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Biomedical subjects

A D Struthers

Publications and source records attributed to A D Struthers.

At least 145 records · Page 8Linked to original sources
PubMed1995

Serial changes in blood pressure, renal function, endothelin and lipoprotein (a) during the first 9 days of cyclosporin therapy in males.

OBJECTIVE: To elucidate the sequential mechanisms underlying cyclosporin-induced hypertension and nephrotoxicity. DESIGN: A study of healthy males over the first 9 days of drug ingestion to permit the detection of serial changes in renal function and blood pressure in a situation free from the confounding variables of concomitant disease or drugs. METHODS: Double-blind, placebo-controlled, randomized crossover study with cyclosporin (5 mg/kg twice a day) or placebo. Blood pressure and urinary sodium excretion were measured each day, and glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were measured on days 1, 4, 7 and 9. Cholesterol, lipoprotein (a) and endothelin were measured on days 1 and 9. RESULTS: GFR decreased by 9% with cyclosporin and was significantly lower than with placebo on day 4 of therapy. ERPF fell by 24%. The fall in GFR correlated significantly with suppressed plasma renin activity (P < 0.0001). Cyclosporin-induced hypertension occurred in the absence of any change in urinary sodium output or in plasma endothelin. Cyclosporin did not affect lipoprotein (a) levels during 9 days of cyclosporin therapy. CONCLUSIONS: Cyclosporin-induced hypertension and renal vasoconstriction are well established after 9 days of cyclosporin 5 mg/kg twice a day. We found no evidence to implicate either circulating endothelin or renal sodium retention in the onset of cyclosporin-induced hypertension. Cyclosporin-induced renal vasoconstriction appeared to occur when the protective mechanism of plasma renin activity suppression became exhausted.

Adult↗
PubMed1995

Cyclosporin-induced renal vasoconstriction is augmented by frusemide and by angiotensin II in humans.

OBJECTIVE: To investigate the role of the renin-angiotensin-aldosterone system as a homoeostatic mechanism by examining whether mild activation of the renin-angiotensin-aldosterone system could enhance cyclosporin-induced renal vasoconstriction and hypertension. METHODS: We artificially activated the renin-angiotensin-aldosterone system by two means: by pretreatment with frusemide (40 mg/day orally for 2 days) and by administering exogenous angiotensin II (1 ng/kg per min intravenously). In both cases the levels of renin-angiotensin-aldosterone system activation achieved did not by themselves alter renal blood flow, glomerular filtration rate or blood pressure. We then examined the effect of cyclosporin (10 mg/kg twice a day orally) in the presence of the activated renin-angiotensin-aldosterone system in normal humans. RESULTS: Cyclosporin alone acutely altered neither glomerular filtration rate (760 versus 734ml, NS; area under the curve for placebo versus cyclosporin) nor effective renal plasma flow (4,163 versus 3,915 ml, NS; area under the curve for placebo versus cyclosporin). Co-administration of exogenous angiotensin II with cyclosporin induced a fall in effective renal plasma flow from baseline but no change in glomerular filtration rate. Frusemide pretreatment together with cyclosporin administration induced a fall in glomerular filtration rate and a fall in effective renal plasma flow. Neither exogenous angiotensin II nor frusemide pretreatment influenced the blood pressure rise induced by cyclosporin. The present findings demonstrate that renin-angiotensin-aldosterone system activation augments cyclosporin-induced renal vasoconstriction but not cyclosporin-induced systemic vasoconstriction. We suggest that the renin-angiotensin-aldosterone system suppression, which normally occurs with cyclosporin, may be a homoeostatic mechanism to help prevent cyclosporin-induced renal vasoconstriction. The renin-angiotensin-aldosterone system appears, however, to play little or no role in mediating or preventing the initial increase in blood pressure caused by cyclosporin. Furthermore, frusemide is commonly prescribed together with cyclosporin even though this combination has the potential to cause a marked increase in renal dysfunction.

Adult↗
PubMed1995

Effects of captopril and enalapril on renal function in elderly patients with chronic heart failure.

