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Biomedical subjects

A D Struthers

Publications and source records attributed to A D Struthers.

At least 199 records · Page 11Linked to original sources
PubMed1992

Elevated levels of brain natriuretic peptide in acute hypoxaemic chronic obstructive pulmonary disease.

1. Studies in vitro have recently shown that both atrial natriuretic peptide and brain natriuretic peptide have pulmonary vasorelaxant activity. The purpose of the present study was to evaluate for the first time whether plasma levels of brain natriuretic peptide are elevated in chronic obstructive pulmonary disease. Plasma levels of brain natriuretic peptide and atrial natriuretic peptide were therefore measured in 12 patients admitted with acute hypoxaemic chronic obstructive pulmonary disease [arterial partial pressure of O2, 6.2 +/- 0.4 kPa; arterial partial pressure of CO2, 6.9 +/- 0.1 kPa; forced expiratory volume in 1 s, 0.6 +/- 0.07 litre (27 +/- 3% of predicted)]. All but three patients had oedema on admission. 2. Plasma levels of both brain natriuretic peptide and atrial natriuretic peptide were elevated in patients with chronic obstructive pulmonary disease (31.4 +/- 4.1 pmol/l and 45.0 +/- 8.1 pmol/l, respectively) compared with healthy control subjects (1.7 +/- 0.8 pmol/l and 8.0 +/- 3.5 pmol/l, respectively). Thus, plasma levels of brain natriuretic peptide and atrial natriuretic peptide in patients with chronic obstructive pulmonary disease were increased by 18.5- and 5.6-fold respectively compared with healthy control subjects. 3. There was a significant inverse correlation between the plasma level of brain natriuretic peptide and the arterial partial pressure of O2 (r = -0.65, r2 = 0.42, P = 0.03), but not between the plasma atrial natriuretic peptide level and the arterial partial pressure of O2 (r2 = 0.07, not significant). The arterial partial pressure of CO2 did not correlate with the plasma level of either brain natriuretic peptide or atrial natriuretic peptide.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗
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

Comparison of three methods of glomerular filtration rate measurement with and without captopril pretreatment in groups of patients with left ventricular dysfunction.

Methods of glomerular filtration rate measurement by 51Cr EDTA elimination, inulin clearance and creatinine clearance were compared with and without captopril pretreatment in 10 chronic heart failure patients and in 20 patients after transmural myocardial infarction. Strong intermethod correlations were found in chronic heart failure patients (EDTA: inulin r = 0.87; EDTA: creatinine r = 0.84; inulin: creatinine r = 0.9; all P less than 0.00001). Despite this, substantial absolute differences were observed in results obtained by different techniques. In particular, creatinine clearance significantly overestimated both 51Cr EDTA (18.0 +/- 18.4 ml.min-1, mean difference +/- SD, P less than 0.001) and inulin clearance (26.8 +/- 17.0 ml.min-1, P less than 0.001). The slight reduction in 51Cr EDTA elimination on captopril versus placebo (-8.3 +/- 9.2 ml.min-1, P less than 0.05) was related to a similar treatment difference in inulin clearance (r = 0.67, p = 0.03), but changes observed by either method were unrelated to captopril-induced changes in creatinine clearance. Thus, creatinine clearance is an unsatisfactory means of assessing the effect of angiotensin converting enzyme inhibition on glomerular filtration rate in chronic heart failure. In the post-myocardial infarction group, correlations between methods were poorer (EDTA: inulin r = 0.79; EDTA: creatinine r = 0.76; inulin: creatinine r = 0.67). In this group no significant effect of captopril on glomerular filtration rate was detected by any technique. As compared to the chronic heart failure patients, the weaker relationship between techniques post-myocardial infarction may be related to interference by thrombolytic or aspirin treatment.

Captopril↗
PubMed1992

Atrial natriuretic factor improves renal function and lowers systolic blood pressure in renal allograft recipients treated with cyclosporin A.

