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Biomedical subjects

Louise M Burrell

Publications and source records attributed to Louise M Burrell.

At least 19 recordsLinked to original sources
PubMed2006

Vascular neutral endopeptidase inhibition improves endothelial function and reduces intimal hyperplasia.

OBJECTIVE: Neutral endopeptidase (NEP, EC 3.4.24.11) metabolises endogenous vasoactive peptides that may protect against atherogenesis. Since NEP is found in the adventitia of arteries, we investigated the anti-atherogenic effects of chronic adventitial NEP inhibition. METHODS: Intimal hyperplasia of rabbit carotid arteries was induced by placement of soft, non-occlusive, peri-arterial silastic collars. NEP localisation was studied with autoradiography 7 and 14 days after collar placement. Vascular NEP was inhibited in vivo by local superfusion of one collared carotid artery with Candoxatrilat (50 pmol/h), for 7 days (n = 7). The contralateral collar was filled with saline vehicle. After 7 days, ring segments of collared and normal (proximal to the collar) arteries were obtained and in vitro functional measurements, immunohistochemical determination of the pro-atherogenic factor plasminogen activator inhibitor-1 (PAI-1), localization of macrophages and morphometric analyses were carried out. RESULTS: Vascular NEP radiolabelled substrate binding, mainly in the media, was increased by approximately 50% after 7 days (n = 5; p < 0.05) and by approximately 300% after 14 days of collar placement (n = 5; p < 0.05). Compared with normal artery segments from the same animal, vehicle-filled collared sections displayed significantly impaired vasorelaxation to acetylcholine (endothelium-independent vasodilatation was preserved), increased PAI-1 immunostaining, macrophage accumulation and intimal thickening. In Candoxatrilat-treated collared arteries, vasorelaxation to acetylcholine was improved, along with reductions in PAI-1 levels, macrophage numbers and intimal area (all p < 0.05). CONCLUSION: Enhancing the activity of local, endogenous peptides by adventitial inhibition of vascular NEP may protect against early atherogenesis. This is of particular relevance to using adventitial therapies to prevent intimal hyperplasia leading to restenosis.

Acetylcholine↗
PubMed2006

Diastolic dysfunction is associated with anaemia in patients with Type II diabetes.

Anaemia is common in patients with diabetes and associated with an increased risk of diabetic complications. Although the role of anaemia in heart failure is established, we hypothesize that anaemia also contributes to an increased risk of cardiac dysfunction in patients with Type II diabetes. In the present study, 228 consecutive adults with diabetes were investigated using transthoracic echocardiography. Echocardiographic parameters were correlated with the Hb (haemoglobin) level and adjusted for other risk factors for cardiac dysfunction using multivariate analysis. More than one in five patients (23%) had anaemia, which was an independent risk factor for cardiac dysfunction on echocardiography. Over one-third of all patients with evidence of abnormal cardiac function (diastolic and/or systolic dysfunction) on echocardiography had anaemia compared with <5% of patients with normal echocardiographic findings. Most patients with anaemia had cardiac dysfunction (94%), with the major abnormality being diastolic dysfunction associated with an increased left ventricular mass and impaired relaxation indices. A continuous association between diastolic function and Hb was also observed in patients without anaemia. In patients with a history of cardiovascular disease, systolic dysfunction was twice as common in patients with anaemia. Anaemia was also correlated with plasma markers of cardiac risk, including BNP (brain natriuretic peptide), CRP (C-reactive protein) and AVP (arginine vasopressin). Notably, the predictive utility of these markers was eliminated after adjusting for Hb. Consequently, the inexpensive measurement of Hb may be a useful tool to identify diabetic patients at increased risk of cardiac dysfunction.

Aged↗
PubMed2005

An unexpected cause of macroscopic haematuria.

A 25-year-old man presented with macroscopic haematuria associated with a body mass index of 20 kg/m and a severe coagulopathy consistent with vitamin K deficiency. The diagnosis of a profound malabsorption syndrome secondary to coeliac disease was confirmed by small bowel histology and positive coeliac serology.

