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Biomedical subjects

D E Newby

Publications and source records attributed to D E Newby.

At least 37 records · Page 2Linked to original sources
PubMed2003

Therapeutic inhibition of tumour necrosis factor alpha in patients with heart failure: cooling an inflamed heart.

Heart failure is a systemic disorder characterised by tissue hypoxia and secondary organ dysfunction which occurs in response to various myocardial insults that include ischaemia, viral infections, and toxins. In addition to maladaptive neurohumoral activation, heart failure is associated with an inflammatory state that appears to have a detrimental effect on cardiac function and prognosis. This has led to the suggestion that anti-inflammatory interventions may have therapeutic potential in the symptomatic and prognostic treatment of patients with heart failure. This review considers the role of inhibition of the cytokine tumour necrosis factor alpha in the treatment of heart failure.

Animals↗
PubMed2002

Randomised controlled trial of continuous positive airway pressure and standard oxygen therapy in acute pulmonary oedema; effects on plasma brain natriuretic peptide concentrations.

AIMS: The study aim was to compare the effects of continuous positive airway pressure (CPAP) on clinical outcomes and plasma neurohormonal concentrations in patients with acute pulmonary oedema. METHODS AND RESULTS: In addition to standard therapy, 58 consecutive patients were randomized to receive 60% inhaled oxygen with or without CPAP at 7.5 cmH(2)O pressure. Clinical variables, symptoms and oxygenation were monitored and plasma epinephrine, norepinephrine and brain natriuretic peptide (BNP) concentrations estimated at 0, 1, 6 and 24 h. CPAP was associated with less breathlessness at 1 h (P<0.001), no treatment failures and more rapid resolution in respiratory rate (P<0.001), heart rate (P<0.001) and acidosis (P<0.005). Length of hospital stay was similar but there was a trend for a reduction in overall hospital mortality in the CPAP group (0.10>P>0.05). Plasma BNP concentrations rose progressively (P<0.001) before falling below admission concentrations at 24 h. Plasma neurohumoral concentrations were unaffected by CPAP treatment but were elevated in patients who died or had acute myocardial infarction. CONCLUSION: CPAP produces a more rapid clinical and symptomatic improvement in patients with acute pulmonary oedema, particularly within the first hour. CPAP is a useful adjunctive treatment in the early management of acute heart failure.

Acute Disease↗
PubMed2002

Abnormal endothelin B receptor vasomotor responses in patients with Hirschsprung's disease.

BACKGROUND: Hirschsprung's disease is associated with defects in the endothelin-3 and endothelin B receptor genes. AIM: To assess the in vivo vasomotor responses to endothelin B receptor stimulation in patients with Hirschsprung's disease. METHODS: Forearm blood flow was measured using venous occlusion plethysmography in 10 patients with Hirschsprung's disease and 10 matched healthy controls during intra-brachial infusion of the highly selective endothelin B receptor agonist, sarafotoxin S6c. To simulate endothelin B receptor dysfunction, sarafotoxin S6c was co-infused with the highly selective endothelin B receptor antagonist, BQ-788, in six of the healthy controls. RESULTS: Sarafotoxin S6c caused a brief initial vasodilatation followed by a slow-onset, sustained vasoconstriction (p<0.001). Compared to control subjects, patients with Hirschsprung's disease had a substantial impairment of the initial vasodilatation whilst producing a more pronounced subsequent vasoconstriction (p<0.001). In healthy controls, co-infusion of BQ-788 and sarafotoxin S6c caused a similar pattern of responses to those obtained in patients with Hirschsprung's disease: abolition of the initial vasodilatation and augmentation of subsequent vasoconstriction (p<0.001). DISCUSSION: In the majority of patients with Hirschsprung's disease, there is a functional defect of the vascular endothelin B receptor.

Adult↗
PubMed2002

Hypercholesterolaemia and lipid lowering treatment do not affect the acute endogenous fibrinolytic capacity in vivo.