OBJECTIVE: Atrial natriuretic factor (ANF) has several properties which suggest that it may ameliorate cyclosporin A nephrotoxicity. We therefore investigated the response to a pharmacological dose of ANF in renal transplant recipients treated with cyclosporin A. DESIGN: A single-blind randomized crossover design comparing the renal and haemodynamic effects of D-glucose (placebo) with ANF. METHODS: Seven patients with stable renal function following renal transplantation were studied under maximal water diuresis. Glomerular filtration rate and effective renal plasma flow were estimated from clearances of inulin and para-aminohippurate, respectively. RESULTS: Plasma ANF levels increased significantly in association with increased diuresis and natriuresis. Glomerular filtration rate was unchanged after placebo but increased significantly after ANF fusion. Likewise, effective renal plasma flow increased significantly with ANF infusion. There was a significant fall in systolic blood pressure, with no apparent change in heart rate and diastolic blood pressure. CONCLUSIONS: These results suggest that ANF may have beneficial effects in protecting against cyclosporin A-induced nephrotoxicity and hypertension.

Atrial Natriuretic Factor↗
PubMed1992

Prazosin blunts the antinatriuretic effect of circulating angiotensin II in man.

OBJECTIVE: The present study examines the role of alpha 1-adrenoceptors in determining the renal haemodynamic and sodium excretory responses to a physiological dose of angiotensin II in man. DESIGN: The effects of a low-dose infusion of angiotensin II (1 ng/kg per min) and a non-depressor dose of prazosin (0.25 mg), alone and in combination, on urinary sodium excretion (UNaV), effective renal plasma flow (ERPF), glomerular filtration rate (GFR) and segmental tubular function were studied in eight normal male subjects. METHODS: Subjects were studied undergoing maximal water diuresis. Clearances of inulin and para-aminohippurate were employed to estimate GFR and ERPF, respectively. Segmental tubular handling was assessed by both lithium clearance (CLi) and solute-free water methods. RESULTS: Angiotensin II decreased UNaV without altering ERPF and GFR. Angiotensin II caused a significant fall in fractional CLi, which may indicate a proximal tubular effect of angiotensin II. Angiotensin II alone also increased fractional reabsorption of sodium delivered to the distal nephron, as evaluated by both the CLi method and by estimation of solute-free water clearance. When angiotensin II was given in combination with prazosin, which on its own had no apparent effects on any renal parameters, the antinatriuretic and tubular effects of angiotensin II were significantly blunted. CONCLUSIONS: These findings suggest that low doses of circulating angiotensin II are able to modulate UNaV by increasing sodium reabsorption in the proximal and, to some extent, the distal nephron segment in man. The study also showed that a non-depressor dose of prazosin blunted the renal effects of angiotensin II, thereby providing tentative evidence of a renal interaction between alpha-adrenoceptors and angiotensin II in man.

Adult↗
PubMed1992

Captopril augments both basal and frusemide-induced natriuresis in normal man by suppression of circulating angiotensin II.

1. We studied the renal effects of reinfusing low dose angiotensin II (1 ng kg-1 min-1) into seven salt-replete healthy volunteers after pretreatment with the angiotensin converting enzyme (ACE) inhibitor captopril (25 mg) to establish whether the natriuretic and renal haemodynamic responses to ACE inhibition in normal man result from suppression of circulating angiotensin II. In the same subjects we also studied the effect of captopril (25 mg) with and without exogenous angiotensin II (1 ng kg-1 min-1) on the natriuretic response to intravenous frusemide (20 mg). 2. In the pre-frusemide study captopril increased absolute and fractional excretion of sodium and paraaminohippurate clearance but had no effect on inulin clearance. 3. Reinfusion of angiotensin II after captopril pretreatment completely suppressed the renal effects of ACE inhibition, yielding renal vasoconstrictor and antinatriuretic effects equivalent to those produced by infused angiotensin II in the absence of captopril. 4. Frusemide increased renal sodium excretion without affecting paraaminohippurate or inulin clearance. Captopril augmented frusemide-induced natriuresis and again this effect was reversed by angiotensin II reinfusion. 5. We conclude that captopril augments both basal and frusemide-induced renal sodium excretion in normal man. Our findings suggest that these renal responses to ACE inhibition may be mediated by inhibition of circulating angiotensin II, specifically its renal tubular salt-retaining actions, rather than via effects on other neurohumoral systems.

