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Biomedical subjects

A D Struthers

Publications and source records attributed to A D Struthers.

At least 181 records · Page 10Linked to original sources
PubMed1993

Dose-ranging effects of candoxatril on elimination of exogenous atrial natriuretic peptide in chronic heart failure.

Seven patients with chronic heart failure were treated in single-blind crossover fashion with placebo and 10 mg, 50 mg, and 200 mg doses of the neutral endopeptidase inhibitor candoxatril to determine the effects of candoxatril on the elimination kinetics of exogenously infused atrial natriuretic peptide (ANP). An incremental dose-response effect was observed on the mean maximum observed plasma concentration (Cmax) of the active metabolite candoxatrilat (107.4, 453.5, and 1584 ng/ml in response to 10, 50, and 200 mg candoxatril, respectively). Pooled active versus placebo comparisons showed that candoxatril reduced the clearance (p = 0.021) and elimination rate constant (p = 0.006) and increased Cmax (p = 0.002) and time to reach Cmax (p = 0.01) of exogenous ANP. Individually, both 50 mg and 200 mg but not 10 mg candoxatril significantly altered the elimination kinetics of ANP. The most favorable effects were observed in response to 200 mg candoxatril, although even this dose may not have achieved the maximal modulating effect on elimination of circulating ANP.

Aged↗
PubMed1993

Circulating angiotensin II and renal sodium handling in man: a dose-response study.

1. Animal studies have shown that angiotensin II has a biphasic effect on urinary sodium excretion. To examine whether this is also true in man, we studied seven salt-replete male subjects in a single-blind placebo-controlled manner. 2. While undergoing maximum diuresis, subjects were infused with 0, 1, 2, 5 or 10 ng of angiotensin II min-1 kg-1 over 80 min. Subjects were studied while seated, and stood every 20 min for urine collection. 3. Angiotensin II produced a dose-dependent antidiuretic effect. The urine flow rate, in ml/min expressed as the change from baseline with increasing dose of angiotensin, was: +3.4 +/- 1.77, -1.26 +/- 0.49 (P < 0.05), -2.75 +/- 1.23 (P < 0.05), -4.21 +/- 0.82 (P < 0.05) and -6.51 +/- 1.07 (P < 0.01). 4. In contrast, the effect of angiotensin II on sodium excretion showed a flat dose-response curve beyond 5 ng min-1 kg-1. The urinary sodium excretion, in mumol/min expressed as the change from baseline with increasing dose of angiotensin, was: 9.5 +/- 21.2, -18.9 +/- 29.6, -37.0 +/- 11.6 (P < 0.05), -67.7 +/- 19.6 (P < 0.01) and -63.8 +/- 14.3 (P < 0.01). 5. The fractional distal reabsorption of sodium, determined by using the lithium clearance technique, showed a rise with all doses of angiotensin II used and reached statistical significance with the top two doses. 6. Unlike antidiuresis, antinatriuresis after graded doses of angiotensin II in human subjects showed a flat dose-response curve beyond 5 ng min-1 kg-1. Pressor doses of angiotensin II also have a significant effect on the distal tubule in promoting sodium reabsorption.

Adult↗
PubMed1993

Effect of noradrenaline on renal sodium and water handling in euhydrated and overhydrated man.

1. The renal effects of incremental doses of intravenously infused noradrenaline were evaluated in normal subjects during two different water loads, 5 ml/kg (n = 6) and 20 ml/kg (n = 9), producing conditions of euhydration and overhydration, respectively. 2. Noradrenaline infusion rates ranged from 0.015 to 0.075 microgram min-1 kg-1. In the euhydrated subjects, noradrenaline caused a dose-dependent fall in urinary sodium excretion and an increase in urinary flow rate. During overhydration similar doses of noradrenaline caused a fall in urinary sodium excretion but a decrease in urinary flow rate. 3. Although there was no detectable change in glomerular filtration rate, a dose-dependent fall in effective renal plasma flow was observed in both hydration states during noradrenaline infusion. 4. Noradrenaline infusion was associated with a dose-dependent increase in proximal tubular sodium reabsorption as assessed by the lithium clearance method. Fractional reabsorption of sodium by the distal nephron was, however, unchanged by noradrenaline in both hydration states. 5. Plasma vasopressin concentration was unchanged by noradrenaline in euhydrated subjects. The renin-angiotensin-aldosterone axis was stimulated by noradrenaline in both euhydrated and overhydrated subjects. 6. Thus we conclude that plasma circulating noradrenaline has a dose-dependent antinatriuretic effect in man. The antinatriuretic effect of noradrenaline is mediated mainly at the proximal tubule in man. We have also shown that during overhydration, noradrenaline decreased urinary flow rate. In contrast, in euhydrated subjects, noradrenaline increased urinary flow rate with no accompanying changes in plasma vasopressin concentration, which suggests a direct effect of noradrenaline on the renal tubular permeability to water.

