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J McMurray

Publications and source records attributed to J McMurray.

At least 73 records · Page 4Linked to original sources
PubMed1996

Captopril and norepinephrine-induced hypertrophy and haemodynamics in rats.

We wished to determine whether pretreatment with captopril, an angiotension-converting enzyme (ACE) inhibitor, modified the myocardial and haemodynamic consequences of chronic administration of norepinephrine (NE) in rats. Administration of NE (0.15 mg kg(-1) h(-1) by an osmotic minipump implanted subcutaneously for 28 days) resulted in left but not right ventricular hypertrophy. Captopril (250 but not 52 mu g kg(-1) h(1) administered for 28 days) significantly attenuated the development of left ventricular hypertrophy (weight of left ventricle to body weight ratio was 0.46 +/- 0.01 0.57 +/- 0.02, 0.53 +/- 0.02, and 0.51 +/- 0.01 for vehicle, NE, and NE plus low and high dose of captopril, respectively). Chronic administration of NE caused significant increases in systolic arterial blood pressure (BP: 194 +/- 11 vs. 130 +/- 6 mm Hg), systolic left ventricular pressure, heart rate (HR: 458 +/- 13 vs. 389 +/- 15 beats/min) and dP dt(-1)(max) P(-1), an index of myocardial contractility (202 +/- 29 vs. 91 +/- 3 s(-1)). Captopril (250 mu g kg(-1) h(-1) for 28 days) significantly reduced diastolic arterial BP (from 86 +/- 6 to 53 +/- 3 mm Hg). Concomitant administration of this dose of captopril together with NE prevented the NE-induced increase in systolic arterial BP but did not modify the increases in HR or dP dt(-1) max P(-1) (261 +/- 41 and 202 +/- 29 s(-1) in captopril and NE vs. NE-alone groups). Acute administration of NE (0.1-10 mu g kg(-1) intravenously, i.v.) produced less marked increases in cardiac contractility and in arterial BP in rats chronically pretreated with NE or NE plus captopril than in animals receiving vehicle or captopril alone. Chronic administration of NE and/or captopril did not significantly modify the haemodynamic effects of the acute administration of calcium chloride. We conclude that administration of captopril at 250 but not 52 mu g kg(-1) h(-1) for 28 days attenuates NE-induced cardiac hypertrophy and that this effect is associated with a decrease in systolic arterial BP. Captopril did not modify the reduced effects of acutely administered NE in rats treated with NE for a prolonged period.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1996

The pharmacoeconomics of ACE inhibitors in chronic heart failure.

Because heart failure is common and disabling, patients with this condition utilise healthcare resources to a considerable extent. In particular, patients with heart failure frequently require hospital admission, and inpatient care is often protracted. Patients with the most advanced stages of heart failure make the greatest demands on the healthcare system. Expenditure related to the consumption of healthcare resources accounts for the 1 to 2% of total healthcare spending related to heart failure. Between two-thirds and three-quarters of this is due to the costs of hospital care. ACE inhibitors reduce progression of heart failure and also reduce the need for hospitalisation by approximately 30%. In so doing, these drugs substantially or totally offset their cost and the cost of extended life. Five independent economic analyses collectively show ACE inhibitors, at worst, to be very cost effective (in comparison to other cardiovascular therapies), cost neutral or to lead to overall cost savings when used to treat heart failure.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1995

Effects of chronic norepinephrine administration on cardiac function in rats.

We assessed the changes in the contractile response of rat hearts in vivo after chronic exposure to a range of doses of norepinephrine (NE) and determined whether free radical production played a role in these changes. Osmotic minipumps were implanted subcutaneously (s.c.) in male rats and delivered either NE (0.15-0.35 mg/kg/h) or acid saline for 10-28 days. The animals were then anaesthetised and prepared for haemodynamic measurement, and dose-response curves to acutely administered NE and calcium chloride were constructed. We analysed plasma for evidence of free radical activity by measuring the levels of thiobarbituric acid-reactive substances (TBARS). All doses of NE studied produced left, but not right, ventricular hypertrophy. Treatment with 0.25 mg/kg/h NE for 28 days produced signs of distress and, by 10 days, treatment with 0.35 mg/kg/h resulted in 33% mortality. Treatment with the two lower doses, but not the highest dose, of NE resulted in increases in basal left ventricular (LV) maximum rate of pressure generation and a marked increase in systolic, but not diastolic, arterial blood pressure (SBP, DBP). All doses of NE caused reduced responses to acutely administered NE but no marked change in the response to calcium chloride. Levels of plasma free radicals were increased only with the highest dose of NE. Over the concentration range studied, chronic administration of NE to rats causes beta-adrenoceptor downregulation and free radical production was associated only with the administration of a dose of NE that resulted in high mortality.

Analysis of Variance↗
PubMed1995

Effect of captopril, enalaprilat and mercaptopropionyl glycine (MPG) on the oxidative activity of human isolated neutrophils.