Administration, Oral↗
PubMed1992

Sex differences in hypokalaemic and electrocardiographic effects of inhaled terbutaline.

BACKGROUND: Gender differences in the chronotropic effects of infused isoprenaline have previously been described. The aim of the present study was to investigate possible gender differences in hypokalaemic, chronotropic, and electrocardiographic effects of inhaled terbutaline. METHODS: Twenty healthy volunteers (10 female) were recruited (mean age 24 years for women (F) and 22 years for men (M). Subjects were given either inhaled terbutaline 5 mg or placebo in single blind, randomised crossover fashion and the following measurements were made for four hours after inhalation: (a) serum potassium concentration; (b) heart rate; (c) electrocardiographic sequelae (T wave amplitude, Q-Tc interval). The effects of terbutaline on serum potassium was chosen as the primary end point for detecting a 0.3 mmol/l difference between sexes, with a beta error of 0.2 and alpha set at 0.05. RESULTS: The hypokalaemic effects of terbutaline were significantly greater in women, the potassium results (means and 95% CI) being as follows: lowest potassium concentration--F 3.12 (2.96-3.28) mmol/l v M 3.65 (3.49-3.81) mmol/l; percentage change from baseline at one hour--F 15.4% (11.5-19.3%) v M 8.5% (4.6-12.3%); average potassium concentration during the four hours--F 3.39 (3.33-3.46) mmol/l v M 3.78 (3.72-3.85) mmol/l. There was no significant regression between body weight and the potassium response to terbutaline. There were also significant sex differences for T wave, Q-Tc, and heart rate response. The percentage fall in T wave amplitude 30 minutes after terbutaline was: F 44.6% (32.1-57.0%) v M 22.4% (9.9-34.8%). CONCLUSIONS: Women are more sensitive to the hypokalaemic, chronotropic, and electrocardiographic sequelae of inhaled terbutaline.

Administration, Inhalation↗
PubMed1992

Furosemide-induced natriuresis is augmented by ultra-low-dose captopril but not by standard doses of captopril in chronic heart failure.

BACKGROUND: Ten chronic heart failure patients were studied on three occasions in randomized double-blind fashion to compare the acute hemodynamic, neurohormonal, and renal sodium-handling responses to 1 mg captopril versus 25 mg captopril, both in the absence of loop diuretic therapy and during furosemide-stimulated natriuresis. METHODS AND RESULTS: Compared with placebo, 1 mg captopril caused nonsignificant decreases in mean arterial pressure and circulating angiotensin II level and had no effect on glomerular filtration rate as determined by 51Cr-EDTA elimination. Captopril (25 mg) produced marked suppression of serum angiotensin II with or without oral furosemide (both p less than 0.002), a marked decrease in mean arterial pressure (p less than 0.001) that was accentuated by furosemide (p less than 0.00001), and a decrease in glomerular filtration rate (p = 0.0007). No difference from placebo in renal sodium excretion was noted with either 1 or 25 mg captopril in the absence of furosemide. In contrast, while 25 mg captopril caused slight attenuation of the natriuretic response to furosemide, 1 mg captopril significantly enhanced furosemide-induced natriuresis (p less than 0.05). No correlation was found in our patients between the natriuretic effect of furosemide and either absolute mean arterial pressure or change in mean arterial pressure during the furosemide phase of each study session. This suggests that blood pressure is not the important factor mediating the divergent renal responses to furosemide of the two captopril dosage regimens. CONCLUSIONS: We propose that in the face of furosemide-induced postglomerular vasodilatation in chronic heart failure, captopril at a starting dose of 1 mg (but not 25 mg) preserves enough circulating angiotensin II to maintain efferent arteriolar tone and thus glomerular filtration, while offsetting the antinatriuretic renal tubular effects of angiotensin II.

Aged↗
PubMed1992

The effects of enalapril and spironolactone on terbutaline-induced hypokalemia.

