls. Plasma bradykinin concentrations were not higher in patients with chronic congestive heart failure (median 2.1 fmol/ml) than in healthy subjects (2.6 fmol/ml). In contrast, plasma atrial natriuretic peptide levels were clearly higher (patients, 63 fmol/ml; controls, 24 fmol/ml; P < 0.0001), despite diuretic treatment and in the presence of high plasma renin activity (patients, 13.0 ng·h-1·ml-1; controls, 0.3 ng·h-1·ml-1; P < 0.0001). Tumour necrosis factor was elevated in heart failure patients in NYHA class IV only (27 pg/ml, compared with 21 pg/ml in controls; P = 0.013). Bradykinin, atrial natriuretic peptide and plasma renin activity levels were not correlated with the severity of the disease, as assessed by NYHA classification. These results indicate that a rather selective cytokine activation, without concomitant stimulation of the kallikrein–kinin system, occurs in human chronic congestive heart failure.
Induction of the stress response increases interleukin-6 production in the intestinal mucosa of endotoxaemic mice
Authors: WANG Quan , SUN Xiaoyan , PRITTS Timothy A. , WONG Hector R. , HASSELGREN Per-Olof
Published: August 2015

Previous studies suggest that production of interleukin-6 (IL-6) is increased in the intestinal mucosa during sepsis and endotoxaemia. We tested the hypothesis that mucosal IL-6 production during endotoxaemia is increased further by the heat-shock (stress) response. The stress response was induced in mice by hyperthermia (rectal temperature of 42 °C for 3 min) or by intraperitoneal injection of sodium arsenite (10 mg/kg). At 2 h after induction of the stress response, groups of mice were injected subcutaneously with endotoxin (10 mg/kg) or sterile saline. IL-6 mRNA and protein levels in the jejunal mucosa were determined by an RNase protection assay and an ELISA respectively, and levels of hsp72 (heat-shock protein of 72 kDa) were determined by Western blot analysis. Hyperthermia and sodium arsenite increased hsp72 levels in the intestinal mucosa. IL-6 concentrations were increased in the jejunal mucosa of endotoxaemic mice, and this effect of endotoxaemia was potentiated by the stress response. Mucosal IL-6 mRNA levels were increased in endotoxaemic mice, and were increased further by the stress response. Thus it is concluded that mucosal IL-6 production during endotoxaemia may be further stimulated by the stress response. Increased IL-6 levels in the intestinal mucosa may be a potential mechanism by which the stress response exerts a protective effect during sepsis and endotoxaemia.
Role of the l-arginine/nitric oxide pathway in ischaemic/reoxygenation injury of the human myocardium
Authors: ZHANG Jin-Gang , GALIÑANES Manuel
Published: August 2015

The role of the L-arginine/nitric oxide (NO) pathway in myocardial ischaemic/reperfusion injury remains controversial in experimental animal models. The aim of the present studies was to investigate the role of this pathway in the human myocardium. Myocardial specimens from right atrial appendages of patients undergoing elective coronary bypass graft surgery were incubated in crystalloid buffer at 37 °C and subjected to 120 min of simulated ischaemia followed by 120 min of reoxygenation. Tested drugs were added 15 min before ischaemia, and maintained during ischaemia and throughout reoxygenation. Ischaemia resulted in severe myocardial damage, as assessed by the leakage of lactate dehydrogenase (LDH) into the incubation medium and by the capacity of the tissue to reduce 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) to formazan product. L-Arginine (10 mM), a precursor of NO, significantly decreased LDH leakage (from 9.0±0.6 to 5.3±0.3 units/g wet wt; P < 0.05), but had no effect on MTT reduction or oxygen consumption. D-Arginine (10 mM), NG-nitro-L-arginine methyl ester (L-NAME; 0.5 mM), an NO synthase inhibitor, and S-nitroso-N-acetylpenicillamine (at 1, 100, 500 and 1000 µM), an NO donor, had no significant effects on the measured indices, and L-NAME did not reverse the protection afforded by L-arginine against LDH leakage. In addition, the formation of nitrotyrosine was not influenced by ischaemia/reoxygenation alone or by the agents investigated. In conclusion, these data suggest that L-arginine affords modest protection against ischaemic/reoxygenation injury of the human myocardium, an action that is NO-independent, and that NO metabolism does not play a significant role in this model.
Resting peripheral blood flow in normal pregnancy and in pre-eclampsia
Authors: ANIM-NYAME N. , SOORANNA S. R. , JOHNSON M. R. , GAMBLE J. , STEER P. J.
Published: August 2015