Abdominal Pain↗
PubMed2005

Immunolocalization of ACE2 and AT2 receptors in rabbit atherosclerotic plaques.

Evidence suggests that angiotensin type 2 receptor (AT2R) and angiotensin-converting enzyme 2 (ACE2) play a protective role in atherogenesis. These factors have not been identified in rabbit atherosclerotic plaques. Our goal was to localize ACE2 and AT2R in rabbit atherosclerotic tissues, and determine which cell types express these factors. New Zealand White rabbits were fed either a control diet or a 0.5% cholesterol diet (n=8/group) for 12 weeks. Paraffin-fixed thoracic aorta were serially sectioned and processed for immunohistochemistry using commercially available antibodies to ACE2, AT2R, RAM 11 (to identify macrophages), and alpha smooth muscle cell actin (alphaSMC) to identify smooth muscle cells and myofibroblasts. AT2R immunoreactivity, but not ACE2 immunoreactivity, was clearly present in endothelia overlying normal wall. However, both AT2R and ACE2 immunoreactivity were clearly present in endothelia overlying neo-intima formation and atherosclerotic plaques. Within plaques, both AT2R and ACE2 immunoreactivity were observed in macrophages and alphaSMC actin-positive cells. Examination of serial sections showed that the majority of cells were both ACE2- and AT2R-positive. Macrophages and alphaSMC actin-positive cells produce ACE2 and the AT2R in atherosclerotic plaques. Determining a role for these factors in the control of atherosclerosis will require additional studies.

Actins↗
PubMed2005

Connective tissue growth factor and cardiac fibrosis after myocardial infarction.

The temporal and spatial expression of transforming growth factor (TGF)-beta(1) and connective tissue growth factor (CTGF) was assessed in the left ventricle of a myocardial infarction (MI) model of injury with and without angiotensin-converting enzyme (ACE) inhibition. Coronary artery ligated rats were killed 1, 3, 7, 28, and 180 days after MI. TGF-beta(1), CTGF, and procollagen alpha1(I) mRNA were localized by in situ hybridization, and TGF-beta(1) and CTGF protein levels by immunohistochemistry. Collagen protein was measured using picrosirius red staining. In a separate group, rats were treated for 6 months with an ACE inhibitor. There were temporal and regional differences in the expression of TGF-beta(1), CTGF, and collagen after MI. Procollagen alpha1(I) mRNA expression increased in the border zone and scar peaking 1 week after MI, whereas collagen protein increased in all areas of the heart over the 180 days. Expression of TGF-beta(1) mRNA and protein showed major increases in the border zone and scar peaking 1 week after MI. The major increases in CTGF mRNA and protein occurred in the viable myocardium at 180 days after MI. Long-term ACE inhibition reduced left ventricular mass and decreased fibrosis in the viable myocardium, but had no effect on cardiac TGF-beta(1) or CTGF. TGF-beta(1) is involved in the initial, acute phase of inflammation and repair after MI, whereas CTGF is involved in the ongoing fibrosis of the heart. The antifibrotic benefits of captopril are not mediated through a reduction in CTGF.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2005

Myocardial infarction increases ACE2 expression in rat and humans.

AIMS: Angiotensin converting enzyme (ACE) 2 catalyses the cleavage of angiotensin (Ang) I to Ang 1-9 and of Ang II to Ang 1-7. ACE2 deficiency impairs cardiac contractility and upregulates hypoxia-induced genes, suggesting a link with myocardial ischaemia. We studied the expression of ACE2 after myocardial infarction (MI) in the rat as well as in human failing hearts. METHODS AND RESULTS: Rats were killed at days 1, 3, and 28 after MI, or treated for 4 weeks with the ACE inhibitor ramipril (1 mg/kg). Cardiac gene and protein expression of ACE and ACE2 were assessed by quantitative real-time reverse transcriptase-polymerase chain reaction and immunohistochemistry/activity assays/in vitro autoradiography, respectively. Both ACE (P = 0.022) and ACE2 (P = 0.015) mRNA increased in the border/infarct area compared with the viable area at day 3 after MI. By day 28, increases in ACE (P = 0.005) and ACE2 (P = 0.006) mRNA were also seen in the viable myocardium of MI rats compared with myocardium of control rats. ACE2 protein localized to macrophages, vascular endothelium, smooth muscle, and myocytes. Ramipril attenuated cardiac hypertrophy and inhibited cardiac ACE. In contrast, ramipril had no effect on cardiac ACE2 mRNA, which remained elevated in all areas of the MI rat heart. Immunoreactivity of both ACE and ACE2 increased in failing human hearts. CONCLUSION: The increase in ACE2 after MI suggests that it plays an important role in the negative modulation of the renin angiotensin system in the generation and degradation of angiotensin peptides after cardiac injury.