OBJECTIVE: To investigate whether enalapril (E) 10 mg and spironolactone (S) 100 mg attenuate the hypokalemic effect of inhaled terbutaline (T). DESIGN: Randomized single-blind crossover. Subjects received the following treatment combinations: (a) placebo (P), (b) T alone, (c) T + E, or (d) T + S. SETTING: University Department of Clinical Pharmacology. PARTICIPANTS: Twenty healthy volunteers (ten male, ten female) of mean age 22.8 +/- 3.1 years. MAIN OUTCOME MEASURES: Serum potassium, magnesium, ECG changes (R-R interval, T wave, and QTc interval) for 4 h after terbutaline inhalation. MAIN RESULTS: Baseline serum potassium levels were higher following prior treatment with E and S; P, 3.78 mmol/L (3.67 to 3.88); T + E, 3.93 mmol-1 (3.82 to 4.03); and T + S, 4.03 mmol/L (3.93 to 4.14) (p less than 0.05). Mean potassium concentrations over 4 h were also higher following prior treatment with E and S; T, 3.58 mmol/L (3.54 to 3.63); T + E, 3.68 mmol/L (3.64 to 3.72) (p less than 0.05); and T + S, 3.73 mmol/L (3.68 to 3.78) (p less than 0.01). CONCLUSIONS: Enalapril and spironolactone protect against the fall in serum potassium over 4 h by elevating baseline potassium concentration. These potassium-sparing drugs, however, should not be used to prevent the hypokalemic and electrocardiographic sequelae of inhaled beta 2-agonists.

Adult↗
PubMed1991

The effect of angiotensin II on haemodynamic and plasma noradrenaline responses to tyramine infusion in man.

Six normal volunteers were studied on four separate occasions. On each occasion they received two concomitant infusions which were either placebo/placebo, placebo/tyramine, angiotensin II/placebo or angiotensin II/tyramine. Angiotensin II infusion was given at a constant rate of 2ng/kg/min whereas the tyramine infusion consisted of 10 min increments at 1.25, 2.5, 3.75, 5, 7.5 and 10 micrograms.kg-1.min-1. Tyramine infusion caused a dose dependent increase in systolic blood pressure with increases in diastolic blood pressure and plasma noradrenaline only at the highest doses. These changes were not affected by concomitant angiotensin infusion. We have therefore found no evidence to support the enhancement of haemodynamic or plasma noradrenaline responses to tyramine infusion by low dose infusion of angiotensin II in man.

Adolescent↗
PubMed1991

Interactions between atrial natriuretic factor and the autonomic nervous system.

In addition to its natriuretic, hormonal and vascular actions, atrial natriuretic factor (ANF) may interact importantly with the function of the autonomic nervous system. It has been hypothesized that ANF may exert its cardiovascular and possibly renal effects by interfering with autonomic control mechanisms. In, animal experiments the hypotension that is caused by ANF is usually not associated with the expected reflex tachycardia or increased efferent sympathetic activity. Furthermore, bilateral vagotomy can attenuate the hypotensive action of ANF which suggest that ANF may stimulate sympathoinhibitory afferent vagal activity from the cardiopulmonary baroreceptor system. In man, ANF may alter reflexogenic-mediated forearm vascular responses to cardiopulmonary deactivation which suggest that ANF may have an important role as a neuromodulator of autonomic nervous function, a role that could serve to amplify or facilitate the peripheral hormonal actions of ANF. This neuromodulating influence of ANF could be due to several mechanisms: it could modulate baroreflex mechanisms or it could have direct effects on autonomic centres in the brain or it could have effects on peripheral neurotransmission. The role of the autonomic nervous system in modulating the release of ANF remains controversial. Finally, there is growing evidence to suggest that there is a reciprocal interplay between ANF and the sympathetic nervous system in peripheral target tissues which may have important pathophysiological significance.

Animals↗
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

Angiotensin II augments sympathetically mediated arteriolar constriction in man.