Multiple organ dysfunction followed by end organ failure occurs in pre-eclampsia. While one would intuitively reason that one of the factors contributing to the end organ failure is poor nutritional blood flow, this has yet to be demonstrated. The aim of the present study was to determine whether changes in resting nutritional blood flow occur in pre-eclampsia. We used strain-gauge plethysmography to study calf blood flow in 19 women with pre-eclampsia, 13 normal pregnant women and 17 non-pregnant controls. We reasoned that, since the calf comprises mostly skeletal muscle, without anastomotic channels, blood flowing through this region would primarily reflect nutritive flow. Calf blood flow was significantly reduced in women with pre-eclampsia (1.95±0.9 ml·min-1·100 ml-1) compared with normal pregnant (3.9±1.4 ml·min-1·100 ml-1) and non-pregnant (3.8±1.0 ml·min-1·100 ml-1) women (P = 0.0004 and P = 0.0005 respectively; ANOVA). Blood flow in pre-eclampsia was also correlated significantly with platelet count as an index of disease severity. In addition, there was a significant negative correlation between blood flow and systolic blood pressure (r = -0.69, P = 0.004) in the women with pre-eclampsia. These findings support the hypothesis that nutritional blood flow is reduced in pre-eclampsia. We suggest that measurement of resting calf blood flow could give a non-invasive index of deterioration of nutritive blood flow to vital organs in pre-eclampsia.
Improved neoangiogenesis in transmyocardial laser revascularization combined with angiogenic adjunct in a pig model
Authors: MUELLER Xavier M. , TEVAEARAI Hendrik T. , GENTON Claude-Yves , CHAUBERT Pascal , SEGESSER Ludwig K. von
Published: August 2015

Recent research has revealed neoangiogenesis as a basic phenomenon in transmyocardial laser revascularization (TMLR). Theoretically, myocardial neoangiogenesis could be further enhanced by the addition of angiogenic growth factors. Triads of TMLR channels were created in the lateral wall of the left ventricles of 12 pigs (mean body weight 73±5 kg), using a holmium:yttrium—aluminium garnet (YAG) laser. The animals were allocated randomly either to receive an injection of 100 µg of a bovine bone-derived growth factor mixture within the triads (n = 6), or to a control group (n = 6). Animals were killed 1 month later. Capillary and arteriolar densities were determined by computed morphometric analysis of histological sections of the triads. The capillary density of myocardial areas within the triads was significantly greater in the group receiving the bovine bone-derived growth factor mixture than in the control group (14.3±3.5/mm2 and 5.7±1.4/mm2 respectively; P < 0.001). The difference was also significant when considering arteriolar density (0.7±0.4/mm2 and 0.2±0.1/mm2 respectively; P < 0.001). For comparison, capillary and arteriolar densities of the TMLR channel scars were 48.7±9.7 and 1.9±0.5/mm2 respectively in the angiogenic group, and 46.3±13.7 and 2.3±1.3/mm2 respectively in the control group (no significant differences). These results demonstrate that the addition of angiogenic factors to TMLR stimulates neoangiogenesis significantly in the areas adjacent to the channels, but not within the channel scars. The latter are themselves strongly vascularized. Hence this combined approach, potentiating the effect of TMLR by establishing vascular connections between the neovessels of the channel scars, has the potential for improved clinical outcome.
Increased gene expression of adrenomedullin and adrenomedullin-receptor complexes, receptor-activity modifying protein (RAMP)2 and calcitonin-receptor-like receptor (CRLR) in the hearts of rats with congestive heart failure
Authors: TOTSUNE Kazuhito , TAKAHASHI Kazuhiro , MACKENZIE Harald S. , MURAKAMI Osamu , ARIHARA Zenei , SONE Masahiko , MOURI Toraichi , BRENNER Barry M. , ITO Sadayoshi
Published: August 2015

Adrenomedullin is a vasodilator peptide produced in various organs, including heart and kidney. A novel adrenomedullin receptor complex has recently been identified, namely the calcitonin receptor-like receptor (CRLR) and receptor-activity modifying protein (RAMP) 2. In the present study, we have examined gene expression of RAMP2, CRLR and adrenomedullin in hearts and kidneys of rats with congestive heart failure caused by coronary artery ligation. Partial cloning was performed to determine the rat RAMP2 nucleotide sequence. Messenger RNA levels were then determined using competitive, quantitative reverse transcription-PCR techniques. Significantly increased expression levels (means±S.E.) of RAMP2, CRLR and adrenomedullin mRNA were found in the atrium (1.8±0.2-fold, 1.8±0.2-fold and 2.1±0.1-fold, respectively, compared with sham operated rats) and in the ventricle (1.4±0.1-fold, 1.3±0.03-fold and 3.0±0.5-fold respectively). On the other hand, expression levels of RAMP2, CRLR and adrenomedullin mRNAs were not significantly changed in the kidney. These findings suggest potential roles of locally-produced and locally-acting adrenomedullin in the failing heart.
Effect of inhibition of nitric oxide synthase on dynamic cerebral autoregulation in humans
Authors: WHITE R. P. , VALLANCE P. , MARKUS H. S.
Published: August 2015

