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Biomedical subjects

David J Webb

Publications and source records attributed to David J Webb.

At least 73 records · Page 4Linked to original sources
PubMed2004

Chronic administration of losartan, an angiotensin II receptor antagonist, is not effective in reducing portal pressure in patients with preascitic cirrhosis.

OBJECTIVES: Plasma angiotensin II (ANG II) concentrations are elevated in cirrhosis and have been implicated as a cause of portal hypertension. We aimed to study both the systemic and portal hemodynamics, and tolerability after chronic administration of losartan, an ANG II receptor antagonist. METHODS: Twelve patients with preascitic cirrhosis were studied: mean age of 53.8 +/- 3.3 yr; average Child-Pugh score of 5.8 +/- 0.3; alcohol etiology (5), hepatitis B/C (1/3), primary biliary cirrhosis (3). No patients were on diuretics or vasoactive medication. Hemodynamic measurements were performed at baseline and 4 weeks after daily administration of 25 mg losartan. RESULTS: There was no significant change in the hepatic venous pressure gradient (15.4 +/- 1.5 to 13.6 +/- 1.6 mmHg, -11.7%, p = NS), despite a significant reduction in the wedge hepatic venous pressure (20.3 +/- 1.8 to 17.3 +/- 1.8 mmHg, -14.8%, p < 0.05). Cardiac output, hepatic blood flow, systemic vascular resistance, creatinine clearance, and natriuresis were unaffected. The plasma renin activity increased significantly from 2.7 +/- 0.4 to 5.2 +/- 1.1 ng/ml/h (p < 0.05). There was a significant reduction in the mean arterial pressure from 96.9 +/- 3.3 to 89.3 +/- 3.5 mmHg, -7.8 +/- 3.0% (p = 0.02), with 1 patient experiencing symptomatic hypotension. CONCLUSIONS: Chronic administration of low-dose losartan does not lead to a significant reduction in the portal pressure gradient. Losartan is unlikely to be useful in the management of patients with early cirrhosis, who are at risk of variceal bleeding.

Angiotensin Receptor Antagonists↗
PubMed2003

Bradykinin receptor antagonism and endothelial tissue plasminogen activator release in humans.

OBJECTIVE: We sought to assess pharmacodynamic responses to the bradykinin antagonist B9340 and to determine the contribution of the endothelial bradykinin receptor to stimulated tissue plasminogen activator (t-PA) release in humans. METHODS AND RESULTS: Bilateral forearm blood flow and plasma fibrinolytic variables were measured in 8 volunteers during 100 minutes of intrabrachial infusions of saline placebo, B9340 at 4.5 nmol/min, or B9340 at 13.5 nmol/min. On each occasion, intra-arterial bradykinin (30 to 3000 pmol/min) and substance P (4 to 16 pmol/min) were coinfused for 10 minutes at each dose. To assess the onset and offset of action, 6 additional subjects on 2 occasions received intra-arterial bradykinin (100 pmol/min) for 60 minutes with a coinfusion of either saline placebo or B9340 (13.5 nmol/min) for 12 minutes. During placebo infusion, bradykinin and substance P caused dose-dependent vasodilatation in the infused forearm (P<0.001). B9340 caused a dose-dependent inhibition of bradykinin-induced forearm vasodilatation and t-PA release (P<0.001) without affecting substance P-induced vasodilatation or t-PA release (P=NS). B9340 caused a reversible inhibition of bradykinin-induced vasodilatation (P<0.001) with a rapid onset and offset of action. CONCLUSIONS: B9340 is a potent, reversible, and selective competitive receptor antagonist of bradykinin-induced vasodilatation and t-PA release in humans.

Adult↗
PubMed2003

Sensing characteristics of a novel two-section long-period grating.

The behavior of a temperature self-compensating, fiber, long-period grating (LPG) device is studied. This device consists of a single 325-microm-period LPG recorded across two sections of single-mode B-Ge-codoped fiber--one section bare and the other coated with a 1-microm thickness of Ag. This structure generates two attenuation bands associated with the eighth and ninth cladding modes, which are spectrally close together (approximately 60 nm). The attenuation band associated with the Ag-coated section is unaffected by changes in the refractive index of the surrounding medium and can be used to compensate for the temperature of the bare-fiber section. The sensor has a resolution of +/-1.0 x 10(-3) for the refractive index and +/-0.3 degrees C for the temperature. The effect of bending on the spectral characteristics of the two attenuation bands was found to be nonlinear, with the Ag-coated LPG having the greater sensitivity.