Adult↗
PubMed1993

Renal effects of low dose prazosin in patients with congestive heart failure.

Activation of the sympathetic nervous system may contribute to the renal vasoconstriction and sodium retention seen in congestive heart failure. Previous studies in congestive heart failure patients employing large doses of prazosin that lowered systemic blood pressure have been generally disappointing. The renal haemodynamic and segmental tubular effects of low non-depressor doses of prazosin (0.25 mg and 0.50 mg) were examined in eight female patients with mild to moderate congestive heart failure. Segmental tubular function was assessed by the lithium clearance method. Compared to placebo, prazosin caused a significant increase in urinary sodium excretion (from 56 +/- 7 to 92 +/- 7 mumol.min-1, P < 0.01), paralleled by significant increases in fractional excretion of sodium and lithium. Glomerular filtration rate and effective renal plasma flow were not altered by prazosin. Prazosin pre-treatment did not alter any of the renal responses to frusemide treatment (mean dose 85 +/- 14 mg). This study demonstrates that low non-depressor doses of prazosin have a clear natriuretic effect in congestive heart failure patients, which is predominantly established by interference with tubular reabsorption.

Aged↗
PubMed1993

Enalapril blunts the antinatriuretic effect of circulating noradrenaline in man.

OBJECTIVE: The present study examines the effect of angiotensin converting enzyme inhibition on the renal haemodynamic and sodium excretory responses to noradrenaline in man. DESIGN: We studied the effects of intravenous noradrenaline (0.075 micrograms/kg per min) and enalapril pretreatment (5 mg/day for 5 days), alone and in combination, on urinary sodium excretion, effective renal plasma flow, glomerular filtration rate and segmental tubular function in nine normal subjects. METHODS: The subjects were studied during maximal water diuresis. The clearance of inulin and of para-aminohippurate were used to estimate the glomerular filtration rate and effective renal plasma flow, respectively. Segmental tubule handling of sodium was assessed by the lithium clearance method. RESULTS: Noradrenaline alone decreased urinary sodium excretion (P < 0.01) and the effective renal plasma flow (P < 0.01) without altering the glomerular filtration rate. Enalapril pretreatment significantly attenuated this fall in sodium excretion (P < 0.05) and effective renal plasma flow (P < 0.05), and had a similar attenuating effect on the noradrenaline-induced decrease in the fractional excretion of lithium. The pressor response to noradrenaline infusion was not, however, influenced by the enalapril pretreatment. CONCLUSIONS: Enalapril blunts the renal vasoconstrictive effect and the antinatriuretic effect of noradrenaline in man. Our results indicate that there is an important interaction between the sympathetic nervous system and the renin-angiotensin system in the kidneys in man.

Adult↗
PubMed1993

The effect of intravenous saline loading on plasma levels of brain natriuretic peptide in man.