OBJECTIVE: To assess acute tissue plasminogen activator (t-PA) release in vivo in patients with hypercholesterolaemia in the presence and absence of lipid lowering treatment and in matched normocholesterolaemic controls. DESIGN: Parallel group comparison and double blind randomised crossover. SETTING: University hospital. PATIENTS: Eight patients with hypercholesterolaemia (> 7.8 mmol/l) and eight matched normocholesterolaemic controls (< 5.5 mmol/l). METHODS: Blood flow and plasma fibrinolytic factors were measured in both forearms during unilateral brachial artery infusions of the endothelium dependent vasodilator substance P (2-8 pmol/min) and the endothelium independent vasodilator sodium nitroprusside (1-4 microg/min). INTERVENTIONS: In patients, measurements were made on three occasions: at baseline and after six weeks of placebo or pravastatin 40 mg daily administered in a double blind randomised crossover design. MAIN OUTCOME MEASURES: Acute release of t-PA. RESULTS: Compared with patients, in normocholesterolaemic control subjects substance P caused greater dose dependent increases in forearm blood flow (p < 0.05) but similar increases in plasma t-PA antigen and activity concentrations. During pravastatin treatment in patients, total serum cholesterol fell by 22% from a mean (SEM) of 8.1 (0.3) to 6.4 (0.4) mmol/l (p = 0.002) and substance P induced vasodilatation was no longer significantly impaired in comparison with controls. However, despite reproducible responses, pravastatin treatment was not associated with significant changes in basal or substance P induced t-PA release. CONCLUSIONS: Hypercholesterolaemia and lipid lowering treatment cause no demonstrable effects on acute substance P induced t-PA release in vivo. This suggests that the preventative benefits of lipid lowering treatment are unlikely to be mediated by improvements in endogenous fibrinolysis.

Adult↗
PubMed2001

Potentiation of bradykinin-induced tissue plasminogen activator release by angiotensin-converting enzyme inhibition.

OBJECTIVES: The aim of the present study was to determine the effect of angiotensin-converting enzyme (ACE) inhibition on the local stimulated release of tissue plasminogen activator (t-PA) from the endothelium. BACKGROUND: Angiotensin-converting enzyme inhibitor therapy may exert a beneficial effect on the endogenous fibrinolytic balance. METHODS: Blood flow and plasma fibrinolytic factors were measured in both forearms of eight healthy males who received unilateral brachial artery infusions of the endothelium-dependent vasodilators substance P (2 to 8 pmol/min) and bradykinin (100 to 1,000 pmol/min), and the endothelium-independent vasodilator sodium nitroprusside (2 to 8 microg/min). These measurements were performed on each of three occasions following one week of matched placebo, quinapril 40 mg or losartan 50 mg daily administered in a double-blind randomized crossover design. RESULTS: Sodium nitroprusside, substance P and bradykinin produced dose-dependent increases in the blood flow of infused forearm (analysis of variance [ANOVA], p < 0.001 for all). Although sodium nitroprusside did not affect plasma t-PA concentrations, they were increased dose-dependently in the infused forearm by substance P and bradykinin infusion (ANOVA, p < 0.001 for both). Bradykinin-induced release of active t-PA was more than doubled during treatment with quinapril in comparison to placebo or losartan (two-way ANOVA: p < 0.003 for treatment group, p < 0.001 for t-PA response and p = ns for interaction), whereas the substance P response was unaffected. CONCLUSIONS: We have shown a selective and marked augmentation of bradykinin-induced t-PA release during ACE inhibition. These findings suggest that the beneficial clinical and vascular effects of ACE inhibition may, in part, be mediated through local augmentation of bradykinin-induced t-PA release.

Adult↗
PubMed2001

Bradykinin contributes to the vasodilator effects of chronic angiotensin-converting enzyme inhibition in patients with heart failure.

