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Biomedical subjects

M Barton

Publications and source records attributed to M Barton.

At least 37 records · Page 2Linked to original sources
PubMed2001

Endothelium and atherogenesis: endothelial therapy revisited.

Atherosclerosis, a chronic systemic disease of the vasculature with an inflammatory component, is the primary cause of cardiovascular morbidity and mortality in industrialized countries. Impairment of vascular endothelial cell function in atherosclerosis and in conditions associated with increased cardiovascular risk are important determinants of disease progression. Reduced endothelium-dependent relaxation in the coronary and systemic circulation due to decreased bioavailability of nitric oxide (NO) and increased release of oxygen-derived free radicals promotes the adhesion of leukocytes, thrombosis, inflammation, cell proliferation, and increases in vascular tone. In addition to decreases in bioactive NO, enhanced production of the 21-amino acid peptide endothelin-1 contributes to the progression of atherosclerosis. This paper discusses mechanisms and therapeutic approaches to improving endothelial pathways in atherosclerosis. Restoration of endothelium-derived NO bioactivity through inhibition of the renin-angiotensin system, the endothelin system, or statin therapy improves vascular function in experimental hypercholesterolemia, hypertension and heart failure. These treatments may also have therapeutic benefit for patients at risk or with overt atherosclerosis, and are likely to reduce vascular and myocardial complications of this disease.

Angiotensin Receptor Antagonists↗
PubMed2001

Postmenopausal oestrogen replacement therapy and atherosclerosis: can current compounds provide cardiovascular protection?

The natural oestrogen, 17 beta-oestradiol, has been implicated in protection from atherosclerosis, a chronic systemic vascular disease with an inflammatory component accounting for the majority of morbidity and mortality in Western countries. Despite the protective effects of 17 beta-oestradiol in premenopausal women and experimental evidence demonstrating inhibitory effects of oestrogen on atherosclerosis progression, it is currently unclear whether hormone replacement therapy can affect cardiovascular morbidity and mortality in postmenopausal women. The recent advances in understanding the mechanisms of oestrogen action demonstrated roles for different oestrogen receptors and oestrogen metabolites in the pathogenesis of vascular injury and endothelial cell dysfunction. However, their respective role in the process of atherogenesis remains yet to be elucidated. Moreover, the availability of novel drugs with tissue- and/or receptor-specific actions will help to understand the role of oestrogen in cardiovascular diseases. Several ongoing large-scale clinical trials using opposed or unopposed replacement therapy with natural or synthetic oestrogens, or selective oestrogen receptor modulators (SERMs) will resolve the question whether the drugs currently available have therapeutic potential to interfere with the progression of atherosclerosis and its complications.

Arteriosclerosis↗
PubMed2000

Endothelins and endothelin receptor antagonists: therapeutic considerations for a novel class of cardiovascular drugs.

The 21-amino acid peptide endothelin-1 (ET-1) is the predominant isoform of the endothelin peptide family, which includes ET-2, ET-3, and ET-4. It exerts various biological effects, including vasoconstriction and the stimulation of cell proliferation in tissues both within and outside of the cardiovascular system. ET-1 is synthesized by endothelin-converting enzymes (ECE), chymases, and non-ECE metalloproteases; it is regulated in an autocrine fashion in vascular and nonvascular cells. ET-1 acts through the activation of G(i)-protein-coupled receptors. ET(A) receptors mediate vasoconstriction and cell proliferation, whereas ET(B) receptors are important for the clearance of ET-1, endothelial cell survival, the release of nitric oxide and prostacyclin, and the inhibition of ECE-1. ET is activated in hypertension, atherosclerosis, restenosis, heart failure, idiopathic cardiomyopathy, and renal failure. Tissue concentrations more reliably reflect the activation of the ET system because increased vascular ET-1 levels occur in the absence of changes in plasma. Experimental studies using molecular and pharmacological inhibition of the ET system and the first clinical trials have demonstrated that ET-1 takes part in normal cardiovascular homeostasis. Thus, ET-1 plays a major role in the functional and structural changes observed in arterial and pulmonary hypertension, glomerulosclerosis, atherosclerosis, and heart failure, mainly through pressure-independent mechanisms. ET antagonists are promising new agents in the treatment of cardiovascular diseases.