OBJECTIVE: Recent evidence suggests the presence of a dual natriuretic peptide system consisting of atrial natriuretic factor (ANF) from the atrium and brain natriuretic peptide (BNP) from the ventricle. Discrete roles have been postulated for these two natriuretic peptides in the control of circulatory homeostasis. We have therefore compared the release of ANF and BNP in response to an acute saline load to explore a differential pattern of release for the two natriuretic peptides in man. DESIGN: The effects of an acute saline infusion on plasma ANF and BNP concentrations were studied in 10 normal male volunteers. METHODS: Subjects were studied on two study days in the semirecumbent position. An acute intravenous saline infusion (250 ml/min) of 18 ml/kg isotonic sodium chloride-potassium chloride solution was administered on one of the two study days. No infusion was administered on the other day as a control. RESULTS: Plasma ANF concentrations increased significantly (P < 0.01) with saline loading without any detectable changes in plasma BNP concentrations up to 60 min following infusion. Heart rate and systolic and diastolic blood pressure were unchanged after saline loading. CONCLUSIONS: We have shown that an acute intravenous saline load causes an increase in plasma ANF concentrations with no detectable increase in plasma BNP at least up to 60 min after the acute saline load in man. These results support the view that the release of ANF and BNP may be regulated differently, especially with regard to the time required for the acute release of each peptide.

Adult↗
PubMed1993

Cyclosporin-induced hypertension precedes renal dysfunction and sodium retention in man.

OBJECTIVE: To study the acute effects of cyclosporin on blood pressure, renal function and hormones within the first few hours of drug ingestion in healthy man. DESIGN: A therapeutic (12 mg/kg) and a supratherapeutic (30 mg/kg) dose of cyclosporin were administered orally to 10 salt-replete normal healthy volunteers. Their renal haemodynamic parameters were assessed by inulin and para-aminohippurate clearances, and their blood pressure was recorded every 20 min. RESULTS: Cyclosporin had an acute hypertensive effect while having no effect on sodium excretion or renal function. The earliest renal effect of cyclosporin was on water handling, with a marked antidiuretic effect. CONCLUSIONS: Our findings contradict previous data and currently held views regarding the pathogenesis of cyclosporin-induced hypertension. In particular, we have demonstrated that hypertension precedes any measurable change in renal haemodynamic parameters and occurs without apparent overall alterations in renal sodium excretion. We have also found that an antidiuresis is a very early renal effect of cyclosporin.

Adult↗
PubMed1993

Echocardiography in chronic heart failure in the community.

A total of 128 patients from a single practice population who were receiving loop diuretics for treatment of presumptive cardiac failure were identified from prescribing data captured by the Medicines Monitoring Unit. A subgroup of 78 patients underwent echocardiography to determine the prevalence of true left ventricular systolic dysfunction in this population and the validity of the diagnosis of cardiac failure in primary care. A further 50 patients were studied to assess the workload generated by these patients for both primary health care and hospital services. The estimated prevalence of left ventricular systolic dysfunction was 0.84%, whereas 1.6% of the population received loop diuretics for this indication. A false-positive diagnosis occurred in 47% and was more likely in females (73%) than males (37%). Of all consultations 79% were seen by GPs, 14% as hospital out-patients and 7% as in-patients. Within the hospital general physicians have most contact with these patients. In summary chronic heart failure is common within the community, although the false-positive rate for diagnosis of this condition is high. GPs and general physicians treat the majority of these patients and should therefore receive continuing education regarding recent advances in this area. Echocardiography should be performed early in the management of all patients suspected of having cardiac failure.

Adult↗
PubMed1992

The clinical pharmacology of angiotensin converting enzyme inhibitors in chronic heart failure.

ACE inhibitors (ACEIs) have now been shown to improve symptoms and survival in patients with mild, moderate and severe chronic heart failure. Their mechanism of action is thought to be a combination of RAAS suppression and augmentation of bradykinin and prostaglandins. Although ACE inhibitors improve hemodynamics post myocardial infarction, we do not yet have consistent data on their effects on symptoms or survival in these particular patients. One other potential benefit is their effects on reperfusion injury and free radicals. As yet only minor differences have been found to exist between different ACEIs but increasing attention is now being focussed in this direction.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1992

Prazosin attenuates the natriuretic response to atrial natriuretic factor in man.