Cerebral blood flow is maintained constant over a range of cerebral perfusion pressures by cerebral autoregulation. Impaired cerebral autoregulation may be important in the pathogenesis of cerebral ischaemia. The mechanisms mediating normal cerebral autoregulation in humans are poorly understood. We used a recently described transcranial Doppler technique, which allows non-invasive measurement of dynamic cerebral autoregulation, to test the hypothesis that nitric oxide mediates cerebral autoregulation. The rate of rise of middle cerebral artery blood flow velocity, compared with that of arterial blood pressure, was determined following a stepwise fall in arterial blood pressure, in order to calculate an autoregulatory index. The effect of the nitric oxide synthase inhibitor NG-monomethyl-L-arginine (L-NMMA) on dynamic autoregulation was compared with that of noradrenaline titrated to result in a similar rise in blood pressure. Six healthy subjects were studied in each group. The mean (S.D.) change in autoregulatory index following noradrenaline at a similar pressor dose was significantly greater than the change following the L-NMMA bolus: 1.1 (1.2) compared with -0.8 (0.8) for the left middle cerebral artery (P = 0.002), and 1.1 (0.8) compared with -0.8 (0.8) for the right middle cerebral artery (P = 0.002). There was no difference in the mean (S.D.) blood pressure increase resulting from the two agents: L-NMMA, 19.7 (7.4) mmHg; noradrenaline, 15.5 (4.8) mmHg (P = 0.281). These results suggest that nitric oxide mediates at least part of the dynamic phase of cerebral autoregulation in humans. Reduced nitric oxide release may play a role in the impaired cerebral autoregulation seen in patients with, or at risk of, cerebral ischaemia.
Role of inducible nitric oxide synthase in the regulation of leucocyte recruitment
Authors: HICKEY Michael J.
Published: August 2015

Constitutively produced nitric oxide released by endothelial cells has been shown to act as an endogenous agent which inhibits the rolling and adhesion of leucocytes in the microcirculation. However, during various types of inflammation, expression of the inducible form of nitric oxide synthase (iNOS) can dramatically increase the amount of nitric oxide present in tissues. Furthermore, as iNOS can be expressed by a wide variety of cell types, the distribution of nitric oxide is likely to be altered relative to that in unstimulated tissue. Under these conditions, it is less well understood whether iNOS-derived nitric oxide retains the anti-adhesive capabilities of constitutively produced nitric oxide. This review summarizes work done to examine this issue. Three main approaches have been used. In vitro studies have examined the role of iNOS in adhesive interactions between stimulated endothelial cells and leucocytes, providing evidence of an anti-adhesive effect of iNOS. In addition, the role of iNOS has been examined in vivo in animal models of inflammation using pharmacological iNOS inhibitors. These experiments were extended by the advent of the iNOS-deficient (iNOS-/-) mouse. Intravital microscopy studies of these mice have indicated that, under conditions of low-dose endotoxaemia, iNOS-derived nitric oxide can inhibit leucocyte rolling and adhesion. The potential mechanisms for these effects are discussed. In contrast, several other studies have observed either no effect or an enhancing effect of iNOS on inflammatory leucocyte recruitment. Taken together, these studies suggest that the importance of iNOS in modulating leucocyte recruitment can vary according to the type of inflammatory response.
Losartan, an angiotensin type I receptor antagonist, improves conduit vessel endothelial function in Type II diabetes
Authors: CHEETHAM Craig , O'DRISCOLL Gerard , STANTON Kim , TAYLOR Roger , GREEN Daniel
Published: August 2015

We have demonstrated previously that inhibition of angiotensin-converting enzyme (ACE) with enalapril and angiotensin II blockade with losartan improve acetylcholine-dependent endothelial function in resistance vessels of patients with Type II diabetes. It was therefore of interest to examine the effect of losartan on conduit vessel function in this group. The influence of losartan (50 mg daily for 4 weeks) on endothelium-dependent and -independent vasodilator function was determined in 12 subjects with Type II diabetes using a randomized, double-blind, placebo-controlled crossover protocol. Conduit vessel endothelial function was assessed using high-resolution ultrasound and the brachial artery response to reactive hyperaemia (flow-mediated dilation; FMD); glyceryl trinitrate (GTN) was used as a non-endothelium-dependent dilator. Losartan administration significantly increased the FMD response from 5.2±0.7% (mean±S.E.M.) to 7.4±0.6% of vessel diameter (P < 0.05; paired t-test). There was no effect of losartan on the endothelium-independent responses to GTN (17.8±1.8% to 17.6±1.2%). Consistent with our previous findings in resistance vessels, administration of 50 mg of losartan daily improves NO-mediated dilation in the conduit vessels of subjects with Type II diabetes. Together with the findings that both ACE inhibition and angiotensin II blockade improve resistance vessel function in this group, it is likely that at least some of the beneficial effect is mediated through the angiotensin II/type 1 receptor pathway. A type 1 receptor antagonist seems a reasonable alternative to an ACE inhibitor to maintain conduit vessel endothelial function in Type II diabetic subjects.
Thrombosis in one coronary artery causes generalized coronary vasoconstriction in a dog model of unstable angina
Authors: MANSARAY Mohammed , HYND John W. , VERGROESEN Isobel , BELCHER Philip R. , DRAKE-HOLLAND Angela J. , NOBLE Mark I. M.
Published: August 2015