Aspartic Acid Endopeptidases↗
PubMed2000

Deloading of the left ventricle by ventricular assist device normalizes increased expression of endothelin ET(A) receptors but not endothelin-converting enzyme-1 in patients with end-stage heart failure.

BACKGROUND: Ventricular assist devices (VAD) are implanted in patients with end-stage heart failure for bridging the time until heart transplantation, resulting in hemodynamic unloading of the failing heart, improved cardiac contractile and mitochondrial function, and reversal of cardiac hypertrophy. It is unknown whether VAD unloading may affect the cardiac endothelin (ET) system, which has been proposed as one of the putative pathomechanisms of heart failure. METHODS AND RESULTS: With the use of standard-calibrated, competitive reverse-transcription-polymerase chain reaction mRNA expression of components of the ET system was analyzed in left ventricular myocardium from nonfailing donor hearts, from failing hearts without and with ACE inhibitor therapy, and from patients with end-stage heart failure at the time of VAD implantation and 103+/-15 days after VAD implantation during removal with subsequent heart transplantation. ET receptor A (ET(A)) was markedly upregulated in failing human myocardium. This increased ET(A) expression was not affected by ACE inhibitor treatment but was normalized by VAD unloading. ET(A) expression before or after VAD implantation did not correlate with duration of VAD implantation or suppression of Pro-ANP mRNA. ET(B) mRNA expression was unaffected by heart failure or VAD. In contrast, increased ET-converting enzyme-1 mRNA and ET-1 peptide levels in failing myocardium were partially normalized by ACE inhibition but not by VAD unloading. CONCLUSIONS: We conclude that VAD implantation normalizes ET(A) expression in failing human left ventricular myocardium, probably as the result of the beneficial effects of VAD unloading.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2000

Endothelial dysfunction and atherosclerosis: endothelin receptor antagonists as novel therapeutics.

Atherosclerosis, a chronic systemic disease of the vasculature with an inflammatory component, is the primary cause of cardiovascular morbidity and mortality in industrialized countries. It is associated with the impairment of endothelium-dependent relaxation in the coronary, systemic circulation due to decreased bioavailability of nitric oxide, and increased release oxygen-derived free radicals, thus promoting vasoconstriction, leukocyte adhesion, thrombosis, inflammation, and cell proliferation. Expression of endothelin (ET)-1, a 21-amino acid peptide and major isoform of the endothelin peptide family, is produced by endothelial, vascular smooth muscle cells, and macrophages and acts through Gi-protein-coupled ET(A) and ET(B) receptors. Endothelin-1 increases in hypercholesterolemia and atherosclerosis in humans and experimental animals. This paper reviews current experimental and clinical evidence for the involvement of ET-1 in atherogenesis. Furthermore, the effects of ET receptor blockade on experimental hypercholesterolemia and atherosclerosis will be discussed. As chronic endothelin blockade inhibits fatty streak formation and improves vascular function in experimental hypercholesterolemia, hypertension, and heart failure, and as it restores nitric oxide (NO)-mediated endothelial function and reduces atheroma formation in animals with atherosclerosis, endothelin receptor blockade may therefore offer a novel approach for the treatment of atherosclerosis and its vascular complications.

Coronary Artery Disease↗
PubMed2000

Radiotherapy utilization in New South Wales from 1996 to 1998.

The purpose of the present study was to examine utilization rates of radiotherapy by newly diagnosed cancer patients in New South Wales (NSW) from 1996 to 1998. The 1989 report of the Australian Health Ministers' Advisory Council (AHMAC) recommended that 50% of all newly diagnosed cancer patients should receive radiotherapy. Previous reports showed that the true rate was between 30 and 36%. In 1991 and 1995 the NSW Department of Health developed strategic plans that were intended to implement the AHMAC recommendation. An analysis was carried out of activity reports of radiation oncology departments in NSW and its component Area Health Services (AHS). All NSW patients newly diagnosed with cancer between 1996 and 1998 and treated by radiotherapy were included in the study. A total of 37% of newly diagnosed cancer patients received radiotherapy in NSW in 1998. This has increased from 30% since 1990-91. Rural AHS in 1998 had an identical average rate of 37% (range: 23-54%) when compared to urban AHS (average: 37%; range: 26-49%). Rural AHS have increased utilization from 19% in 1990-91. Area health services with a radiation oncology department had a slightly higher rate of utilization than those AHS without a radiation oncology department (39 and 36%, respectively). The rates of utilization of radiotherapy in NSW in 1998 continued to be well below the benchmark set by AHMAC and varied widely between AHS. Attention to and expansion of services should be focused on both rural and urban areas of need.