Aged↗
PubMed2005

Glomerular permeability defect in hypertension is dependent on renin angiotensin system activation.

BACKGROUND: The aim of the present study was to compare glomerular permeability alterations associated with experimental hypertension models known to have different effects on the circulating renin-angiotensin system (RAS). METHODS: Five groups, 10 animals each, were studied. One group served as a nonhypertensive control. The other four groups of hypertensive animals were composed of spontaneously hypertensive rats, deoxycorticosterone acetate hypertensive rats, Goldblatt two-kidney, one-clip rats, and a group of Wistar rats infused with angiotensin II (200 ng/kg/min). Tail-cuff sphygmomanometric systolic blood pressure (BP), albumin permeability determined in isolated glomeruli exposed to oncotic gradients (P(alb)), glomerular filtration rate (GFR, iopamidol method), plasma renin activity (PRA), and albuminuria were evaluated. RESULTS: Alterations in P(alb) and albumin excretion rate were more evident in the experimental models with an activation of the RAS despite similar levels of systolic BP and GFR. A positive correlation was found between P(alb) and albuminuria (r = 0.51; P < .001) and between systolic BP and albuminuria (r = 0.37; P < .01). No relation was found between systolic BP and P(alb). CONCLUSIONS: The present study indicates that the activation of the RAS plays a significant role in the development of glomerular albumin permeability defects in hypertensive models and may contribute to the mechanisms that lead to target organ damage in hypertension.

Albumins↗
PubMed2005

Lateral vs medial mitral annular tissue Doppler in the echocardiographic assessment of diastolic function and filling pressures: which should we use?

Tissue Doppler echocardiography (TDE) is used in the assessment of diastolic function, however, it is unclear whether the medial (E' med) or lateral (E' lat) annulus should be used. Our aim was to compare the diagnostic utility of E' med and E' lat. In 232 subjects left ventricular (LV) systolic and diastolic function was assessed via transthoracic echocardiography with TDE measurements obtained from both annuli. LV function was normal in 91 subjects (39%), with diastolic dysfunction found in 141 subjects (61%). TDE velocities decreased with age and progressive diastolic dysfunction for either annulus. E' med recorded significantly lower myocardial velocities than E' lat. Receiver operator curves showed improved area under the curve (AUC) for E' med than E' lat. Furthermore the AUC was significantly improved compared to E/A ratio and deceleration time. For diagnosing diastolic dysfunction, an E' med<11cm/s provided a sensitivity of 78%, specificity of 67% and positive predictive value of 70%. Whilst for diagnosing elevated filling pressures an E/E' medial ratio>8 provided values of 56%, 93% and 91%, respectively. In conclusion, although either annulus can be used, E' med provides better diagnostic utility.

Aged↗
PubMed2005

Anti-atherosclerotic and renoprotective effects of combined angiotensin-converting enzyme and neutral endopeptidase inhibition in diabetic apolipoprotein E-knockout mice.

