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Biomedical subjects

J McMurray

Publications and source records attributed to J McMurray.

At least 91 records · Page 5Linked to original sources
PubMed1993

Trends in hospitalization for heart failure in Scotland 1980-1990.

Heart failure is a growing public health problem in industrialized countries with ageing populations. Scotland has a relatively stable population of approximately 5 million and a well described system for recording details of hospitalizations (Scottish Hospital In-Patients Statistics-SHIPS). We have examined SHIPS data for hospitalizations for heart failure in Scotland 1980-1990. Discharges for heart failure as the primary diagnosis increased by almost 60%, from 1.30 to 2.12/1000 population in this period (as either primary or secondary diagnosis the rate increased from 2.51 to 4.24/1000). Seventy-eight percent of discharges were in persons aged > or = 65 years and 48% of discharges were male. Heart failure (primary diagnosis) accounted for almost 4% of all general (internal) medicine discharges. In-patient case fatality was 18% in 1990. Mean duration of in-patient stay on Internal Medicine wards was approximately 11 days. The number of hospitalizations for heart failure is now almost identical to those for myocardial infarction. These trends mirror those recently reported from the United States. Heart failure is an increasingly common and costly cause of hospitalization in Scotland. Approaches which can reduce this burden on the hospital service require urgent attention.

Adult↗
PubMed1993

Effects of a xanthine oxidase/hypoxanthine free radical and reactive oxygen species generating system on endothelial function in New Zealand white rabbit aortic rings.

We investigated the effects of the xanthine oxidase (XO)/hypoxanthine (HX) free radical (FR) generating system on the relaxant properties of aortic rings from New Zealand White rabbits. This system generates superoxide anions, hydroxyl radicals, and H2O2. We wished to identify which of these species is responsible for impairment of vascular function. After obtaining dose-response curves to phenylephrine (PE) and carbachol or sodium nitroprusside (SNP), we exposed rings to the FR generating system or H2O2 for 30 min, either with or without a range of potentially protective agents. Dose-response curves to carbachol or SNP were then repeated. Exposure to the XO/HX system impaired endothelium-dependent, carbachol-induced relaxation. The hydroxyl radical scavengers mannitol, N-(2-mercaptopropionyl)-glycine (MPG), and captopril offered no protection. Superoxide dismutase (SOD) increased the impairment of response, catalase provided partial protection, and a combination of SOD and catalase completely prevented impairment of the response. H2O2 mimicked the effects of XO/HX system. H2O2 appears to be the primary species involved in mediating the toxic effects of the XO/HX FR generating system, but the superoxide anion is probably responsible for some of the loss of relaxation and a role for intracellular generation of hydroxyl radicals cannot be excluded.

Animals↗
PubMed1992

Practical issues when initiating captopril therapy in chronic heart failure. What is the appropriate dose and how long should patients be observed?

To assess the feasibility of introducing captopril in patients with chronic heart failure on an outpatient rather than an inpatient basis a double-blind placebo-controlled study was carried out to compare either 6.25 mg or 25.0 mg of captopril as a starting dose; followed by either incremental doses of 6.25, 12.5, and 25.0 mg (low dose group), or 25.0 mg 8 hourly (high dose group) respectively. Forty-one patients in a general medical ward within a large teaching hospital with moderate to severe, stable, diuretic-controlled chronic heart failure, who were not hyponatraemic, hypokalaemic or on a dose of diuretic greater than 120 mg of frusemide took part. No patient experienced symptomatic hypotension. Both doses of captopril produced a significant drop in blood pressure (BP), the magnitude of which was similar in both groups. The first dose-induced fall correlated significantly with subsequent dose-related reductions in BP. Therefore if a patient did not have a hypotensive response to the first dose of captopril he/she would be unlikely to have one with subsequent doses. In the group as a whole, the magnitude of the fall in BP after the first dose correlated significantly with starting plasma levels of angiotensin II, atrial natriuretic peptide (ANP), aldosterone, and renin. However, on an individual basis, the two patients with the greatest fall in blood pressure did not have the most activated renin-angiotensin-aldosterone (RAA) system. This serves to emphasise the unpredictability of this response and the need to initiate therapy under clinical observation.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1992

Antioxidant effects of angiotensin-converting enzyme (ACE) inhibitors: free radical and oxidant scavenging are sulfhydryl dependent, but lipid peroxidation is inhibited by both sulfhydryl- and nonsulfhydryl-containing ACE inhibitors.