We investigated the effect of thrombosis in one coronary artery upon the vascular resistance of another coronary artery. In previous investigations, using an animal model of unstable angina, we have observed increased resistance downstream from thrombus within a left circumflex coronary artery (LCx) stenosis and vasoconstriction of collateral vessels from the left anterior descending artery (LAD) supplying the distal LCx vascular bed. In the present paper, we induced thrombosis within a stenosis of the LCx of 16 beagle dogs, and observed the changes in blood flow to the myocardium supplied by the LAD using the radioactive microsphere technique. This blood flow decreased with thrombosis (P = 0.005) in these animals, whereas it did not do so in three time-control experiments. The pressures across the coronary vascular bed, i.e. arterial pressure to coronary venous pressure (coronary sinus catheter), did not change. Thus the vascular resistance of the LAD bed increased significantly from 147±ll.5 mmHg/ml/sec/g of tissue to 172±13.4 mmHg/ml/sec/g of tissue (P = 0.02). As the LAD territory is not perfused with blood from the artery containing thrombus, we conclude that the effect observed is caused either by release of vasoconstrictors from the thrombus into the general circulation, or by activation of a neural reflex vasoconstriction. The study suggests that unstable angina involving thrombosis in one coronary artery is a global coronary vascular disease.
Assessment of regional long-axis function during dobutamine echocardiography
Authors: CAIN Peter , MARWICK Thomas H. , CASE Colin , BAGLIN Terri , DART Jared , SHORT Leanne , OLSTAD Bjorn
Published: August 2015

Echocardiographic analysis of regional left ventricular function is based upon the assessment of radial motion. Long-axis motion is an important contributor to overall function, but has been difficult to evaluate clinically until the recent development of tissue Doppler techniques. We sought to compare the standard visual assessment of radial motion with quantitative tissue Doppler measurement of peak systolic velocity, timing and strain rate (SRI) in 104 patients with known or suspected coronary artery disease undergoing dobutamine stress echocardiography (DbE). A standard DbE protocol was used with colour tissue Doppler images acquired in digital ciné-loop format. Peak systolic velocity (PSV), time to peak velocity (TPV) and SRI were assessed off-line by an independent operator. Wall motion was assessed by an experienced reader. Mean PSV, TPV and SRI values were compared with wall motion and the presence of coronary artery disease by angiography. A further analysis included assessing the extent of jeopardized myocardium by comparing average values of PSV, TPV and SRI against the previously validated angiographic score. Segments identified as having normal and abnormal radial wall motion showed significant differences in mean PSV (7.9±3.8 and 5.9±3.3 cm/s respectively; P < 0.001), TPV (84±40 and 95±48 ms respectively; P = 0.005) and SRI (-1.45±0.5 and -1.1±0.9 s-1 respectively; P < 0.001). The presence of a stenosed subtending coronary artery was also associated with significant differences from normally perfused segments for mean PSV (8.1±3.4 compared with 5.7±3.7 cm/s; P < 0.001), TPV (78±50 compared with 92±45 ms; P < 0.001) and SRI (-1.35±0.5 compared with -1.20±0.4 s-1; P = 0.05). PSV, TPV and SRI also varied significantly according to the extent of jeopardized myocardium within a vascular territory. These results suggest that peak systolic velocity, timing of contraction and SRI reflect the underlying physiological characteristics of the regional myocardium during DbE, and may potentially allow objective analysis of wall motion.
Influence of posture on the Valsalva manoeuvre
Authors: SINGER Wolfgang , OPFER-GEHRKING Tonette L. , MCPHEE Benjamin R. , HILZ Max J. , LOW Phillip A.
Published: August 2015

The objective of the present study was to evaluate the influence of posture on the responses of blood pressure (BP) and heart rate (HR) to the Valsalva manoeuvre (VM). Neurohumoral activation, as well as changes in intravascular and intracardiac volumes and pressures, are well known effects of orthostatic stress. These changes are likely to have significant effects on cardiovascular reflexes, such as the response to the VM. However, the influence of posture on the VM has not been intensively evaluated, except for a few studies involving small sex- and age-selected case series. We therefore investigated the effects of posture on the VM in a larger non-selected group of healthy control subjects. In 19 healthy volunteers (ten female/nine male; age range 20–72 years, mean age 43 years), two reproducible VMs (40 mmHg; 15 s) were performed after 10 min of supine rest, 10 min of sitting and 10 min of standing. HR and BP were monitored continuously. End-diastolic volume, total peripheral resistance and cardiac output were calculated at baseline for each position. We found that assuming an upright position resulted in increases in total peripheral resistance and HR, accompanied by decreases in end-diastolic volume and cardiac output. The fall in BP during early phase II and the BP overshoot during phase IV were clearly more pronounced with increasing orthostatic stress, whereas the rise in BP during late phase II remained unchanged; pulse pressure was more compressed during phase II, but higher during phase IV. The Valsalva ratio was not significantly affected, but baroreflex gain (calculated from early phase II) was significantly decreased in the upright position. While a reduced late phase II was observed on one occasion in each of the lying and sitting positions, three abnormal responses were observed during standing. We conclude that posture has a significant influence on BP responses to the VM, probably resulting from changes in the intrathoracic blood volume. Standing results in a lower rate of ‘flat-top’ responses, but also seems to reduce the specificity of this test. Sympathetic activation in the upright position seems to blunt baroreflexes, leading to similar HR responses in spite of larger changes in BP.
Radial artery hypertrophy occurs in coronary atherosclerosis and is independent of blood pressure
Authors: MACKAY Alison J. , HAMILTON Carlene A. , McARTHUR Kenneth , BERG Geoffrey , TROPEANO Anne-Isabelle , BOUTOUYRIE Pierre , REID John L. , DOMINICZAK Anna F.
Published: August 2015