OBJECTIVE: To investigate the effects of the combined angiotensin-converting enzyme (ACE)/neutral endopeptidase (NEP) inhibitor omapatrilat on atherosclerosis and renal injury in a model of diabetes-associated accelerated atherosclerosis and renal injury. DESIGN: The study was performed using diabetic apolipoprotein E-knockout (apo E-KO) mice, a model combining hyperlipidemia and hyperglycemia, which leads to accelerated atherosclerosis and renal injury. METHODS: Diabetes was induced by the injection of streptozotocin in 6-week old apo E-KO mice. Diabetic animals received no treatment (n = 12) or treatment with the ACE/NEP inhibitor omapatrilat (30 mg/kg per day, via gavage, n = 12) or quinapril (10 mg/kg per day, in drinking water, n = 12) for 20 weeks. Non-diabetic apo E-KO mice (n = 12) served as controls. RESULTS: Omapatrilat reduced atherosclerosis and protected the mice from renal structural injury and albuminuria. The protective effects were associated with tissue inhibition of aortic and renal ACE and NEP as well as a significant reduction in blood pressure. Omapatrilat had similar anti-atherosclerotic effects compared with the ACE inhibitor quinapril in association with an almost complete inhibition of aortic ACE activity by both drugs. Omapatrilat conferred superior renoprotection in the diabetic apo E-KO mouse compared with quinapril in the context of greater renal ACE inhibition by omapatrilat than seen with quinapril, additional renal NEP inhibition and a modestly enhanced antihypertensive response. CONCLUSIONS: These studies demonstrate the anti-atherosclerotic and renoprotective effects of omapatrilat in diabetic apo E-KO mice, a model of accelerated atherosclerosis and renal injury. These effects were observed in association with the local inhibition of ACE and NEP at the tissue level in the aorta and kidney. These results suggest that the anti-atherosclerotic effect conferred by omapatrilat treatment in the diabetic apo E-KO mouse is predominantly mediated by its capacity to inhibit local vascular ACE. By contrast, in the kidney, local renal ACE and NEP inhibition and the superior antihypertensive effect of omapatrilat all contribute to the renoprotective effect conferred by omapatrilat treatment in the diabetic apo E-KO mouse.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2004

Cardiorenal protective effects of vasopeptidase inhibition with omapatrilat in hypertensive transgenic (mREN-2)27 rats.

Vasopeptidase inhibitors simultaneously inhibit both angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP). The aim of this study was to determine the cardiorenal effects of the vasopeptidase inhibitor omapatrilat in the transgenic m(Ren-2)27 rat which exhibits fulminant hypertension and severe organ pathology. At 6 weeks of age, male Ren-2 rats were randomized to receive no treatment (N = 10), the ACE inhibitor fosinopril 10 mg/kg/day (N = 10), or omapatrilat 10 mg/kg/day (N = 10) or 40 mg/kg/day (N = 10) by daily gavage for 24 weeks. Various cardiorenal functional and structural parameters were assessed. Compared to controls, all treatment groups reduced hypertension in control Ren-2 rats, with both doses of omapatrilat reducing systolic blood pressure significantly more than fosinopril (control, 178 +/- 3 mmHg; fosinopril 10 mg/kg/day, 130 +/- 4 mmHg; omapatrilat 10 mg/kg/day, 110 +/- 3 mmHg; omapatrilat 40 mg/kg/day, 91 +/- 3 mmHg). Omapatrilat dose-dependently reduced cardiac hypertrophy, caused a greater inhibition of renal ACE than fosinopril, and was the only treatment to inhibit renal NEP. Attenuation of albuminuria, glomerulosclerosis and cardiorenal fibrosis occurred to a similar degree with omapatrilat and fosinopril. Omapatrilat confers cardiorenal protection in the hypertensive Ren-2 rat. Although inhibition of tissue NEP may contribute to the superior blood pressure reduction by omapatrilat, overall, the results are consistent with the central role that angiotensin II plays in renal and cardiac fibrosis in this model of hypertension.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2003

Vasopressin receptor expression in the placenta.