Journal Article↗
PubMed2003

Validation of laser Doppler flowmetry coupled with intra-dermal injection for investigating effects of vasoactive agents on the skin microcirculation in man.

OBJECTIVE: To determine the reproducibility of laser Doppler flowmetry coupled with intra-dermal saline delivery. METHODS: Delivery of saline was judged visually by two operators ( n=100), using a graduated syringe (Becton-Dickinson), by expelling saline onto a weighing boat. Volume was assessed by weight. Skin blood flow following intra-dermal injection of saline was assessed in 18 healthy volunteers; 10 attended twice to assess between-day reproducibility, and 8 attended once to assess between-site reproducibility. Results are expressed as mean value+/-SEM and 95% confidence interval for mean differences. RESULTS: There was no difference between operators in mean injection weight, both weights being 10.3+/-0.1 mg (mean difference 0.08, 95% confidence interval, CI -0.23 to 0.39 mg; n=100, P=0.9). Intra-dermal saline caused a nine-fold increase in blood flow (0.03+/-0.003 to 0.27+/-0.02 perfusion units, PU; n=18, P<0.001). This response had a rapid onset, with the maximal effect seen at 4 min and a duration of greater than 30 min. There was no difference in the magnitude of the response between the dominant and non-dominant arms, AUC was 2.9+/-0.4 and 2.9+/-0.4, respectively (mean difference -0.05, 95% CI -0.8 to 0.73 PU; n=18, P=0.93). However, there was a trend towards differences between study visits 1 and 2: AUC was 3.2+/-0.6 and 2.0+/-0.5, respectively (mean difference 1.2, 95% CI -0.03 to 2.43 PU; n=10, P=0.7). There was no difference in the magnitude of responses between different sites on the forearm ( n=64, P=0.6). CONCLUSIONS: These studies demonstrate that the technique of laser Doppler flowmetry coupled with intra-dermal injection is a safe, well-tolerated technique with good reproducibility. A trend towards reduced between-day reproducibility emphasizes the importance of vehicle control sites when investigating the effects of vasoactive compounds. This technique provides a reliable method for the intra-dermal delivery of drugs, despite the direct effect of injection of saline on blood flow.

Adult↗
PubMed2003

Noninvasive assessment of arterial stiffness and risk of atherosclerotic events.

Investigation of arterial stiffness, especially of the large arteries, has gathered pace in recent years with the development of readily available noninvasive assessment techniques. These include the measurement of pulse wave velocity, the use of ultrasound to relate the change in diameter or area of an artery to distending pressure, and analysis of arterial waveforms obtained by applanation tonometry. Here, we describe each of these techniques and their limitations and discuss how the measured parameters relate to established cardiovascular risk factors and clinical outcome. We also consider which techniques might be most appropriate for wider clinical application. Finally, the effects of current and future cardiovascular drugs on arterial stiffness are also discussed, as is the relationship between arterial elasticity and endothelial function.

Arteries↗
PubMed2003

A novel S-nitrosothiol causes prolonged and selective inhibition of platelet adhesion at sites of vascular injury.

OBJECTIVE: Platelet adhesion to areas of endothelial denudation following angioplasty is an important factor contributing to the limitations of this technique. Lipophilic S-nitrosothiols like S-nitroso-N-valerylpenicillamine (SNVP) are novel nitric oxide (NO) donor drugs with anti-platelet and vasodilator properties that are selective for areas of endothelial denudation. Here we assess the inhibitory effect of SNVP on platelet adhesion to angioplastied rabbit carotid arteries. METHODS: A rabbit model was used to measure adhesion of radiolabelled platelets to carotid arteries following balloon angioplasty. The effects of SNVP were compared to the conventional NO donor, nitroglycerin (NTG). Electron microscopy was used to visualize adhering platelets. RESULTS: Angioplasty resulted in endothelial denudation with only a modest reduction in vessel contractility. In vivo administration of NTG and SNVP (both 200 nmol) prevented the hyper-aggregability (approximately 20%) of circulating platelets caused by angioplasty. However, bolus NTG failed to inhibit adhesion of radiolabelled platelets 30 min after angioplasty, despite inducing a transient 30% reduction in systemic blood pressure. In contrast, equimolar SNVP had little effect on blood pressure but markedly inhibited platelet adhesion (62% compared to control; P=0.003). Platelet adhesion was confirmed with electron microscopy. CONCLUSION: The prolonged effects of SNVP at sites of endothelial damage suggest that novel S-nitrosothiols might offer a means of targeted delivery of an antiplatelet agent to areas of vascular injury.