Endothelial dysfunction, believed to underlie the structural changes of atherosclerosis, is a systemic phenomenon. Despite this, the radial artery has been considered as devoid of atherosclerosis and is commonly used as a conduit in coronary artery bypass grafting (CABG). Recently, histological study has shown intimal hyperplasia and other structural changes consistent with early atherosclerosis in the radial artery. The objective of the present study was to determine if structural changes in the radial artery could be detected invivo in patients with coronary atherosclerosis. Using high resolution echo-tracking, measurements of radial artery internal diameter, wall thickness and wall cross-sectional area were made in 25 patients awaiting CABG and in 20 controls. Digital and brachial blood pressures were also recorded. Mean arterial pressures did not differ between the patient and control groups. All measures of wall thickness were greater in the patient than the control group. Neither current arterial pressures nor past history of hypertension correlated with wall thickness. Using a model of analysis of covariance, coronary artery disease was the best single predictor of intima-media thickness, R2 = 48%, n = 44, P< 0.0005. We concluded that increased radial artery wall thickness can be demonstrated invivo in patients with coronary atherosclerosis. This is a novel observation which seems to be independent of blood pressure, and is consistent both with the hypothesis of systemic endothelial dysfunction leading to systemic structural changes and also to the recent histological evidence for atherosclerotic changes in this vessel.
The effect of different methods of storage on the results of serum total CO2 assays
Authors: HOWSE Matthew L. P. , LEONARD Maureen , VENNING Michael , SOLOMAN Laurence
Published: August 2015

Metabolic acidosis frequently complicates end-stage renal failure. In haemodialysis patients its severity is usually monitored by measurement of the total CO2 (TCO2) level. Samples from ‘satellite dialysis’ patients are often stored prior to analysis. We investigated the affect of storage of 21 samples for 24 h under different conditions prior to analysis. If samples were stored at room temperature the TCO2 fell from 22.7±4.2 mmol/l to 21.6±3.7 mmol/l (P = 0.001). If the same samples were spun and stored at 4 °C the TCO2 was 22.4±3.9 mmol/l (P = not significant). We conclude that the magnitude in the fall of TCO2 stored at room temperature for 24 h is unlikely to be clinically significant and can be prevented by spinning the sample and refrigerating it.
Lisinopril improves endothelial function in chronic cigarette smokers
Authors: BUTLER Robert , MORRIS Andrew D. , STRUTHERS Allan D.
Published: August 2015

Cigarette smoking is a pernicious risk factor for the pathogenesis of coronary artery disease, and endothelial dysfunction is an important antecedent event in this process. This is important, as cigarette smoke is directly toxic to endothelial cells. Inhibitors of angiotensin-converting enzyme (ACE) have been shown to improve endothelial function in diabetes and hypercholesterolaemia, and are a promising option in smokers. We treated 23 subjects (age 38±12 years; mean±S.D.) for 8 weeks with 20 mg of lisinopril in a randomized controlled trial. Endothelial function was assessed by measurement of forearm blood flow responses to intra-arterial infusions of endothelial-dependent and -independent vasodilators and an endothelial-dependent vasoconstrictor [acetylcholine, sodium nitroprusside and monomethyl-l-arginine (l-NMMA) respectively] using venous occlusion plethysmography. Lisinopril significantly increased the forearm blood flow response to acetylcholine by 20% [lisinopril, 3.12±0.37 (mean±S.E.M.); placebo, 2.58±0.25;P = 0.02, 95% confidence intervals (CI) 0.09, 1.06] (values given are ratios of flow in the infused arm to that in the control arm); there was no effect on the response to sodium nitroprusside (lisinopril, 3.97±0.40; placebo, 3.92±0.39; P = 0.84; 95% CI -0.50, 0.61). The vasoconstrictor response to l-NMMA demonstrated a significant improvement (lisinopril, 0.77±0.06; placebo, 0.95±0.05; P < 0.001; 95% CI -0.09, -0.27). In conclusion, these results indicate that ACE inhibition can improve endothelial function in cigarette smokers. We show that lisinopril improves both receptor-mediated and tonic NO release. The mechanism could be either that lisinopril limits the angiotensin II-induced production of superoxide radicals which would normally inactivate NO, or that lisinopril may increase bradykinin-mediated NO release.
Diminished skin blood flow in Type I diabetes: evidence for non-endothelium-dependent dysfunction
Authors: KATZ Abram , EKBERG Karin , JOHANSSON Bo-Lennart , WAHREN John
Published: August 2015