With an assay that generates free radicals (FR) through photooxidation of dianisidine sensitized by riboflavin, 4 x 10(-5) M captopril, epicaptopril (SQ 14,534, captopril's stereoisomer), zofenopril, and fentiapril [all sulfhydryl (-SH)-containing angiotensin-converting enzyme (ACE) inhibitors] were shown effective scavengers of nonsuperoxide free radicals whereas non-SH ACE inhibitors were not. Captopril was a more effective FR scavenger at pH 5.0 than at pH 7.5. Captopril (2 x 10(-5) M) also scavenged the other toxic oxygen species hydrogen peroxide and singlet oxygen and inhibited microsomal lipid peroxidation. Finally, captopril reduced the amount of superoxide anion-radical detected after neutrophils in whole blood were activated with zymosan, probably by inhibiting leukocyte superoxide production.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1992

Evidence for oxidative stress in unstable angina.

OBJECTIVE: To determine whether unstable angina, which is characterised by recurring episodes of myocardial ischaemia and reperfusion, is associated with oxidative stress (that is, where there is an imbalance between oxidants, such as free radicals, which are in excess and antioxidants). DESIGN: Between group comparison of patients with unstable angina, stable angina, and healthy controls. SETTING: The coronary care unit and cardiac investigation ward of a regional cardiology centre. PATIENTS: Twenty five consecutive patients admitted to the coronary care unit with unstable angina. Twenty five consecutive patients admitted to the cardiac investigation ward (patients with stable angina undergoing coronary angiography) were used as controls for the presence of atherosclerosis, drug treatment, and smoking habit. Thirty eight healthy controls (hospital staff and patients admitted for minor surgical procedures who were otherwise healthy) were also studied. MAIN OUTCOME MEASURES: Thiobarbituric acid related substances (TBARS) in plasma and plasma reduced thiol (PSH) as indicators of oxidative damage to lipids and proteins respectively were measured. Coronary angiography was performed in all patients with stable angina and roughly half of those with unstable angina. RESULTS: Mean (SEM) plasma TBARS in unstable angina and stable angina were 9.95 (0.36) nmol/ml and 9.14 (0.28) nmol/ml respectively (p = 0.08). Mean plasma TBARS in healthy controls were 8.09 (0.21) nmol/ml (p < 0.05 compared with both angina groups). Mean (SEM) PSH concentration in unstable angina was 4.21 (9) nmol/ml and in stable angina was 4.85 (9) nmol/ml (p < 0.05). Mean PSH in healthy controls was 5.64 (8) nmol/ml (p < 0.001 compared with both angina groups). The extent of coronary artery disease, use of medication, and smoking habit were not significantly different between the angina groups. CONCLUSIONS: Biochemical indicators of oxidative stress are more abnormal in unstable than stable angina. This is in keeping with experimental evidence that episodes of ischaemia and reperfusion lead to generation of free radicals and toxic oxygen species and depression of endogenous antioxidant activity. The clinical significance of this finding remains to be determined, although, experimentally, free radicals and toxic oxygen species have adverse effects on myocardial contractile function, myocardial electrical stability, endothelial mediated vasodilatation, and coagulation.

Adult↗
PubMed1991

Synergism of histidyl dipeptides as antioxidants.