OBJECTIVE: To compare the effects on renal function of captopril and enalapril in elderly patients with chronic heart failure. DESIGN: A multi-centre double-blind parallel-group comparison of the two angiotensin-converting enzyme (ACE) inhibitors, captopril (12.5 mg bid) and enalapril (2.5 mg bid). SUBJECTS: 80 elderly patients with chronic heart failure (41 in the captopril group, 39 in the enalapril group). MAIN OUTCOME MEASURES: The blood pressure and pulse rate response to the first dose of ACE inhibitor was assessed in all patients. Glomerular filtration rate (GFR) was measured radioisotopically by 99mTcDTPA or 51CrEDTA clearance after three and six months of each treatment. Subgroups were assessed for effective renal plasma flow (33 patients), exercise tolerance (25 patients) and by a symptom-oriented questionnaire (45 patients). RESULTS: No serious adverse effect on GFR was noticed. There was no significant difference between the two treatments in the mean baseline GFR or in changes from baseline at three and six months (captopril mean baseline GFR 49.6 ml min-1 1.76 m-2, enalapril 54.7 ml min-1 1.76 m-2; mean change (95% confidence interval) at three months captopril 12 ml min-1 (+3.0, +21.0), enalapril -2 ml min-1 (-13.0; +9.0); mean change at six months, captopril 3.7 ml min-1 (-6.7; +14.2), enalapril -6.0 ml min-1 (-21.0; +9.4). Significantly more patients given captopril had an improvement in GFR during the study period (26/31 compared with 20/31 enalapril-treated patients at three months, p = 0.0096, and 23/30 compared with 15/27 at six months, p = 0.021). There were no significant changes in effective renal plasma flow. Three patients treated with enalapril developed symptomatic hypotension within three days of starting treatment. Quality of life questionnaires revealed more gastrointestinal symptoms in the enalapril group (p = 0.039). CONCLUSIONS: Captopril seems marginally preferable to enalapril in the treatment of chronic heart failure in elderly patients.

Aged↗
PubMed1995

Abnormal myocardial repolarisation in response to hypoxaemia and fenoterol.

BACKGROUND: Prolongation of the QTc interval has been associated with cardiac dysrhythmias and sudden death. QTc dispersion (interlead variability in QTc interval) has recently been proposed as being a more sensitive marker of repolarisation abnormalities and shown to be a more specific index of arrhythmia risk. Although hypoxaemia and fenoterol have previously been shown to prolong the QTc interval, this does not reflect regional myocardial repolarisation abnormalities. METHODS: Electrophysiological effects were measured at baseline and after 30 minutes steady state hypoxaemia at an arterial oxygen saturation (SaO2) of 75-80% (study 1) and at baseline then 30 minutes after inhaled fenoterol 2.4 mg (study 2). From the ECG, lead II corrected QT interval (QTc) and overall corrected QT dispersion were measured using a computer linked digitising tablet according to standard criteria. RESULTS: QTc dispersion was increased during hypoxia compared with baseline values (mean (SE) 69 (6) ms v 50 (5) ms) and after fenoterol compared with baseline (79 (13) v 46 (4) ms), respectively. There was also an increase in QTc interval and heart rate after fenoterol (493 (23) v 420 (6) ms and 98 (3) v 71 (6) bpm, respectively). The heart rate was increased during hypoxaemia compared with baseline (78 (3) v 64 (2) bpm), but no change occurred in the QTc interval. CONCLUSIONS: Both hypoxaemia and fenoterol cause myocardial repolarisation abnormalities in man in terms of increased QTc dispersion, but only fenoterol increased the QTc interval. This may be relevant in the aetiology of arrhythmias in patients with acute severe asthma where beta agonist therapy and hypoxaemia coexist.

Adrenergic beta-Agonists↗
PubMed1995

Natriuretic response to neutral endopeptidase inhibition is blunted by enalapril in healthy men.

We studied six healthy male subjects in a randomized, placebo-controlled, single-blind fashion to determine the comparative effects on renal hemodynamics and natriuresis of the angiotensin-converting enzyme inhibitor enalapril (5 mg on each of 5 days preceding the study), the neutral endopeptidase inhibitor candoxatrilat (200 mg IV), and the combination of enalapril and candoxatrilat. Enalapril pretreatment alone, compared with placebo, produced slight nonsignificant increments in absolute and fractional sodium excretions and a marked increase in effective renal plasma flow but no change in glomerular filtration rate. Candoxatrilat alone produced marked augmentation of both absolute and fractional sodium excretions. The candoxatrilat-mediated increment in absolute sodium excretion was significantly correlated with increases in urinary cGMP and plasma atrial natriuretic peptide in response to this drug, but neither effective renal plasma flow nor glomerular filtration rate was altered compared with placebo. Combining enalapril pretreatment with candoxatrilat significantly attenuated the increments in absolute and fractional sodium excretions in response to the neutral endopeptidase inhibitor. Blood pressure was reduced by enalapril alone compared with placebo, whereas candoxatrilat treatment alone led to a marginal but significant enhancement of blood pressure. The combination of enalapril and candoxatrilat abolished any significant blood pressure change compared with placebo. Thus, candoxatrilat-mediated natriuresis occurs via a renal tubular rather than glomerular mechanism and is blunted by enalapril. This attenuation by enalapril may occur by interference with angiotensin II-dependent effects on the renal tubule or on systemic blood pressure.