The purpose of this study was to quantify the extent to which skin blood flow (SBF) responses to application of endothelium-dependent and -independent vasodilating agents differ between Type I diabetic patients and healthy subjects. Patients and matched controls were studied after an overnight fast. SBF was determined with laser Doppler perfusion imaging before and after iontophoresis of acetylcholine (Ach; endothelium-dependent) and sodium nitroprusside (SNP; endothelium-independent). Basal SBF did not differ significantly between groups. Iontophoresis of ACh and SNP increased SBF 20-fold in controls. In the patients, the increases in SBF following iontophoresis of ACh and SNP were reduced by 18% and 19%, respectively, versus controls (P < 0.05 for both). These data demonstrate that Type I diabetic patients have similar diminished SBF responses to iontophoresis of ACh and SNP, which suggests that non-endothelial-dependent factors are primarily responsible for the diminished SBF responses.
Effect of salt intake on endothelium-derived factors in a group of patients with essential hypertension
Authors: BRAGULAT Ernesto , de la SIERRA Alejandro , ANTONIO María T. , JIMÉNEZ Wladimiro , URBANO-MÁRQUEZ Álvaro , COCA Antonio
Published: August 2015

The aim of the present study was to evaluate the effects of the level of salt intake on endothelium-derived factors in a group of patients with essential hypertension. A group of 50 patients with essential hypertension who had never been treated for the condition were placed on a low-sodium (50 mmol/day), low-nitrate (400 µmol/day) diet, which was supplemented, in a single-blind fashion, with placebo tablets for the first 7 days and then with NaCl tablets (200 mmol/day) for a further 7 days (total sodium intake 250 mmol/day). At the end of both periods, 24-h ambulatory blood pressure monitoring was performed. In addition, plasma levels and 24-h urinary excretion of nitrites plus nitrates and cGMP were measured, along with plasma levels of endothelin. A high salt intake promoted significant decreases in plasma levels of nitrites plus nitrates (from 41.0±2.1 to 32.8±1.8 nmol/ml; P < 0.001), 24-h urinary nitrate excretion (from 417±36 to 334±37 µmol/24 h; P = 0.045) and plasma endothelin levels (from 5.6±0.3 to 4.6±0.3 pg/ml; P = 0.007). The plasma concentration and 24-h urinary excretion of cGMP were not altered significantly by a high salt intake. We did not find any relationship between endothelium-derived products and 24-h mean blood pressure, at either low or high salt intakes, or between changes induced by the high-salt diet. A high salt intake also induced significant decreases in plasma renin activity, angiotensin II and aldosterone, and a significant increase in atrial natriuretic peptide. We conclude that a high salt intake decreases the plasma concentration and urinary excretion of nitrates and plasma levels of endothelin in patients with essential hypertension, suggesting that the level of salt intake may affect endothelial cell function. However, these alterations are not correlated with changes in blood pressure induced by the high salt intake.
Mechanics of the carotid artery wall and baroreflex sensitivity after acute ethanol administration in young healthy volunteers
Authors: FAZIO Massimiliano , BARDELLI Moreno , MACALUSO Loredana , FIAMMENGO Fabio , MATTEI Piero Luigi , BOSSI Monica , FABRIS Bruno , FISCHETTI Fabio , PASCAZIO Lorenzo , CANDIDO Riccardo , CARRETTA Renzo
Published: August 2015

The effects of ethanol administered orally (300 mg/kg in 250 ml of water) or intravenously (7.5 mg·min-1·kg-1 in 250 ml of saline over 40 min) on common carotid haemodynamics, wall mechanics and baroreflex sensitivity were compared with the effects of the intravenous infusion of 250 ml of saline. Ethanol or saline was administered to 10 healthy volunteers after 30 min of supine rest, and measurements were obtained 40 min (median; range 34–46 min) after administration. After ethanol administration, the plasma alcohol level rose from 0 to 0.3±0.07 g/l. Mean arterial blood pressure had risen slightly at 20 min, but was normalized by 40 min, the time at which the haemodynamic study was performed. Heart rate decreased after infusion of either saline or alcohol, but was unchanged after oral ethanol administration. Both oral and intravenous ethanol administration were associated with significant decreases in baroreflex sensitivity, carotid shear stress and blood velocity, compared with resting values, while the mean carotid artery diameter was increased, and blood viscosity and mean blood flow were unchanged. No changes were observed in these parameters after saline administration. Ethanol, administered either intravenously or orally, increased the stiffness of the carotid artery and decreased the pulsatility (systo–diastolic changes) of its diameter. A direct, statistically significant correlation was found between the decrease in shear stress and the decrease in baroreflex heart rate control sensitivity after both modes of alcohol administration, while no such correlation was found between the increase in the Peterson elastic modulus and the decrease in carotid diameter pulsatility on the one hand or the decrease in baroreflex sensitivity on the other. In conclusion, reduced shear stress associated with vasodilatation of the carotid artery wall may contribute to the decrease in baroreflex sensitivity observed after acute ethanol administration.
Sequential changes in in vivo muscle and liver protein synthesis and plasma and tissue glutamine levels in sepsis in the rat
Authors: O'LEARY Michael J. , FERGUSON Colin N. , RENNIE Michael J. , HINDS Charles J. , COAKLEY John H. , PREEDY Victor R.
Published: August 2015