Health Services Research↗
PubMed2000

Doppler mirror image artifacts mimicking mitral regurgitation in patients with mechanical bileaflet mitral valve prostheses.

AIMS: To characterize the origin and mechanisms of generation of Doppler mirror images in the left atrium observed in patients with mechanical bileaflet mitral valve prosthesis. We hypothesized that these systolic colour Doppler images are artifactual and generated by reflection of the left ventricular outflow tract flow at the leaflet of the mitral valve prosthesis. METHODS AND RESULTS: Fifty patients with mechanical bileaflet mitral valves were prospectively examined by means of transthoracic Doppler-echocardiography. From different apical views, the left atrium was carefully interrogated for systolic colour flow signals, which were further analysed by pulsed wave Doppler. In all patients, a systolic colour Doppler signal was detected in the left atrium. Pulsed wave Doppler analysis revealed a low velocity signal (= mirror image) corresponding to the shape and duration of the left ventricular outflow tract signal. The peak velocities of these mirror images, however, were consistently lower than the velocities obtained from the left ventricular outflow tract. In addition, if paravalvular mitral valve leakage was present, a high velocity signal identical to the duration of mitral regurgitation time was detected outside the ring of the prosthesis. CONCLUSIONS: Mirror image artifacts mimicking mitral regurgitation occur in patients with mechanical mitral valves prosthesis. As mirror image artifacts can be specifically identified by analysis of shape. velocity, and duration of pulsed wave Doppler spectra, their identification will help to avoid misinterpretation of both spectral and colour Doppler signals in patients with prosthetic mitral valves.

Aged↗
PubMed2000

Receptor- and non-receptor-mediated clearance of big-endothelin and endothelin-1: differential effects of acute and chronic ETA receptor blockade.

AIMS: The aims of this study were to define and characterize the different mechanisms and sites of clearance of plasma endothelin-1 (ET-1) and big endothelin-1 (BigET-1) and evaluate possible effects of ETA versus combined ETA and ETB receptor blockade or endothelin converting enzyme (ECE) inhibition. METHODS: Time courses and sites of clearance were evaluated in Wistar-Kyoto rats after bolus injection of radiolabelled peptides into the carotid artery before or after treatment with LU1 35252 (ETA) and bosentan (ETA and ETB) as receptor antagonists or the ECE inhibitor phosphoramidon. RESULTS: The study shows that differential clearance of 125I-ET-1 and 125I-BigET-1 is mediated by distinct tissue-specific, receptor- and non-receptor-mediated mechanisms. Low levels of plasma ET-1 are rapidly cleared, mainly in the pulmonary circulation, through a low-capacity saturable ETB receptor-linked mechanism. In contrast, BigET-1 clearance is markedly slower, confined largely to liver and kidneys, is essentially non-receptor-mediated and is independent of converting enzyme activity. Acute inhibition of both ETA and ETB receptors with bosentan dramatically prolonged 125I-ET-1 plasma half-life and shifted tissue uptake from lung to liver and kidneys. Pulmonary clearance of 125I-ET-1 was decreased by chronic but not acute treatment with the specific ETA receptor antagonist LU135252. In contrast, 125I-Big-ET-1 clearance and tissue uptake were essentially unchanged by all treatments. CONCLUSIONS: Plasma levels and clearance studies on ET-1 and BigET-1 may provide differential information regarding pathological changes in their separate uptake mechanisms. Such data could have diagnostic or prognostic value in pulmonary, hepatic and renal pathophysiology or future therapeutic monitoring of treatment efficacy following administration of selective receptor antagonists.

Administration, Oral↗
PubMed2000

Endothelin in atherosclerosis: importance of risk factors and therapeutic implications.