The arginine vasopressin (AVP) type 1a receptor (V1a) is well known to mediate vasoconstriction. In pregnancy, blood flow in the placenta is crucial for sustaining normal growth and development of the fetus. This is the first AVP receptor study in the placenta and fetal membranes. The aim was to compare, quantitatively, the level of V1a gene expression with that of a known marker for vascularization, aquaporin 1 (AQP1). V1a and AQP1 gene expression did not correlate; placental V1a mRNA levels were significantly upregulated at 45 and 66+/-1 compared with 27, 100+/-4, and 140 days (term approximately 150 days). V1a mRNA levels were much lower in fetal membranes in which no significant difference across gestation was observed. In situ hybridization histochemistry localized V1a gene expression in the maternal component of the placenta similar to the receptor-binding studies using 125I-labeled [d(CH2)5, sarcosine7] vasopressin. No AVP gene expression was observed in the placenta and fetal membranes, which eliminates local AVP production. This increase in V1a expression at 45 and 66+/-1 days of gestation correlates with the period of maximal placental growth in the sheep and suggests that AVP and V1a receptors may play a hitherto unrecognized role in placental growth, differentiation, and/or function, particularly in the deleterious effects of heat stress, early in pregnancy, on fetal growth.

Allantoin↗
PubMed2003

A breaker of advanced glycation end products attenuates diabetes-induced myocardial structural changes.

The formation of advanced glycation end products (AGEs) on extracellular matrix components leads to accelerated increases in collagen cross linking that contributes to myocardial stiffness in diabetes. This study determined the effect of the crosslink breaker, ALT-711 on diabetes-induced cardiac disease. Streptozotocin diabetes was induced in Sprague-Dawley rats for 32 weeks. Treatment with ALT-711 (10 mg/kg) was initiated at week 16. Diabetic hearts were characterized by increased left ventricular (LV) mass and brain natriuretic peptide (BNP) expression, decreased LV collagen solubility, and increased collagen III gene and protein expression. Diabetic hearts had significant increases in AGEs and increased expression of the AGE receptors, RAGE and AGE-R3, in association with increases in gene and protein expression of connective tissue growth factor (CTGF). ALT-711 treatment restored LV collagen solubility and cardiac BNP in association with reduced cardiac AGE levels and abrogated the increase in RAGE, AGE-R3, CTGF, and collagen III expression. The present study suggests that AGEs play a central role in many of the alterations observed in the diabetic heart and that cleavage of preformed AGE crosslinks with ALT-711 leads to attenuation of diabetes-associated cardiac abnormalities in rats. This provides a potential new therapeutic approach for cardiovascular disease in human diabetes.

Animals↗
PubMed2003

Characterization of renal angiotensin-converting enzyme 2 in diabetic nephropathy.

ACE2, initially cloned from a human heart, is a recently described homologue of angiotensin-converting enzyme (ACE) but contains only a single enzymatic site that catalyzes the cleavage of angiotensin I to angiotensin 1-9 [Ang(1-9)] and is not inhibited by classic ACE inhibitors. It also converts angiotensin II to Ang(1-7). Although the role of ACE2 in the regulation of the renin-angiotensin system is not known, the renin-angiotensin system has been implicated in the pathogenesis of diabetic complications and in particular in diabetic nephropathy. Therefore, the aim of this study was to assess the possible involvement of this new enzyme in the kidney from diabetic Sprague-Dawley rats to compare and contrast it to ACE. ACE2 and ACE gene and protein expression were measured in the kidney after 24 weeks of streptozocin diabetes. ACE2 and ACE mRNA levels were decreased in diabetic renal tubules by approximately 50% and were not influenced by ACE inhibitor treatment with ramipril. By immunostaining, both ACE2 and ACE protein were localized predominantly to renal tubules. In the diabetic kidney, there was reduced ACE2 protein expression that was prevented by ACE inhibitor therapy. The identification of ACE2 in the kidney, its modulation in diabetes, and the recent description that this enzyme plays a biological role in the generation and degradation of various angiotensin peptides provides a rationale to further explore the role of this enzyme in various pathophysiological states including diabetic complications.

Angiotensin-Converting Enzyme 2↗
PubMed2003

Differential tissue and enzyme inhibitory effects of the vasopeptidase inhibitor omapatrilat in the rat.