We have investigated sequential changes in skeletal muscle and hepatic protein synthesis following sepsis, and their relationship to changes in circulating and tissue glutamine concentrations. Male Wistar rats underwent caecal ligation and puncture (CLP) or sham operation, with starvation, and were killed 24, 72 or 96 h later. A group of non-operated animals were killed at the time of surgery. Protein synthesis was determined using a flooding dose of l-[4-3H] phenylalanine, and glutamine concentrations were measured by an enzymic fluorimetric assay. Protein synthesis in gastrocnemius muscle fell in all groups. Gastrocnemius total protein content was reduced after CLP and at 72 and 96 h after sham operation. After CLP, protein synthesis was lower at 24 h, and total protein content was lower at 72 and 96 h, than in sham-operated animals. CLP was associated with increased liver protein synthesis at all time points, whereas there was no change after sham operation. Liver protein content did not change after CLP, but was lower at 72 and 96 h after sham operation than in non-operated animals. Plasma glutamine concentrations were reduced at 24 h after sham operation, and at 72 and 96 h after CLP. Muscle glutamine concentrations were reduced in all groups, with the decrease being greater following CLP than after sham operation. In the liver, glutamine concentrations were unchanged after CLP, but increased after sham operation. In rats with sepsis, decreases in muscle protein synthesis and content are associated with markedly reduced muscle glutamine concentrations. Plasma glutamine concentrations are initially maintained, but fall later. In liver, protein synthesis is increased, while glutamine concentrations are preserved. These results support a peripheral-to-splanchnic glutamine flux in sepsis.
Increase in circulating levels of cardiac natriuretic peptides after hormone replacement therapy in postmenopausal women
Authors: MAFFEI Silvia , DEL RY Silvia , PRONTERA Concetta , CLERICO Aldo
Published: August 2015

The mechanisms that mediate the cardioprotective action of steroid hormones in postmenopausal women are poorly understood. To study the inter-relationship between female steroid hormones and cardiac natriuretic peptides, plasma levels of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) were measured in postmenopausal women, both before and after oestrogen replacement therapy. A total of 22 healthy postmenopausal women (mean age 51.9±4.6 years) were enrolled in the study; all had been postmenopausal for at least 1 year and all reported climacteric symptoms accompanied by increased levels of follicle-stimulating hormone (>30m-i.u./ml) and luteinizing hormone (>20m-i.u./ml), and a reduction in oestradiol (<25pg/ml). All women were given hormone replacement therapy with transdermal oestradiol, either patch (50μg/24 h) or gel (1mg/day), cyclically combined with oral dihydrogesterone (10mg/day for 12 days/month, on days 19-30 of the month). ANP and BNP were measured directly in plasma samples with specific and sensitive immunoradiometric assays before and after hormone replacement therapy (transdermal oestradiol combined with oral dihydrogesterone). Body weight, arterial blood pressure and echocardiographic examination values did not change after hormone replacement therapy. As expected, serum oestradiol increased significantly and gonadotropins decreased as an effect of the hormone replacement therapy. On average, both ANP and BNP had increased significantly after 3 months of hormone replacement therapy [ANP: before treatment, 17.6±9.6pg/ml; after, 23.6±5.6pg/ml (P = 0.0173); BNP: before treatment, 12.6±10.2pg/ml; after, 19.8±14.0pg/ml (P<0.0001)]. Our study indicates that hormone replacement therapy for a period of 3 months induces a rise in the circulating levels of cardiac natriuretic hormones in postmenopausal women. Our data also suggest the working hypothesis that cardiac natriuretic peptides may play an important role in mediating the cardioprotective effects of female steroid sex hormones in women throughout life.
Quantification of vascular endothelial growth factor-A in leiomyomas and adjacent myometrium
Authors: GENTRY Cheryl C. , OKOLO Stanley O. , Te FONG Lan Fong Wong , CROW Julie C. , MACLEAN Allan B. , PERRETT Christopher W.
Published: August 2015