BACKGROUND: Bradykinin, an endogenous vasodilator peptide, is metabolized by ACE. The aims of the present study were to determine the doses of B9340, a bradykinin receptor antagonist, that inhibit vasodilatation to exogenous bradykinin and to assess the contribution of bradykinin to the maintenance of basal vascular tone in patients with heart failure receiving chronic ACE inhibitor therapy. METHODS AND RESULTS: Forearm blood flow was measured using bilateral venous occlusion plethysmography. On three occasions in a double-blind randomized manner, 8 healthy volunteers received intrabrachial infusions of placebo or B9340 (at 4.5 and 13.5 nmol/min). On each occasion, placebo or B9340 was coinfused with bradykinin (30 to 3000 pmol/min) and substance P (4 to 16 pmol/min). B9340 caused no change in basal FBF but produced dose-dependent inhibition of the vasodilatation to bradykinin (P<0.001) but not substance P. The effects of bradykinin antagonism were studied in 17 patients with NYHA grade II through IV heart failure maintained on chronic ACE inhibitor therapy. Incremental doses of B9340, but not HOE-140, produced a dose-dependent vasoconstriction (P=0.01). After withdrawal of ACE inhibitor therapy, B9340 produced no significant change in forearm blood flow. After reinstitution of therapy, B9340 again resulted in vasoconstriction (P<0.03). CONCLUSIONS: B9340 is a potent and selective inhibitor of bradykinin-induced vasodilatation. Bradykinin does not contribute to the maintenance of basal peripheral arteriolar tone in healthy humans or patients with heart failure but contributes to the vasodilatation associated with chronic ACE inhibitor therapy in patients with heart failure via the B(1) receptor.

Adrenergic beta-Antagonists↗
PubMed2001

Impaired coronary tissue plasminogen activator release is associated with coronary atherosclerosis and cigarette smoking: direct link between endothelial dysfunction and atherothrombosis.

BACKGROUND: The aim of the study was to establish the influence of proximal coronary artery atheroma and smoking habit on the stimulated release of tissue plasminogen activator (tPA) from the heart. METHODS AND RESULTS: After diagnostic coronary angiography in 25 patients, the left anterior descending coronary artery (LAD) was instrumented, and the proximal LAD plaque volume was determined by use of intravascular ultrasound (IVUS). Blood flow and fibrinolytic responses to selective LAD infusion of saline, substance P (10 to 40 pmol/min; endothelium-dependent), and sodium nitroprusside (5 to 20 microgram/min; endothelium-independent) were measured by intracoronary IVUS and Doppler, combined with arterial and coronary sinus blood sampling. Mean plaque burden was 5.5+/-0.8 mm(3)/mm vessel (range 0.6 to 13.7 mm(3)/mm vessel). LAD blood flow increased with both substance P and sodium nitroprusside (P<0.001), although coronary sinus plasma tPA antigen and activity concentrations increased only during substance P infusion (P<0.006 for both). There was a strong inverse correlation between the LAD plaque burden and release of active tPA (r=-0.61, P=0.003). Cigarette smoking was associated with impaired coronary release of active tPA (current smokers, 31+/-23 IU/min; ex-smokers, 50+/-33 IU/min; nonsmokers 202+/-73 IU/min; P<0.05). CONCLUSIONS: We found that both the coronary atheromatous plaque burden and smoking habit are associated with a reduced acute local fibrinolytic capacity of the heart. These important findings provide evidence of a direct link between endogenous fibrinolysis, endothelial dysfunction, and atherothrombosis in the coronary circulation and may explain the greater efficacy of thrombolytic therapy for myocardial infarction in cigarette smokers.

Area Under Curve↗
PubMed2001

Association between calcific aortic stenosis and hypercholesterolemia: is there a need for a randomized controlled trial of cholesterol-lowering therapy?

BACKGROUND: Calcific aortic stenosis may have common etiological factors with atherosclerosis. HYPOTHESIS: In this retrospective, case-control study, we aimed to determine whether there is an association between hypercholesterolemia and calcific aortic valve stenosis. METHODS: Consecutive patients undergoing single aortic or mitral valve replacement in a regional cardiothoracic surgical center were reviewed and preoperative patient characteristics were recorded: demographics, comorbidity (including coronary artery disease and associated risk factors), serum total cholesterol, lipid-lowering therapy, and serum creatinine. RESULTS: Serum total cholesterol concentrations were significantly higher in patients with calcific aortic stenosis than in controls (6.2+/-1.1 vs. 5.3+/-1.1 mmol/l; p < 0.001). The significant difference in serum cholesterol concentrations remained following correction for gender and body mass index (p = 0.02) and when patients with coronary artery disease were excluded (6.3+/-1.1 vs. 5.3+/-1.4 mmol/l; p<0.001). Subgroup analysis demonstrated that the association between elevated serum cholesterol concentrations and calcific aortic stenosis was particularly strong in patients with tricuspid aortic valves (6.4+/-1.2 vs. 5.3+/-1.1 mmol/l; p < 0.001) compared with those with bicuspid valves (5.9+/-1.1 vs. 5.3+/-1.1 mmol/l; p = 0.06). CONCLUSIONS: We conclude that hypercholesterolemia is associated with calcific aortic stenosis and may be implicated in its pathogenesis and progression. We believe that there is now a need for a randomized, controlled trial of cholesterol-lowering therapy in patients with calcific aortic stenosis.