Vasopeptidase inhibitors simultaneously inhibit angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP). The present study characterized the tissue distributions of ACE and NEP, and assessed the effects of the vasopeptidase inhibitor omapatrilat on ACE and NEP in rat tissues. In vivo ACE and NEP inhibition was studied by in vitro autoradiography and using the ACE inhibitor radioligand (125)I-MK351A and the NEP inhibitor radioligand (125)I-RB104 in rats that received oral omapatrilat (40 mg x day(-1) x kg(-1)) for 3 days. In vitro autoradiography was used to examine the distribution of ACE and NEP in the kidney, aorta, heart, adrenal gland, lung, intestine, liver, spleen and brain, and to assess enzyme inhibition after oral omapatrilat. Omapatrilat inhibited plasma ACE and increased plasma renin activity (P <0.01). Tissue ACE was inhibited by 70-95% (P <0.01), except in the brain, where ACE was not inhibited. NEP was inhibited by 87% in the kidney and by 20-40% in atria, aorta, adrenal gland, lung, liver and intestine; it was not inhibited in the brain, the ventricle or the spleen. Omapatrilat is a potent vasopeptidase inhibitor that significantly inhibits tissue ACE and NEP, with the degree of inhibition varying according to the enzyme and the tissue under assessment. The degree and site of tissue enzyme inhibition by vasopeptidase inhibitors may be relevant to end-organ protection as well as to the side-effect profiles of these agents.

Administration, Oral↗
PubMed2003

Upregulation of cardiac insulin-like growth factor-I receptor by ACE inhibition after myocardial infarction: potential role in remodeling.

This study evaluated the effects of angiotensin-converting enzyme (ACE) inhibition after myocardial infarction (MI) on cardiac remodeling and gene expression and localization of components (ligands, receptors, and binding proteins) of the cardiac insulin-like growth factor (IGF) system. After ligation of the coronary artery, rats were randomized to vehicle or ACE inhibitor (Captopril, 50 mg/kg/day) for 4 weeks. Blood pressure, cardiac remodeling, and components of the IGF system were localized in the heart using in situ hybridization (ISH) and immunohistochemistry (IHC). The average infarct size was 42%. There were regional differences in the expression of the IGF system after MI, with increased IGF-I mRNA abundance in the border (24-fold) and infarct (12-fold) and increased IGF-binding protein (IGFBP)-3 mRNA in all areas of the failing left ventricle (threefold). Captopril reduced blood pressure, attenuated cardiac remodeling, and caused a threefold increase in IGF-I receptor mRNA and protein in infarct, border zone, and viable myocardium (p<0.01). Captopril had no effect on IGF-I mRNA but further increased IGFBP-3 mRNA and protein in the border zone, (p<0.05). The changes in the cardiac IGF system following MI are highly localized, persist for at least 4 weeks, and can be modulated by ACE inhibition. These data suggest that the benefits of ACE inhibitors in attenuation of cardiac remodeling may be mediated in part through increased expression of the IGF-I receptor sensitizing the myocardium to the positive effects of endogenous IGF-I.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2003

Diabetes mellitus: a cardiovascular disease.

Cardiovascular disease (CVD) is the major cause of morbidity and mortality in patients with diabetes mellitus (DM). The pathophysiology of CVD in diabetes involves traditional and novel cardiac risk factors, including hypertension, dyslipidemia, smoking, genetic factors, hyperglycemia, insulin resistance/hyperinsulinemia, metabolic abnormalities, oxidative/glycoxidative stress, inflammation, endothelial dysfunction, a procoagulant state and myocardial fibrosis. Specific vascular, myopathic and neuropathic alterations have been suggested to be responsible for the excessive cardiovascular morbidity and mortality in diabetes. These alterations manifest themselves clinically as coronary heart disease, congestive heart failure and/or sudden cardiac death. In order to contain the emerging epidemic of CVD in DM, diabetic patients should ideally have excellent glycemic control, a low normal blood pressure and low levels of low-density lipoprotein cholesterol, and be taking an angiotensin-converting enzyme inhibitor and aspirin, which may go some way to containing the emerging epidemic of CVD in DM.

Cardiovascular Diseases↗