Although uterine leiomyomas constitute the commonest benign tumour in women, the regulation of their growth is poorly understood. It is believed that angiogenesis, the process by which new capillaries develop from pre-existing blood vessels, may be involved. We therefore investigated the expression of vascular endothelial growth factor-A (VEGF-A), a primary regulator of angiogenesis, in leiomyoma tissue and the adjacent myometrium in 36 pre-menopausal women undergoing hysterectomy for leiomyomas, with or without prior treatment with gonadotrophin-releasing hormone analogue (GnRHa). In 5μm sections prepared from archival paraffin-wax blocks, VEGF-A was demonstrated by standard immunohistochemistry using a monoclonal antibody. VEGF-A was expressed in 14 of 18 (77.8%) leiomyoma sections from women without GnRHa pretreatment, and in 15 of 18 (83%) of those from women with prior treatment. VEGF-A expression in the adjacent myometrium was much lower, being noted in two of 18 (11.1%) sections from women without prior GnRHa treatment and in one of 18 (5.5%) sections from tissue that had been subject to prior down-regulation. Moreover, when VEGF-A expression was present, expression was strong in leiomyomas (⩾ 20 focal areas/cm2), but not in adjacent myometrium. The differential expression of VEGF-A antigen in leiomyomas compared with the adjacent myometrium indicates that local angiogenesis may be important in the development and growth of these tumours. GnRHa therapy does not appear to alter this pattern of VEGF-A expression.
Arterial waves in humans during peripheral vascular surgery
Authors: KHIR Ashraf W. , HENEIN Michael Y. , KOH Tat , DAS Saroj K. , PARKER Kim H. , GIBSON Derek G.
Published: August 2015

The purpose of this study was to investigate the effect of aortic clamping on arterial waves during peripheral vascular surgery. We measured pressure and velocity simultaneously in the ascending aorta, in ten patients (70±5 years) with aortic-iliac disease intra-operatively. Pressure was measured using a catheter tip manometer, and velocity was measured using Doppler ultrasound. Data were collected before aortic clamping, during aortic clamping and after unclamping. Hydraulic work in the aortic root was calculated from the measured data, the reflected waves were determined by wave-intensity analysis and wave speed was determined by the PU-loop (pressure-velocity-loop) method; a new technique based on the ‘water-hammer’ equation. The wave speed is approx. 32% (P < 0.05) higher during clamping than before clamping. Although the peak intensity of the reflected wave does not alter with clamping, it arrives 30ms (P < 0.05) earlier and its duration is 25% (P < 0.05) longer than before clamping. During clamping, left ventricule (LV) hydraulic systolic work and the energy carried by the reflected wave increased by 27% (P < 0.05) and 20% (P < 0.05) respectively, compared with before clamping. The higher wave speed during clamping explains the earlier arrival of the reflected waves suggesting an increase in the afterload, since the LV has to overcome earlier reflected compression waves. The longer duration of the reflected wave during clamping is associated with an increase in the total energy carried by the wave, which causes an increase in hydraulic work. Increased hydraulic work during clamping may increase LV oxygen consumption, provoke myocardial ischaemia and hence contribute to the intra-operative impairment of LV function known in patients with peripheral vascular disease.
Cimetidine administration and tubular creatinine secretion in patients with compensated cirrhosis
Authors: SANSOÈ Giovanni , FERRARI Alberto , CASTELLANA Carmen Nives , BONARDI Lorenzo , VILLA Erica , MANENTI Federico
Published: August 2015

Cimetidine inhibits the tubular secretion of creatinine, without altering the glomerular filtration rate (GFR). During cimetidine administration the creatinine/inulin clearance ratio approaches unity in patients with renal failure. We determined the clearance of lithium (an index of fluid delivery to the distal nephron), inulin (a measure of the actual GFR) and creatinine during cimetidine administration to investigate the occurrence of tubular creatinine secretion in patients with compensated cirrhosis. A total of 12 patients with Child-Pugh A cirrhosis were studied initially. The subjects consumed a stable diet containing 100mmol of sodium. On successive days, 9h creatinine clearances were measured, first without and then with the oral administration of cimetidine (400mg as a priming dose, followed by 200mg every 3h). During the first study day, 4h renal lithium clearance was also calculated. A further group of five patients with fully compensated cirrhosis underwent the measurement (on successive days) of plasma inulin clearance, first without and then with the oral administration of cimetidine (same schedule of drug administration). Cimetidine administration unmasked a marked overestimation of GFR when calculated as creatinine clearance (baseline, 138±20ml/min; +cimetidine, 89±13ml/min; P < 0.01). Consequently, during cimetidine administration the calculated lithium fractional excretion (a measure of the fraction of filtered sodium load that is delivered to the loop of Henle) rose from 21.4±13.2% to 32.3±18.9% (P < 0.05), and the ratio between absolute distal tubular sodium reabsorption and filtered sodium load rose from 20.6±13.1% to 31.6±19.3% (P < 0.01). Cimetidine caused no significant decrease in the actual GFR (i.e. inulin clearance) when administered to the second group of patients with compensated cirrhosis. Our data demonstrate significant tubular secretion of creatinine in patients with compensated cirrhosis and, consequently, a marked overestimation of GFR and filtered sodium load and an underestimation of the fractional distal tubular sodium reabsorption when these parameters are calculated by means of the traditional creatinine and lithium clearance computation. The true GFR (measured as inulin clearance) is unaffected by cimetidine administration.