Histidyl dipeptides such as carnosine (beta-alanyl-L-histidine) and homocarnosine (gamma-amino-butyryl-L-histidine) are reported at millimolar concentrations in several mammalian tissues (O'Dowd et al., 1988; House et al., 1989), but their precise physiological function, or functions, is uncertain. These compounds are known to be potent buffers at physiological pH (Davey, 1960). They are also able to restore functional capacity to fatigued muscle preparations, stimulate some glycolytic enzymes and maintain coupling between mitochondrial oxidation and phosphorylation (Severin, 1964). Histidyl dipeptides may also have antioxidant activity, though this finding is controversial. For example, Aruoma et al. have argued that these compounds, individually, are unable to scavenge superoxide (O2-.), hydrogen peroxide (H2O2) or hypochlorous acid (HOCl) at rates which could offer antioxidant protection in vivo. Since there is a range of these histidyl dipeptides within mammalian tissue we have investigated possible synergism between them in respect of antioxidant activity. Our results show that combining histidine-containing compounds at near physiological concentrations results in synergistic antioxidant activity.

Anserine↗
PubMed1991

Effects of xamoterol in acute myocardial infarction: blood pressure, heart rate, arrhythmias and early clinical course.

Xamoterol is a novel partial agonist of beta 1 adrenoceptors that reduces myocardial ischaemia and improves ventricular function in patients with mild to moderate heart failure. In a double blind, randomised, placebo controlled study, the effects of xamoterol given in a dose of 200 mg twice daily were studied in 51 consecutive patients with acute myocardial infarction, including 17 receiving diuretics for left ventricular failure. Treatment was started on the third day of admission and continued for 7 days. Blood pressure was recorded at 0900 daily, and 24 hour ambulatory electrocardiogram monitoring was commenced at this time on days 1 (pre-treatment), 4, 6 and 9 of admission. Additional drug therapy was recorded daily throughout the study. One patient died prior to randomisation and three were withdrawn (1 placebo, 2 xamoterol) with ventricular arrhythmias and/or disturbances of conduction. Compared to placebo, xamoterol had no effect on the rate of ventricular premature beats or ventricular tachycardia. Xamoterol increased nocturnal heart rate (0000-0600 hrs 79 +/- 2; placebo 72 +/- beats/min; P less than 0.03) but did not change blood pressure. Three patients receiving xamoterol, and 7 on placebo, required new (after randomisation) antianginal therapy. One patient treated with placebo developed new heart failure. These results show that xamoterol can be administered safely to selected patients following myocardial infarction, including those treated for mild heart failure.

Adrenergic beta-Agonists↗
PubMed1991

Unique cardioprotective potential of angiotensin converting enzyme inhibitors: a hypothesis still to be tested on humans.

'Primary cardioprotection' has, arguably, already been shown with thiazide diuretics and probably with beta-blockers. The proven safety and efficacy of these established drugs override any theoretical or experimental considerations in favour of ACE inhibitors. It is unfortunate that, as yet, the number of hypotheses generated in support of ACE inhibitors has not been matched by large scale clinical trials employing these drugs. The first report of the clinical use of an ACE inhibitor was in 1984; it is high time comparative studies with conventional, and proven, agents were undertaken. With regard to 'secondary cardioprotection', there is overwhelming evidence in favour of the use of beta-blockers in patients with myocardial ischaemia. Indeed, we would argue that ACE inhibitors should be used with caution in such patients to avoid impairment of coronary infusion. In the patient with acute myocardial infarction, intravenous nitrates are cheap, easy to use, safe and seem to be effective (in preventing early remodelling and reducing mortality). In the subacute phase, beta-blockers improve prognosis and, according to the currently available evidence in humans, nitrates are as effective as captopril in altering late remodelling; as in the acute situation, nitrates are cheaper, simpler to use and have a track record of long-term safety. ACE inhibitors improve symptoms, exercise capacity and prognosis in chronic heart failure. In this condition, they have been a major therapeutic advance and, on the available evidence, are to be initially preferred to other vasodilators though they should be given in addition to diuretics.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗
PubMed1991

Influence of ACE inhibitors on free radicals and reperfusion injury: pharmacological curiosity or therapeutic hope?