Endothelin (ET)-1, a potent vasoconstrictor peptide, is primarily released abluminally from endothelial cells and exerts its biological effect through the activation of specific ET receptors. Endothelin subtype A receptors (ET(A)) are involved in constriction and proliferation of vascular smooth muscle cells, whereas endothelin subtype B receptors (ET(B)) on endothelial cells mediate the formation of nitric oxide, which acts as vasodilator and inhibits platelet aggregation. Cardiovascular risk factors such as hypertension and aging, as well as hypercholesterolemia, which are precursors of atherosclerosis, and elevated ET-1 levels are found. The best approach to determine the contribution of endogenous ET to vascular structural and functional alterations can be achieved by chronic inhibition of ET receptors with ET receptor antagonists. Recent studies showed favourable effects of selective ET(A)-antagonists on vascular alterations in different experimental models of hypertension, hypercholesterolemia and atherosclerosis, suggesting that activation of the local ET system importantly contributes to endothelial dysfunction and vascular remodeling, mainly through ET(A) receptors. Chronic blockade of ET(A) receptors may be a new therapeutic approach for the treatment of atherosclerosis and its risk factors.

Aging↗
PubMed2000

Inverse regulation of endothelin-1 and nitric oxide metabolites in tissue with aging: implications for the age-dependent increase of cardiorenal disease.

Aging is an independent risk factor for cardiovascular and renal disease. The study reported here investigated whether aging affects endothelin-1 (ET-1) and tissue levels of the nitric oxide metabolites nitrite/nitrate in the kidney of rodents. Blood pressure was measured by the tail-cuff method, ET-1 protein was determined by radioimmunoassay/high-performance liquid chromatography (RIA/HPLC) and nitrite/nitrate was measured by ion-pairing chromatography. Compared to young male Wistar Kyoto rats (3 months of age), renal ET-1 protein levels in whole kidneys increased 3.6-fold at 24 months of age (from 70 +/- 9 to 253 +/- 43 pg/g tissue, p < 0.05, n = 6 each group). Similarly, renal ET-1 protein increased 1.7-fold in 18-month-old C57BL/6J mice as compared to 8-month-old adult animals (from 188 +/- 18 to 319 +/- 14 pg/g tissue, p < 0.05, n = 5-7). In female RoRo-Wistar rats (6, 18 and 33 months of age), tissue nitrite/nitrate levels in whole kidneys decreased with increasing age (from 232 +/- 25 to 130 +/- 6 micromol/l/g tissue, p < 0.05). Thus, aging in healthy rodents is associated with a marked upregulation of renal ET-1 protein content and a decrease in tissue nitrite/nitrate levels in whole kidneys, independent of blood pressure. Activation of the ET pathway with aging may promote the development of age-dependent diseases such as glomerulosclerosis, hypertension and atherosclerosis.

Aging↗
PubMed2000

Endothelin regulates angiotensin-converting enzyme in the mouse kidney.

Using the orally active endothelin-A- (ET(A)) receptor antagonist LU135252, we determined whether endothelin-1 (ET-1) and/or dietary fat may be involved in angiotensin-converting enzyme (ACE) regulation in vivo. In C57BL6/J mice, renal and pulmonary tissue ACE activity (nmol/l His-Leu/mg protein) was measured and ACE mRNA expression, tissue ET-1 protein content and nitrite/nitrate level were measured in the kidney. Western-type diet increased renal ACE activity by 70% (55 +/- 4 vs 33 +/- 3 nmol/l His-Leu/mg protein, p < 0.05) and increased renal ET-1 levels (267 +/- 19 pg/g vs 190 +/- 18, p < 0.05). Chronic LU135252 treatment completely prevented activation of renal ACE activity (13.3 +/- 0.3 His-Leu/mg protein nmol/l, p < 0.05) independent of ACE mRNA expression or renal ET-1 protein levels. Thus, dietary fat activates renal ACE activity and ET-1 is involved in regulation of tissue ACE activity in vivo independently of ACE mRNA expression.

Animals↗
PubMed2000

Direct and indirect costs of rheumatoid arthritis to an employer.

This study is among the first to estimate the overall economic burden of rheumatoid arthritis (RA) from an employer perspective. The annual, per capita cost of RA was determined for beneficiaries of a major employer by analyzing medical, pharmaceutical, and disability claims data. The incremental costs related to RA were determined by matching RA patients to a case-control group of individuals with no recorded RA treatment. The utilization of health care services as well as the rate of disability among RA patients was substantially higher than among the controls. For example, annual, per capita employer expenditures for RA employees with disability were almost 3 times those for their controls ($17,822 vs $6131, respectively). Treatment to address not only the severity but also the progression of RA may substantially reduce overall employer expenditures for this disease.

Adult↗