Angioplasty, Balloon↗
PubMed2003

Intra-arterial vasopressin in the human forearm: pharmacodynamics and the role of nitric oxide.

BACKGROUND AND OBJECTIVES: Diverse vascular effects have been ascribed to vasopressin, including the potential to cause vasodilation, vasoconstriction, and nitric oxide release. The objective of this study was to establish the pharmacodynamics, reproducibility, and nitric oxide dependence of the vasomotor actions of vasopressin in the forearm resistance vessels. METHODS: Blood flow in both forearms of 12 healthy men was measured with venous occlusion plethysmography. Continuous and discontinuous doses of 1 to 300 pmol/min vasopressin were administered by the intrabrachial route. For assessment of the contribution of nitric oxide, vasopressin was coadministered with a "nitric oxide clamp," a balanced coinfusion of 4 micromol/min L-N(G)-monomethylarginine (a nitric oxide synthase inhibitor) and 0.3 to 0.8 nmol/min sodium nitroprusside (an exogenous nitric oxide donor) to block endogenous nitric oxide production and restore normal basal blood flow, respectively. RESULTS: Vasopressin produced a dose-dependent biphasic change in blood flow with a maximum reduction in percentage change in blood flow ratio of infused and control arms of 22% +/- 5% at 3 pmol/min (P <.01) and an increase of 80% +/- 30% at 300 pmol/min (P <.01). There were no significant differences in repeated responses obtained either within or between days. Repeated discontinuous dosing did not change the magnitude of the maximum vasoconstriction or vasodilation, but prolonged continuous infusion produced maximal vasodilation at 12 minutes that subsequently resulted in substantial tachyphylaxis (P =.04). Although there was no augmentation of vasoconstriction, the nitric oxide clamp abolished vasopressin-induced vasodilation (P <.05). CONCLUSIONS: Intra-arterial vasopressin causes a reproducible dose-dependent biphasic change in forearm blood flow. Vasomotor responses are time-dependent with a modest delay to peak vasodilation and tachyphylaxis with prolonged sustained infusion. Nitric oxide release is a major contributor to vasopressin-induced vasodilation but does not directly oppose low-dose vasopressin-induced vasoconstriction.

Adult↗
PubMed2003

Acute caffeine intake influences central more than peripheral blood pressure in young adults.

BACKGROUND: The aim of this study was to characterize the acute effects of caffeine on peripheral and central blood pressure (BP) in healthy individuals, using validated noninvasive techniques. METHODS: In a randomized double-blind study, 300 mg caffeine or matching placebo was administered orally to 20 healthy adults and hemodynamic responses were observed. Central BP and augmentation index (AIx) were determined by pulse wave analysis; cardiac index (CI) was estimated by transthoracic bioimpedance; and heart rate variability (HRV) given by power spectral analysis of pulse interval. Pressure amplification (peripheral to central pulse pressure ratio) and systemic vascular resistance index were also calculated. RESULTS: Caffeine administration increased central systolic and diastolic BP by 7 +/- 3 (P <.01) and 3 +/- 2 mm Hg (P <.05), respectively (mean +/- SEM) at 45 min, but had no effect on peripheral BP. Caffeine caused AIx to increase by 7 +/- 2 and 0 +/- 1%, respectively (P <.05), and pressure amplification to decrease by 1.0 +/- 0.1 v 0.2 +/- 0.2 (P <.001) placebo at 45 min. CONCLUSIONS: Acute caffeine intake significantly increases central BP and large artery waveform transmission and diminishes pressure amplification in healthy adults. Therefore, the effects of caffeine on BP may be significantly underestimated by measurement of BP at the brachial artery.

Adolescent↗
PubMed2003

Management of chronic heart failure due to systolic left ventricular dysfunction by cardiologist and non-cardiologist physicians.