Aged↗
PubMed2001

Short-term effects of transdermal nicotine on acute tissue plasminogen activator release in vivo in man.

OBJECTIVE: Cigarette smoking impairs peripheral endothelium-dependent vasodilatation and acute tissue plasminogen activator (t-PA) release in man. The aim of the study was to determine if this endothelial dysfunction is, in part, mediated by the effects of nicotine. METHODS: Blood flow and plasma fibrinolytic factors were measured in both forearms of eight healthy male non-smokers during unilateral brachial artery infusion of the endothelium-dependent vasodilator, substance P (2 to 8 pmol/min). Endothelium-independent vasodilatation was assessed using intra-arterial infusion of sodium nitroprusside (2 to 8 microg/min). Subjects attended after 7 days treatment with transdermal nicotine or placebo in a double blind randomised crossover design. RESULTS: Plasma cotinine concentrations rose from 0.4+/-0.1 (placebo) to 125+/-25 ng/ml during nicotine administration (P<0.001). On both treatment days, substance P caused dose-dependent increases in blood flow and plasma t-PA antigen and activity concentrations (P<0.001 for all) but had no effect on plasma plasminogen activator inhibitor type 1 (PAI-1) concentrations. Compared with placebo, nicotine administration increased the substance-P-induced release of t-PA antigen and activity (P<0.05 for both) without an effect on endothelium-dependent or -independent vasodilatation. CONCLUSIONS: Short-term transdermal nicotine treatment does not affect endothelium-dependent vasomotion but does increase substance-P-induced t-PA release in vivo in man. This suggests that nicotine administration alters specific aspects of endothelial function and enhances the acute endogenous fibrinolytic capacity in vivo. The long-term effects of nicotine exposure, including the potential to cause depletion of endothelial t-PA stores, now needs to be assessed.

Administration, Cutaneous↗
PubMed2001

Altered peripheral vascular responses to exogenous and endogenous endothelin-1 in patients with well-compensated cirrhosis.

Plasma endothelin concentrations are elevated in cirrhosis and correlate with disease severity. This study assessed forearm vascular responses to exogenous endothelin-1 (ET-1), and evaluated the contribution of endogenous ET-1 to the maintenance of basal peripheral vascular tone in patients with well-compensated cirrhosis (n = 11) and matched healthy controls (n = 8). Bilateral forearm blood flow (FBF) was measured at baseline and following unilateral, subsystemic, intrabrachial artery infusions of ET-1 (2 and 6 pmol/min); BQ-123, a selective ET(A) receptor antagonist (3 and 10 nmol/min); and BQ-788, a selective ET(B) receptor antagonist (0.3 and 1 nmol/min) using venous occlusion plethysmography. Baseline systemic hemodynamics and plasma ET-1 and big ET-1 concentrations were measured using electrical bioimpedance and radioimmunoassay, respectively. Patients and controls had similar baseline FBF, systemic hemodynamics, and plasma ET-1 and big ET-1 concentrations. In both groups, ET-1 and BQ-788 caused significant vasoconstriction (P < .001) and BQ-123 caused significant vasodilatation (P < .001). Compared with controls, cirrhotic patients had attenuated ET-1 responses (P < .001), augmented BQ-123 responses (P < .001), and similar BQ-788 responses (P = .62). Despite normal systemic hemodynamics and plasma ET-1 concentrations, forearm vascular responses to exogenous ET-1 are reduced in cirrhotic patients. The augmented vasodilatation to BQ-123 in cirrhotic patients is consistent with a compensated vasodilated state, and a greater contribution of ET-1 to the maintenance of basal vascular tone acting through the ET(A) receptor.