The effect of alpha-1-adrenoceptor blockade with 0.25 mg oral prazosin on the renal response to atrial natriuretic factor (ANF) 5 pmol/kg/min was examined in eight healthy male volunteers undergoing maximal water diuresis. ANF on its own decreased mean arterial blood pressure (P less than 0.05) without altering heart rate or increasing plasma norepinephrine. ANF increased urinary sodium excretion by 130% (P less than 0.01) from baseline value with accompanying 18% decrease (P less than 0.05) in PAH clearance (ERPF) without changing inulin clearance (GFR). When compared to placebo infusion, ANF infusion caused a significant increase in fractional excretion lithium (FELi), a marker of proximal tubular function. Fractional distal delivery of sodium, another marker of proximal tubular outflow as determined by free water clearance, was also increased during ANF infusion. As expected, ANF decreased distal nephron fractional sodium reabsorption as evaluated by both the "lithium method" and by the conventional "solute-free water method." Prazosin on its own had no effect on blood pressure, renal function or hormonal parameters. When given in combination with ANF, prazosin blunted the natriuretic effect of ANF from 130% to 35% (P less than 0.01). However, prazosin pretreatment did not influence the ANF-induced fall in blood pressure or ERPF nor the ANF-induced suppression of plasma aldosterone. We have therefore found evidence to support the hypothesis that at basal levels of sympathetic tone, the natriuretic effect of ANF in man is dependent on an intact sympathetic nervous system, since sympathetic blockade by prazosin blunts its sodium excretory effects.

Adult↗
PubMed1992

Effect of haemodialysis on plasma levels of brain natriuretic peptide in patients with chronic renal failure.

1. Plasma human brain natriuretic peptide-like immunoreactivity (hBNP-li) was measured in ten patients with chronic renal failure before and after 4 h of haemodialysis. 2. Plasma hBNP-li was elevated in all patients before dialysis (mean +/- SEM 21.0 +/- 3.8 pmol/l) compared with healthy control subjects (1.3 +/- 0.2 pmol/l, n = 11), but showed considerable inter-patient variability. Before dialysis plasma hBNP-li bore no relationship to the serum creatinine level or to the mean blood pressure. 3. Plasma hBNP-li fell significantly (P = 0.04) during 4 h of haemodialysis. The fall in plasma hBNP-li correlated significantly with the degree of postural blood pressure drop (r2 = 0.44, P = 0.05) and with the fall in body weight (r2 = 0.64, P less than 0.01) after haemodialysis. In all patients, plasma hBNP-li at the end of treatment remained above that in healthy subjects. 4. There was no significant correlation between the fall in plasma hBNP-li and the fall in serum creatinine level, and between the fall in plasma hBNP-li and the fall in supine systolic or diastolic blood pressure, during haemodialysis. 5. We have shown that plasma hBNP-li is elevated in patients with chronic renal failure and is decreased during haemodialysis. The fact that the plasma hBNP-li was not reduced to normal by haemodialysis despite restoration to normovolaemia gives tentative support to the view that, in addition to hypervolaemia, another factor may also be responsible for the elevated plasma hBNP-li seen in these patients.

Adolescent↗
PubMed1992

Dose-response study of the redistribution of intravascular volume by angiotensin II in man.

1. The response of systemic and regional haemodynamic indices to increasing infusion rates of angiotensin II (1, 3 or 10 ng min-1 kg-1) or placebo [5% (w/v) D-glucose] was studied in eight normal male subjects. 2. As compared with placebo, angiotensin II infusion caused an incremental rise in the serum angiotensin II level [14.5 +/- 7.7 (placebo) to 187.2 +/- 36.1 (10 ng of angiotensin II min-1 kg-1) pmol/l; mean +/- 95% confidence interval] associated with a stepwise increase in total peripheral resistance [880 +/- 42 (placebo) to 1284 +/- 58 (10 ng of angiotensin II min-1 kg-1) dyn s cm-5] and a progressive reduction in cardiac output [8.3 +/- 0.4 (placebo) to 7.0 +/- 0.4 (10 ng of angiotensin II min-1 kg-1) litres/min]. 3. A stepwise fall in renal blood flow was observed with increasing angiotensin II infusion rate [1302 +/- 65 (placebo) to 913 +/- 64 (10 ng of angiotensin II min-1 kg-1) ml/min]. In contrast, calf blood flow was unaffected by 1 ng or 3 ng of angiotensin II min-1 kg-1 and was significantly increased by 10 ng of angiotensin II min-1 kg-1 (P less than 0.01). 4. Calf venous capacitance was uninfluenced by 1 ng of angiotensin II min-1 kg-1, but was significantly increased by both 3 ng (P less than 0.005) and 10 ng (P less than 0.001) of angiotensin II min-1 kg-1.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Clearance of brain natriuretic peptide in patients with chronic heart failure: indirect evidence for a neutral endopeptidase mechanism but against an atrial natriuretic peptide clearance receptor mechanism.