Adult↗
PubMed1995

Mineralocorticoid receptor blockade in chronic heart failure.

The effects of ACE inhibitors on plasma aldosterone in chronic heart failure are poor, variable and unsustained. This is important to recognise because aldosterone has many harmful properties of its own. Aldosterone causes magnesium loss, potentiates catecholamines, induces ventricular arrhythmias, alters baroreflex function and stimulates myocardial fibrosis. Strategies to reduce these effects of aldosterone are being explored.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1995

The effect of enalapril on tyramine induced changes in renal function in man.

Increasing animal evidence support an important facilitatory interaction between angiotensin II and norepinephrine within the kidney. This angiotensin II/norepinephrine interaction was investigated in man by examining the effect of enalapril pretreatment (5 mg for 5 days) on the renal response to a low non-pressor dose of intravenous tyramine 4 micrograms/kg/min for 120 min in 8 healthy subjects undergoing water diuresis. Tyramine is an indirect sympathomimetic agent which causes neuronal release of norepinephrine. Enalapril and tyramine, alone and in combination, had no effect on glomerular filtration, effective renal plasma flow or sodium excretion. Tyramine caused a significant increase in urinary flow rate (p < 0.05) but this was not influenced by enalapril pretreatment. The lack of effect of enalapril on the renal response to tyramine contrasts with a previous study which examined the effect of enalapril on the renal response to circulating norepinephrine. This may suggest that enalapril affect renal function only when there is renal vasoconstriction (as with norepinephrine) and not when renal blood flow is unchanged (as with tyramine).

Adult↗
PubMed1995

QT dispersion in essential hypertension.

Increased QT dispersion is associated with sudden cardiac death in congestive heart failure, hypertrophic cardiomyopathy, and following acute myocardial infarction. Patients with hypertension, in particular those with left ventricular hypertrophy, are also at greater risk of sudden cardiac death. We examined whether QT dispersion, which is easily obtained from a routine ECG, correlates with echo LVH. Sixty-nine untreated patients with essential hypertension had QT dispersion measured from a surface 12-lead electrocardiogram, and two-dimensional echocardiography performed to measure interventricular septal thickness, posterior wall thickness, and left ventricular internal diameter. Office blood pressure was recorded, and in 56 patients, 24 h ambulatory blood pressure monitoring was also done. Multivariate analysis demonstrated significant relationships between QT dispersion and office systolic blood pressure, and left ventricular mass index. Similar findings were obtained when QT dispersion was corrected for heart rate (QTc dispersion). After patients with electrocardiographic left ventricular hypertrophy (n = 5) were excluded from the analysis, the above relationships persisted. Increased QT dispersion is thus found in those essential hypertensives at greatest risk of sudden death. Since this relationship persists even in the absence of electrocardiographic left ventricular hypertrophy, measurement of QT dispersion might be a simple, non-invasive screening procedure to identify those hypertensives at greatest risk of sudden death.

Adolescent↗
PubMed1995

Human C-type natriuretic peptide: effects on the haemodynamic and endocrine responses to angiotensin II.