Antihypertensive Agents↗
PubMed2001

Acute changes in cerebral blood flow and metabolism during portasystemic shunting.

This report describes the instantaneous changes in cerebral blood flow (CBF), determined by intravascular ultrasound and Doppler, in a patient with cirrhosis undergoing placement of a transjugular intrahepatic stent-shunt for uncontrolled variceal bleeding. Acute changes in CBF were observed during and after portasystemic shunting, which culminated in cerebral edema and cerebral herniation.

Brain↗
PubMed2001

Unstable angina: the first 48 hours and later in-hospital management.

Unstable angina is a common cardiovascular condition associated with major adverse clinical events. Over the last 15 years, therapeutic advances have dramatically reduced the complication and mortality rates of this serious condition. The standard of therapy in patients with unstable angina now incorporates the combined use of potent antithrombotic (aspirin, clopidogrel, heparin and glycoprotein IIb/IIIa receptor antagonists) and anti-anginal (beta-blockade and intravenous nitrates) regimens complemented by the selective and judicious application of coronary revascularisation strategies. Increasingly, these invasive and non-invasive therapeutic interventions are being guided not only by the clinical risk profile but also by the determination of serum cardiac and inflammatory markers. Moreover, rapid and intensive management of associated risk factors, such as hypercholesterolaemia, would appear to have potentially substantial benefits even within the acute in-hospital phase of unstable angina.

Aged↗
PubMed2001

Effects of acute methionine loading and vitamin C on endogenous fibrinolysis, endothelium-dependent vasomotion and platelet aggregation.

We assessed forearm blood flow and plasma fibrinolytic factors in eight healthy males who received unilateral brachial artery infusions of the endothelium-dependent vasodilator, substance P, and the endothelium-independent vasodilator, sodium nitroprusside. These measurements, together with platelet aggregation studies, were performed on four occasions after double-blind randomized ingestion of placebo, methionine (0.1 mg/kg), vitamin C (2 g) and methionine plus vitamin C. Blood flow and platelet aggregation responses were unaffected by methionine loading. Substance P caused dose-dependent increases in plasma tissue plasminogen activator (t-PA) antigen (from 3.0+/-0.1 to 4.7+/-0.4 ng/ml; P<0.001) and activity (from 1.2+/-0.2 to 4.2+/-0.4 i.u./ml; P<0.001), which were augmented during acute methionine loading (4.7+/-0.4 to 5.6+/-0.5 ng/ml and 4.2+/-0.4 to 5.5+/-0.9 i.u./ml respectively; P</=0.05). Moreover, the estimated net release of t-PA was enhanced during methionine loading (two-way ANOVA; P=0.02), but this was unaffected by vitamin C supplementation. We conclude that, in the absence of alterations in endothelium-dependent vasomotion or platelet aggregation, substance P-induced t-PA release is enhanced following methionine loading. This suggests that the acute endogenous fibrinolytic capacity is augmented during acute hyperhomocysteinaemia in healthy humans via an oxidation-independent mechanism.

Acute Disease↗
PubMed2000

The influence of heart rate on augmentation index and central arterial pressure in humans.

Arterial stiffness is an important determinant of cardiovascular risk. Augmentation index (AIx) is a measure of systemic arterial stiffness derived from the ascending aortic pressure waveform. The aim of the present study was to assess the effect of heart rate on AIx. We elected to use cardiac pacing rather than chronotropic drugs to minimize confounding effects on the systemic circulation and myocardial contractility. Twenty-two subjects (13 male) with a mean age of 63 years and permanent cardiac pacemakers in situ were studied. Pulse wave analysis was used to determine central arterial pressure waveforms, non-invasively, during incremental pacing (from 60 to 110 beats min-1), from which AIx and central blood pressure were calculated. Peripheral blood pressure was recorded non-invasively from the brachial artery. There was a significant, inverse, linear relationship between AIx and heart rate (r = -0.76; P < 0.001). For a 10 beats min-1 increment, AIx fell by around 4 %. Ejection duration and heart rate were also inversely related (r = -0. 51; P < 0.001). Peripheral systolic, diastolic and mean arterial pressure increased significantly during incremental pacing. Although central diastolic pressure increased significantly with pacing, central systolic pressure did not. There was a significant increase in the ratio of peripheral to central pulse pressure (P < 0.001), which was accounted for by the observed change in central pressure augmentation. These results demonstrate an inverse, linear relationship between AIx and heart rate. This is likely to be due to alterations in the timing of the reflected pressure wave, produced by changes in the absolute duration of systole. Consideration of wave reflection and aortic pressure augmentation may explain the lack of rise in central systolic pressure during incremental pacing despite an increase in peripheral pressure.