There are now a number of guidelines outlining the diagnosis and management of patients with chronic heart failure (CHF). The extent to which these guidelines are used and the effects on patient outcomes are not well known. The aim of this study was to examine the implementation of a heart failure guideline among cardiologist and non-cardiologist physicians in a university hospital setting. Case record data were examined from 400 patients with a primary diagnosis of CHF. Management of these patients was assessed using a systolic heart failure guideline (Scottish Intercollegiate Guideline Network, number 35) as a benchmark. Hospital admission data were examined contemporaneously over a 17-month period to assess associations between adherence to drug therapies and number of admissions. Overall, there was poor adherence to the guideline, with relatively high use of angiotensin-converting enzyme (ACE) inhibitors/angiotensin II receptor blockers (ARBs) (80%), low use of beta-blockers (32%) and digoxin (36%), and very low use of spironolactone (13%). Cardiologists used more beta-blockers (37 vs. 21%, P=0.003) and digoxin in sinus rhythm (18 vs. 5%, P<0.001) than non-cardiologists. Hospital admission rate was individually associated with increasing age, NYHA status, beta-blocker, diuretic and spironolactone prescription (all P<0.001). At multivariable analysis, only age, NYHA status and increased diuretic prescription were associated with more frequent admission (P<0.001, R(2)=0.15). Despite carefully designed guidelines, the implementation of evidence-based therapies for CHF remains inadequate, even in a university hospital environment. This may reflect a lack of organisational developments to facilitate the increasingly complex management of patients with CHF.

Aged↗
PubMed2003

Electrophysiologic effects of endothelin receptor-A blockade in patients with coronary artery disease.

Selective endothelin receptor-A antagonists are a promising new treatment in patients with heart failure and/or pulmonary hypertension. Animal studies have suggested that these agents may have additional cardiac electrophysiologic actions, however, no data exist in man. We examined the effects of acute endothelin receptor-A blockade on the sinus node, the atrioventricular node and on the ventricular myocardium, in patients with single-vessel coronary artery disease and preserved left ventricular function. The selective endothelin receptor-A antagonist BQ-123 was administered by the intracoronary route, in order to achieve maximum local cardiac effects. After endothelin receptor-A blockade, QT interval increased from 373 +/- 30 msec (mean +/- SD) to 395 +/- 20 msec (p < 0.01) and QTc interval increased from 394 +/- 36 msec to 421 +/- 28 msec (p < 0.01). QT-dispersion, calculated from 12-lead ECG, decreased from 40 +/- 18 msec to 24 +/- 8 msec (p < 0.01) and QTc-dispersion decreased from 44 +/- 20 msec to 26 +/- 9 msec (p < 0.05). These changes were evident only after infusion in the left, but not in the right coronary artery. No effect was found on the sinus node, the atrioventricular node, or the ventricular effective refractory periods. We conclude that selective endothelin receptor A blockade lengthens ventricular repolarization and decreases its inhomogeneity. Further studies are needed to evaluate possible antiarrhythmic actions of this class of agent.

Aged↗
PubMed2003

Systemic and regional changes in plasma endothelin following transient increase in portal pressure.

An acute increase in portal pressure or reduction in portal inflow has been shown to decrease renal plasma flow (RPF). The aim of the study was to evaluate regional and systemic hemodynamics after acute occlusion of a transjugular intrahepatic portosystemic stent-shunt (TIPSS) and study the effect of the same on plasma endothelin (ET-1) levels in the systemic circulation, renal vein, and hepatic vein. Sixteen patients attending for portography after previous TIPSS placement were studied. The shunt was acutely occluded with an angioplasty balloon for 12 minutes. Changes in portal pressure gradient (PPG), hepatic plasma flow (HPF), RPF, cardiac output (CO), and systemic vascular resistance (SVR) were measured before and after shunt occlusion. Blood was collected from the femoral artery and hepatic and renal veins for ET-1 measurement. At T = 0, SVR correlated with circulating arterial ET-1 level (r = 0.74; P <.05). After shunt occlusion (T = 12 minutes), heart rate, CO, and mean arterial pressure decreased (P <.05), whereas PPG increased (P <.05). RPF decreased from 485 +/- 55 to 282 +/- 47 mL/min (P <.01), whereas HPF increased from 700 +/- 39 to 779 +/- 33 mL/min (P <.001). There was a significant increase in arterial concentration and renal production, and decrease in hepatic production of ET-1. Veno-arterial (V-A) concentration difference in ET-1 level in the renal vein, as well as renal flux of ET-1, increased significantly, whereas hepatic vein V-A concentration difference and hepatic flux of ET-1 decreased significantly. At T = 12 minutes, ET-1 renal output correlated negatively with RPF (r = 0.72; P <.05). Results of this study show that an acute increase in portal pressure and reduction in portal inflow brought about by occlusion of a TIPSS shunt decreases RPF and increases HPF. These hemodynamic changes are accompanied by increases in arterial, renal vein, and hepatic vein ET-1 concentrations, which may possibly mediate the observed findings.