1. Neutrophil NADPH oxidase produces the superoxide anion (O2-) anion radical from oxygen. The thiol containing ACE inhibitor, captopril has been reported to inhibit isolated NADPH oxidase. The above effect of captopril, if present in intact cells, could contribute to the ability of this drug to alleviate neutrophil-mediated tissue damage. We have, therefore, investigated the effect of captopril on the oxidative activity of intact human isolated neutrophils. 2. The effects of captopril on neutrophil oxidative activity were compared with those of enalaprilat (a non-thiol ACE inhibitor) and N-mercaptopropionyl glycine (MPG) (a simple thiol). 3. The oxidative response of PMA-stimulated neutrophils measured by lucigenin chemiluminescence was not affected by any of these test agents. The thiol captopril and MPG (but not enalaprilat) caused an initial delay in luminol chemiluminescence production by PMA-stimulated neutrophils. 4. Captopril and MPG (but not enalaprilat) increased, rather than decreased oxygen uptake, when added to PMA-stimulated neutrophils. Thiol oxidation was determined to be, at least partly, responsible for the excess oxygen uptake observed. 5. NADPH oxidase activity in intact neutrophils was not affected by captopril, MPG or enalaprilat. The inhibition of NADPH oxidase activity is unlikely to contribute to the therapeutic effects of captopril and other thiols.

Acridines↗
PubMed1995

Does luminol chemiluminescence detect free radical scavengers?

Thiol compounds have been reported to abolish hypoxanthine/xanthine oxidase induced luminol chemiluminescence and this effect has been attributed to scavenging of superoxide (O2-)/(H2O2) produced from hypoxanthine/xanthine oxidase. Yet other workers have reported that thiol compounds have shown little, if any, reactivity towards O2-/H2O2. The aim of this study was to examine the discrepancy between these two sets of findings further. Captopril (a thiol angiotensin-converting enzyme (ACE) inhibitor) and MPG (a simple thiol) were observed to abolish hypoxanthine/xanthine oxidase induced chemiluminescence. The reactivity of captopril and MPG towards O2-/H2O2 was then determined by measurement of thiol oxidation in captopril and MPG after their incubation with hypoxanthine/xanthine oxidase. Incubation (at 10 min, 37 degrees C) with 4 mM hypoxanthine/0.03 u ml-1 xanthine oxidase resulted in 7% and 20% thiol oxidation in captopril and MPG (at 1 mM) respectively. Captopril and MPG, therefore, appeared to be ineffective scavengers of oxidants produced by hypoxanthine/xanthine oxidase. Captopril and MPG also did not affect urate production or oxygen consumption by xanthine oxidase which indicated that captopril and MPG quench luminol chemiluminescence by a mechanism that excludes the inhibition of xanthine oxidase. Hypoxanthine/xanthine oxidase induced luminol chemiluminescence may, therefore, be an unsuitable method for measuring free radical scavenging activity by drugs.

Antioxidants↗
PubMed1995

Antigenic and immunogenic properties of synthetic peptide-based T-cell determinant polymers.

Presentation of T-cell determinants to the immune system in multimeric form has clear advantages and the production of synthetic peptide-based polymers using the solubilisable KS resin described by Goddard et al. [1] provides a method of assembling such polymers and also offers the means for making heteropolymers. The present study investigates the potential of polymeric synthetic peptide constructs in eliciting proliferative T-cell responses to determinants of the influenza virus hemagglutinin. The induction of vigorous CD4+ T-cell immunity was achieved with a polymeric construct containing two different T-cell determinants. The data presented here also highlight the fact that distancing the determinant from the support backbone with appropriate amino acid residues is an important consideration for the success of these polymeric immunogens. This approach may be readily applied in other systems where induction of helper T-cell responses are required.

Amino Acid Sequence↗
PubMed1994

Alteration of the erythrocyte glutathione redox balance by N-acetylcysteine, captopril and exogenous glutathione.

The effect of the thiol containing compounds N-acetylcysteine and captopril on glutathione metabolism in human erythrocytes has been investigated non-invasively using 1H spin echo NMR. N-Acetylcysteine was found to increase the reduced form of glutathione while captopril increased the oxidized form, but no changes in the total glutathione concentration were observed. Incubation of the cells with buthionine sulphoximine to inhibit de novo glutathione synthesis did not affect the response. The results show that these compounds act by altering the redox balance of glutathione rather than by stimulating its synthesis, and that their mechanisms of action are different, and not simply due to the presence of the thiol group.

Acetylcysteine↗
PubMed1994

The assessment of the HO. scavenging action of therapeutic agents.

A new method is reported for the assessment of the HO. scavenging action of therapeutic agents. It is based on the photolysis of zinc oxide and has a detection limit of 3.3%. The scavenging order of the compounds tested was penicillamine > rentiapril > ascorbic acid > cysteine > glutathione > thiomalic acid > N-acetylcysteine > myocrysin > methionine. None were as effective as DMSO. It is argued that these compounds can have an in vivo protective effect where HO. is produced from oxidant producing cells, thus limiting radical induced damage.

Azo Compounds↗
PubMed1994

Effects of ACE inhibitors on oxidation of human low density lipoprotein.