1. The currently available evidence shows that thiol containing ACE inhibitors are free radical (FR) scavengers in vitro; in particular the OH. radical is effectively scavenged by these compounds. There is also good evidence that, in vivo, ACE inhibitors can preserve myocardial contractile function following a period of reversible ischaemia (by directly protecting myocytes and/or preserving coronary flow through protection of endothelial cells). These in vivo benefits are probably also due to FR scavening, mainly due to the presence of a thiol group but, also as a consequence of augmented prostanoid production. 2. Use of more relevant animal models and testing of a range of doses of ACE inhibitors might be undertaken before clinical investigation is considered. Because of its nature, however, the existence and importance of reperfusion injury in man will only be proven or disproven by pharmacological intervention. One option is to compare a thiol containing agent with absent or minimal haemodynamic effects with placebo as an adjunct to thrombolysis. This is the simplest approach. An alternative approach is to conduct a comparative study of a -SH containing ACE inhibitor and a non -SH containing ACE inhibitor given prior to thrombolysis. There are many problems with either approach. The lack of reliable measures of FR activity in man and difficulty in measuring accurately left ventricular function post-myocardial infarction means that mortality is likely to be the only reliable end-point in such a study.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1991

Increased concentrations of tumour necrosis factor in "cachectic" patients with severe chronic heart failure.

OBJECTIVE: To ascertain whether patients with cardiac failure and reduced body weight ("cardiac cachexia") have increased circulating concentrations of tumour necrosis factor (cachectin). DESIGN: Patients with cardiac failure were prospectively identified as "cachectic" (body fat less than 27% in men and less than 29% in women measured by skinfold thickness callipers) or "non-cachectic". Tumour necrosis factor was assayed blind to patient group. SETTING: Cardiology unit in a tertiary referral centre. PATIENTS: 26 consecutive patients (10 women) (mean age 61) admitted for investigation or treatment of chronic heart failure. All were in New York Heart Association class III or IV. RESULTS: In nine of the 16 cachectic patients the concentration of tumour necrosis factor was increased (mean (SEM) 74 (20) pg/ml) compared with one of the 10 "non-cachectic" patients (22 pg/ml, p less than 0.001). Patients with a raised circulating concentration of tumour necrosis factor weighed significantly less (55.6 (3.5) kg) than those in whom the concentration of tumour necrosis factor was normal (69.0 (4.1) kg) (p = 0.02). CONCLUSIONS: Circulating concentrations of tumour necrosis factor were increased in a significant proportion of patients with chronic heart failure and low body weight. Tumour necrosis factor stimulates catabolism experimentally and it may be a factor in the weight loss seen in patients with "cardiac cachexia".

Adult↗
PubMed1991

Atrial natriuretic factor in chronic heart failure.

The pathophysiological role of atrial natriuretic factor in patients with chronic heart failure is still unclear. Plasma ANF levels are elevated in this condition, particularly in patients with severe left ventricular dysfunction and during acute exacerbations. Drug therapy, including diuretics, vasodilators and inotropes which reduce cardiac filling pressures also reduce plasma ANF levels. In the clinical setting the measurement of ANF levels may provide a useful means of assessing salt and water retention in patients with heart failure. Intravenous infusion of ANF to patients with heart failure causes a diuresis and natriuresis, a fall in filling pressures and possibly suppression of the renin-angiotensin aldosterone system. High bolus dosing with the peptide may reduce systemic vascular resistance resulting in hypotension, which markedly attenuates the renal effects. A new pharmacological approach in this area is the development of neutral endopeptidase inhibitors, which prolong the half-life of endogenous ANF and potentiate its effects. The therapeutic potential of ANF in heart failure has yet to be realised.

Animals↗
PubMed1990

Oxidative damage in chronic heart failure: protection by captopril through free radical scavenging?

The pathogenesis of heart failure is not yet fully understood. In animal models there is some evidence to suggest a role for free radicals (FRs). We have investigated malondialdehyde - LM in plasma of patients with heart failure and found it to be raised when compared to controls. We present data to show that Captopril, a drug with an ACE inhibitory effect is a FR scavenger both in vitro and ex-vivo in patients with heart failure.

Aged↗