OBJECTIVE: The aim was to study the effects of high dose systemic human C-type natriuretic peptide (CNP) infusion in man on systemic and pulmonary haemodynamics and the renin-angiotensin system before and after infusion of angiotensin II. METHODS: Eight normal male volunteers were studied on two separate occasions when, after the subjects had been rested to reach a baseline haemodynamic state (T0), infusions of either human CNP (10 pmol.kg-1.min-1) or placebo (5% dextrose) were begun. After 30 min (T30) on each study day, a concomitant infusion of angiotensin II (6 ng.kg-1.min-1) was started, and both infusions ran together for a further 30 min (until T60). Measurements of systemic and pulmonary haemodynamic variables and the activity of the renin-angiotensin system were made at baseline (T0), after 30 min of CNP or placebo (T30), and after angiotensin II (T60). RESULTS: Infusion of CNP had no significant effects on systemic or pulmonary haemodynamics or on baseline renin-angiotensin system activity compared with placebo. Infusion of angiotensin II produced significant systemic and pulmonary pressor effects and also stimulated aldosterone secretion. There were, however, no significant differences between the changes induced by angiotensin II (expressed as the difference between T30 and T60) when CNP was infused compared with placebo: change in mean systemic arterial pressure with CNP 26.6(SEM 2.3) mm Hg v placebo 30.3(3.6) mm Hg; change in mean pulmonary artery pressure with CNP 11.7(2.5) mm Hg v placebo 10.9(1.0) mm Hg; change in aldosterone concentration with CNP 219(40) pmol.litre-1 v placebo 242(40) pmol.litre-1. CONCLUSIONS: At a dose of CNP which has previously been found to have marked haemodynamic effects in dogs, no effect on systemic or pulmonary haemodynamics was observed in man. Furthermore, CNP had no effect on the aldosterone or pressor responses to infused angiotensin II. The present study would suggest that CNP does not have a circulating endocrine role in cardiovascular homeostasis, although a paracrine role within vascular endothelium is perhaps more likely.

Adult↗
PubMed1995

Two new culprits in cardiovascular disease: QT dispersion and aldosterone.

Two new culprits have arisen in chronic heart failure (CHF). QT dispersion, which is the maximum QT interval minus the minimum QT interval in an ECG, may well predict sudden cardiac death. Aldosterone produces many harmful effects: magnesium loss, myocardial fibrosis, sympathetic activation, baroreflex dysfunction and ventricular arrhythmias. The RALES study is currently examining whether spironolactone improves mortality in CHF.

Aldosterone↗
PubMed1994

Determinants of the initial effects of captopril on blood pressure, glomerular filtration rate, and natriuresis in mild-to-moderate chronic congestive heart failure secondary to coronary artery disease.

Whereas angiotensin-converting enzyme inhibitors are now indicated for all grades of chronic heart failure, the 2 adverse effects that limit use of these drugs are systemic hypotension and renal dysfunction. The recognized clinical correlates such as hyponatremia and high diuretic dose, which predict occurrence of these adverse effects in severe chronic congestive heart failure (CHF), are rarely evident in patients with mild-to-moderate CHF. Accordingly, we studied 36 patients with stable, moderate CHF in a double-blind, placebo-controlled, crossover fashion to evaluate by multiple discriminate regression analysis the pathophysiologic determinants of changes in blood pressure, glomerular filtration rate, and urinary sodium excretion after initial converting enzyme inhibition with captopril 25 mg. A captopril-mediated decrease in mean arterial pressure was predicted by 3 factors (r2 = 0.74): the decrease in serum angiotensin II (F ratio = 10.3, p < 0.01), the decrease in plasma norepinephrine (F = 8, p = 0.02), and, inversely by pretreatment mean arterial pressure (F = 5.6, p = 0.04), patients with higher initial values exhibiting greater decreases in response to captopril. A captopril-mediated decline in glomerular filtration rate, determined by radioisotope elimination, was also predicted by 3 factors (r2 = 0.67): a decrease in renal plasma flow (F = 48.6, p < 0.01), low pretreatment glomerular filtration rate (F = 11.1, p < 0.01), and low absolute post-treatment serum angiotensin II (F = 5, p = 0.04).(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1994

QT dispersion and sudden unexpected death in chronic heart failure.

Death in chronic heart failure (CHF) can be from progression of disease or sudden and unexpected. We have attempted to identify factors that predict sudden death in CHF. We followed up 44 patients with CHF for 12-50 (mean 36) months. 4 patients died of non-cardiovascular causes and were excluded from analysis. There were 7 sudden deaths (symptoms for less than 1 h in a previously stable patient) and 12 from progressive CHF. Patients who died of progressive CHF had lower left-ventricular ejection fractions and higher concentrations of atrial natriuretic factor than the 21 survivors, but there were no differences in these variables between survivors and those who died suddenly. However, the sudden death group had significantly (p < 0.05) greater inter-lead variability in the QT interval on the electrocardiogram (QT dispersion; 98.6 [95% CI 79.1-118] ms1/2) than survivors (53.1 [41.9-64.3] ms1/2) or the group who died from progressive CHF (66.7 [51.8-81.6] ms1/2). QT dispersion is a marker of myocardial electrical instability. The association of increased QT dispersion with sudden death suggests that patients at high risk of such death could be identified by means of this simple, reproducible test. This group might benefit from more intensive treatment.

Aged↗