1. Brain natriuretic peptide is a new natriuretic hormone with striking similarity to atrial natriuretic peptide, but there are no previous data concerning its clearance in man. Two pathways of clearance for atrial natriuretic peptide are recognized: degradation by neutral endopeptidase and binding to atrial natriuretic peptide clearance receptors. We have examined the effect of candoxatril, an inhibitor of neutral endopeptidase (dose range 10-200 mg), and the effect of an infusion of a pharmacological dose [45 micrograms (90 micrograms in two patients)] of synthetic human atrial natriuretic peptide on plasma human brain natriuretic peptide-like immunoreactivity levels in seven patients with mild to moderate chronic heart failure. 2. Plasma human brain natriuretic peptide-like immunoreactivity levels were elevated in all patients (mean +/- SEM 22.0 +/- 6.2 pmol/l) compared with healthy control subjects (1.3 +/- 0.2 pmol/l, n = 11). 3. In all patients, candoxatril increased both plasma atrial natriuretic peptide (P less than 0.05) and plasma human brain natriuretic peptide-like immunoreactivity (P less than 0.05) levels. 4. By contrast, an exogenous infusion of atrial natriuretic peptide had no effect on plasma human brain natriuretic peptide-like immunoreactivity levels despite increasing the plasma atrial natriuretic peptide concentration to 424 +/- 74 pmol/l, which is a level of atrial natriuretic peptide which would have 'swamped' all atrial natriuretic peptide clearance receptors. 5. We have therefore shown that plasma human brain natriuretic peptide-like immunoreactivity levels in chronic heart failure are increased by a neutral endopeptidase inhibitor, but are unchanged by an exogenous infusion of atrial natriuretic peptide.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1992

Effect of angiotensin-converting enzyme inhibition on plasma brain natriuretic peptide levels in patients with heart failure.

1. The aim of this study was to examine the effect of captopril, an angiotensin-converting enzyme inhibitor, on plasma levels of human brain natriuretic peptide-like immunoreactivity (hBNP-li) in patients with congestive heart failure. 2. Six male patients (aged 52-74 years) with mild to moderate congestive heart failure were studied on two occasions in the semi-recumbent position. After a 30 min rest, patients were randomized to receive oral tablets of either captopril (6.25 mg followed by 25 mg 2 h later) or placebo in a single-blind manner. Plasma hBNP-li, atrial natriuretic peptide-like immunoreactivity (ANP-li) and angiotensin II-like immunoreactivity (ANG II-li) levels and blood pressure were measured. 3. Baseline plasma hBNP-li and ANP-li levels in these patients with mild to moderate congestive heart failure were 13.5 +/- 3.2 pmol/l and 50.9 +/- 11.8 pmol/l, respectively. In 11 healthy male subjects aged 20-23 years, the peripheral plasma hBNP-li and ANP-li levels were 1.3 +/- 0.2 pmol/l and 5.6 +/- 1.7 pmol/l, respectively. In all patients, captopril decreased the plasma ANG II-li level (from 24.3 +/- 8.1 to 6.6 +/- 3.2 pmol/l, P < 0.05) and mean arterial blood pressure (from 92 +/- 3 to 80 +/- 3 mmHg, P < 0.05). Compared with placebo, captopril treatment was associated with significant reductions in plasma hBNP-li (from 14.3 +/- 3.0 to 12.8 +/- 2.1 pmol/l, P < 0.05) and in plasma ANP-li (from 53.9 +/- 1.11 to 36.8 +/- 7.6 pmol/l, P < 0.05) levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