Oxidation of low density lipoprotein (LDL) may be instrumental in the development of atherosclerosis. We have examined the effect of the angiotensin converting enzyme (ACE) inhibitors captopril and quinaprilat and the -SH containing compound N-acetylcysteine on LDL oxidation. Oxidation of isolated human LDL was initiated with CuCl2. Conjugated diene formation (monitored spectrophotometrically at 234 nm) gave a measure of LDL oxidation. Captopril inhibited LDL oxidation but quinaprilat did not. The lag phase to the rapid increase in absorbance at 234 nm determined was 109 (65-157) min median and range for control samples and rose to 209 (168-305) min with captopril 10 microM, a ratio of 2.1:1 for drug to control (P = 0.01). N-acetylcysteine had a similar effect to captopril (drug to control lag time ratio 2.0:1, with NAC 10 microM), i.e. suggesting resistance to oxidation was due to the -SH group of both drugs. Captopril may have a potentially anti-atherosclerotic property not shared by other ACE inhibitors.

Acetylcysteine↗
PubMed1994

The effect of angiotensin-converting enzyme inhibitors on human neutrophil chemotaxis in vitro.

1. Myocardial 'reperfusion injury' has been partly attributed to the production of free radicals which are cytotoxic towards cells. Neutrophils are recruited by ischaemic tissue and are one source of free radicals. Angiotensin-converting enzyme (ACE) inhibitors can reduce 'reperfusion injury' and we decided to determine if ACE inhibitors might contribute to this effect by inhibiting neutrophil chemotaxis. 2. The effects of captopril (a thiol containing ACE inhibitor) and enalaprilat (a nonthiol ACE inhibitor) and N-mercaptopropionyl glycine (MPG) (a simple thiol) on neutrophil chemotaxis were tested in an in vitro Boyden chamber assay. 3. The chemotactic response of human neutrophils to fMLP was reduced by 27.6% with MPG (n = 8; P < 0.05), by 13.2% with enalaprilat (n = 8; P = 0.075) and by 5.2% with captopril (n = 8; P = 0.66) at 5 microM (therapeutic concentration.) 4. Neutrophil chemotaxis was significantly decreased with 50 microM and 500 microM MPG and enalaprilat and 500 microM captopril. 5. Supratherapeutic concentrations of ACE inhibitors can reduce neutrophil chemotaxis at high concentrations and this effect does not appear to be -SH dependent.

Captopril↗
PubMed1993

Effects of the xanthine oxidase system on cardiac function in anaesthetised rats.

This investigation aimed to determine whether contractile dysfunction of the myocardium could be produced upon generation of free radicals in the anaesthetised rat. The enzyme xanthine oxidase, combined with its substrate purine and an iron source, was used to generate free radicals in the venous circulation. The suspended form of xanthine oxidase, with substrate, produced a transient, significant depression in the contractile indices dP dt-1 max and dP dt-1 P-1 and arterial blood pressure, 1146 +/- 87 mm Hg s-1, 9 +/- 1 s-1, and 18 +/- 1 mm Hg, respectively. This could not be attenuated by the enzymatic free radical scavengers superoxide dismutase and catalase. Furthermore, the suspended xanthine oxidase alone or its vehicle were able to produce a similar effect to that of the complete free-radical-generating system. The maximum soluble dose of the crystalline form of the enzyme when employed in the generating system had no effect upon administration despite its production of superoxide radicals in vitro. These results suggest that the haemodynamic effects of the free-radical-generating system containing the suspended form of xanthine oxidase were due to the effects of its vehicle and that the free-radical-generating system containing the crystalline form of the enzyme did not produce sufficient free radicals in vivo to modify myocardial contractility.

Animals↗
PubMed1993

Evidence of oxidative stress in chronic heart failure in humans.

Chronic heart failure (CHF) due to coronary artery disease (CAD) has been shown to be associated with increased plasma thiobarbituric reactive substances (TBARS) and reduced plasma thiol (PSH) concentrations, suggesting oxidative stress (OS). The aims of the present studies were (a) to determine whether OS is due to CAD or CHF per se and (b) to determine if a wider range of more specific markers of OS are abnormal in CHF. In the first study, two groups of patients (n = 15 each) were compared. Group 1 (11 male, mean age 56 years) had CHF due to CAD and group 2 (12 male, mean age 53 years) had non-CAD CHF. Median plasma TBARS in controls was 7.6 nmol.ml-1, 10.0 nmol.ml-1 in group 1 and 9.3 nmol.ml-1 in group 2 (P < 0.01 both groups vs control). Median PSH was 505 384 and 364 nmol.ml-1 (P < 0.05 and P < 0.01 vs control) respectively. Fifty-three patients with CHF were recruited in the second study. Malondialdehyde and PSH were 10.3 and 409 nmol.ml-1 respectively, compared to control values of 7.9 and 560 nmol.ml-1 (both P < 0.001). The median values for the following additional measures of OS in controls and patients were: erythrocyte superoxide dismutase 131 vs 114 U.l-1 (P = 0.005); caeruloplasmin oxidase 97 vs 197 U.l-1 (P < 0.01); erythrocyte glutathione 1.56 nmol.ml-1 vs 1.77 nmol.ml-1 (P < 0.02); plasma conjugated dienes 0.28 vs 0.33 optical density units (P = ns).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