Age Factors↗
PubMed2000

Fibrinolytic actions of intra-arterial angiotensin II and bradykinin in vivo in man.

OBJECTIVES: Angiotensin II and bradykinin are potent endogenous vasoactive peptides which may play a role in the regulation of endogenous fibrinolysis and, thereby, contribute to the beneficial actions of ACE inhibitors. The aims of the study were to determine the acute effect of angiotensin II and bradykinin on the local vascular release of tissue plasminogen activator (t-PA) and its inhibitor, plasminogen activator inhibitor type 1 (PAI-1), and the endothelium-derived haemostatic factor, von Willebrand factor (vWf) from the forearm. METHODS: Blood flow, and plasma haemostatic and fibrinolytic factors, were measured in both forearms of sixteen healthy men: eight subjects received intra-arterial angiotensin II (5, 50 and 500 pmol/min) which was coinfused with sodium nitroprusside (SNP; 0.3, 1.5 and 7.5 microg/min, respectively), and eight received intra-arterial bradykinin at 10-3000 pmol/min. RESULTS: Despite substantial rises in plasma angiotensin II concentrations (P<0.001) which caused pressor effects (P<0.003) at the highest dose, angiotensin II infusion did not affect local plasma t-PA, PAI-1 or vWf concentrations. In contrast, bradykinin caused substantial dose-dependent increases in blood flow and t-PA release (>100 ng/100 ml of tissue/min) in the infused forearm (P<0. 001 for both) without affecting plasma PAI-1 or vWf concentrations. CONCLUSIONS: Despite high local concentrations with breakthrough of significant systemic effects, angiotensin II did not affect acute endothelial cell t-PA, PAI-1 or vWf release in healthy men. In contrast, bradykinin is a potent vasodilator and selective stimulus for acute local t-PA release. This may, at least in part, explain the fibrinolytic actions of ACE inhibitors in heart failure and ischaemic heart disease.

Adult↗
PubMed2000

Role of angiotensin II in regulation of basal and sympathetically stimulated vascular tone in early and advanced cirrhosis.

BACKGROUND & AIMS: The renin-angiotensin and sympathetic nervous systems are activated in cirrhosis. This study aimed to establish the role of angiotensin II (ANG II) in the regulation of basal and sympathetically stimulated vascular tone in preascitic cirrhotic patients and patients with diuretic-refractory ascites compared with age- and sex-matched healthy controls. METHODS: Forearm blood flow (FBF) responses to lower body negative pressure (LBNP) and to subsystemic, intrabrachial infusions of losartan, an angiotensin II type 1 (AT(1)) receptor antagonist, norepinephrine, and ANG II were measured using venous occlusion plethysmography. RESULTS: In all groups, ANG II and norepinephrine caused dose-dependent reductions in FBF (P < 0.001); responses to norepinephrine were similar across the 3 groups but those to ANG II were less in both cirrhotic groups than in controls (P < 0.01). Losartan caused a dose-dependent increase in FBF only in patients with refractory ascites (P < 0.01). LBNP caused less reduction in FBF in refractory ascites patients than in both preascitic patients and controls (P < 0.01). CONCLUSIONS: Despite hyporesponsiveness to exogenous ANG II in both early and advanced cirrhosis, endogenous ANG II contributes to the maintenance of basal vascular tone only in advanced cirrhosis. These findings suggest a role of ANG II in the pathogenesis of ascites. Attenuated LBNP responses occurred only in advanced cirrhosis, without apparent interaction with endogenous ANG II.

Adult↗