Cardiac Output↗
PubMed2003

Cardiovascular effects of acute oxygen administration in healthy adults.

Supplementary oxygen is commonly administered in current medical practice. However, attention has recently been drawn to the potentially disadvantageous hemodynamic consequences in certain patients. Possible mechanisms underlying the cardiovascular responses to acute hyperoxia are unclear. The effects of acute oxygen administration on heart rate, blood pressure, cardiac output, systemic vascular resistance, and baroreflex sensitivity were studied in a series of randomised, placebo-controlled studies in healthy individuals, using validated, non-invasive techniques. The effects of oxygen administration on forearm blood flow responses to locally administered acetylcholine, an endothelium-dependent vasodilator, sodium nitroprusside, an endothelium-independent vasodilator, and l-NG-monomethylarginine, a nitric oxide synthase inhibitor, were studied using venous occlusion plethysmography. Oxygen administration for 1 hour caused a reduction in heart rate (P < 0.01) and cardiac index (P < 0.05), and an increase in mean arterial pressure (P < 0.01), systemic vascular resistance (P < 0.05), large artery stiffness (P < 0.05), and baroreflex sensitivity (P < 0.05). There were no effects on vascular responses in the isolated forearm bed. These findings indicate that oxygen administration causes acute effects on cardiovascular function, which might be important in the context of acute illness.

Acetylcholine↗
PubMed2003

Embedded progressive-three-layered fiber long-period gratings for respiratory monitoring.

A long-period grating (LPG) was written into a progressive three-layered single-mode fiber that was embedded into a flexible platform as a curvature sensor. The spectral location and profile of the LPGs were unaltered after implantation in the platform. The curvature sensitivity was 3.747 nm m with a resolution of +/-1.1 x 10(-2) m(-1). The bend sensor is intended to be part of a respiratory monitoring system and was tested on a resuscitation training manikin.

Elasticity↗
PubMed2003

Local tissue factor pathway inhibitor release in the human forearm.

Nineteen healthy men received unilateral brachial artery infusions of either unfractioned heparin (0.3-100 IU/min), saline or the endothelium-dependent vasodilators substance P (2-8 pmol/min) and bradykinin (100-1000 pmol/min), and the endothelium-independent vasodilator sodium nitroprusside (2-8 micro g/min). Heparin caused a dose-dependent increase in plasma TFPI concentrations in both arms (ANOVA, p <0.0001). Estimated net forearm TFPI release was 7 +/- 16, 29 +/- 20 and 138 +/- 72 ng/100 mL tissue/min during 10, 30 and 100 IU/min of heparin respectively (ANOVA, p <0.0001). Compared to the systemic circulation, the forearm sensitivity to heparin induced TFPI release was 3.6-fold lower (166 +/- 67 ng/IU vs. 596 +/- 252 ng/IU: t-test, p = 0.004). Substance P, bradykinin and sodium nitroprusside all caused substantial dose-dependent increases in blood flow (ANOVA, p <0.001 for all) without affecting plasma TFPI concentrations. There are important regional differences in endothelial TFPI release, with the forearm circulation being relatively insensitive to heparin.

Adult↗
PubMed2002

Lithium carbonate as a potential pharmacological vehicle: intravenous kinetics of single-dose administration in healthy subjects.

OBJECTIVE: We have been developing lithium carbonate solution as a vehicle for delivery of uric acid in a research setting. We wished to determine the pharmacokinetics of a single systemic administration of 500 mg lithium carbonate (13.5 mmol free Li(+)) in healthy subjects. METHODS: Ten healthy subjects received 500 ml of a 0.1% lithium carbonate and 4% dextrose solution intravenously over 1 h. Serum lithium concentrations were determined at baseline, 15, 30, 45, 60, 75, and 90 min, and 2, 3, 7, 24, and 48 h after the start of infusion for kinetic analysis. RESULTS: Administration led to a time-dependent increase in plasma concentration, followed by a rapid decay of serum lithium concentration. Kinetic analysis showed that the pattern best fit a two-compartment model, with rapid extravascular distribution, an elimination phase half-life of 7.8+/-1.7 h, and clearance of 5.3+/-1.1 l/h. CONCLUSIONS: In healthy subjects, lithium half-life is shorter and clearance is higher than suggested by previous reports in other groups. Administration of 500 ml 0.1% lithium carbonate and 4% dextrose over 1 h is safe, well tolerated, and possibly a suitable vehicle for other agents such as uric acid.

Adolescent↗