1. In animal studies, angiotensin II facilitates adrenergic neurotransmission by both pre- and post-synaptic mechanisms. We have investigated whether this interaction occurs in forearm resistance vessels in man. 2. The effect of arterial infusion of angiotensin II (320 fmol/min) on sympathetic vasoconstriction produced by lower-body negative pressure (15 mmHg) was studied in six subjects, and that on the response to exogenous noradrenaline (37.5-150 pmol/min) was studied in a further eight subjects. Forearm blood flow was measured by strain-gauge plethysmography. 3. The dose of angiotensin II was chosen to produce no alteration in resting blood flow, and those of noradrenaline were selected to provide a reduction in blood flow equivalent to that produced by lower-body negative pressure. 4. Lower-body negative pressure produced no change in heart rate or diastolic blood pressure, but caused an initial 5 mmHg fall in systolic blood pressure (P less than 0.01). Blood flow was reduced by 21 +/- 6% in both forearms by lower-body negative pressure during saline infusion. During angiotensin II infusion, there was a marked difference in the response to lower-body negative pressure, with blood flow being reduced by 40 +/- 7% in the infused arm, but only by 21 +/- 4% in the control arm (P less than 0.05). Angiotensin II infusion had no effect on resting blood flow or the responses to noradrenaline. 5. We conclude that angiotensin II augments sympathetic vasoconstriction in forearm resistance vessels in man at a concentration that has no direct effect on blood flow.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Dietary sodium loading increases plasma brain natriuretic peptide levels in man.

The effect of dietary sodium loading on plasma human brain natriuretic peptide-like immunoreactivity (hBNP-li) was examined in 11 normotensive subjects aged 20-23 years. Plasma hBNP-li increased significantly with increasing dietary sodium intake, with levels of 1.33 +/- 0.17 pmol/l on day 5 of a normal-sodium diet (24-h urinary sodium excretion of 171 +/- 16 mmol) and 2.04 +/- 0.10 pmol/l (P less than 0.05, versus normal-sodium diet) on day 5 of a high-sodium diet (24-h urinary sodium excretion 503 +/- 36 mmol). Corresponding plasma atrial natriuretic factor levels were 5.6 +/- 1.7 pmol/l and 11.0 +/- 2.0 pmol/l (P less than 0.05, versus normal-sodium diet) on the normal- and high-sodium diets, respectively. These results suggest that, in addition to atrial natriuretic factor, BNP may be a new and important natriuretic peptide which regulates sodium homeostasis in man during increased sodium intake.

Adult↗
PubMed1991

Angiotensin II augments the stroke volume response to isoprenaline in man.

Many studies in experimental animal models suggest that there is an interaction between angiotensin II and the sympathetic nervous system. We have now sought evidence for such an interaction using angiotensin II and beta-adrenoceptor stimulation with isoprenaline. Ten normal volunteers were infused with placebo/placebo, placebo/angiotensin II, placebo/isoprenaline and angiotensin II/isoprenaline in a randomized single-blind fashion. Isoprenaline alone caused a non-significant 11-20% rise in stroke volume. Angiotensin II alone caused no significant change in stroke volume. However, the combination of angiotensin II/isoprenaline caused a significant increase in stroke volume of 31-55% (p less than 0.01), and this increase was significantly greater than with isoprenaline alone (P less than 0.02, by repeated-measures analysis of variance). This occurred with no difference in heart rate change. Isoprenaline significantly reduced total peripheral resistance and this reduction was not affected by concomitant infusion of angiotensin II. This study provides evidence that a physiological dose of angiotensin II can synergistically augment the stroke volume effect of beta-agonism in man. There are several possible mechanisms, but a regional redistribution of venous blood which causes increased cardiac filling seems likely.

Adult↗
PubMed1991

Lithium does not alter the renal response to a pressor dose of tyramine in man.

Renal clearance of lithium has been used as a marker of proximal tubular function in man. Recently, lithium pre-treatment has been shown to interfere with the natriuretic actions of some natriuretic agents in man. We have therefore investigated the effects of oral lithium carbonate (500 mg) on the natriuretic response to a pressor dose of tyramine (15 micrograms kg-1 min-1) in six normal volunteers. Lithium had no effect on baseline sodium excretion, nor did it affect the tyramine-induced increase in blood pressure and subsequent natriuresis. These results show that oral lithium carbonate (500 mg) does not appear to interfere with the pressure natriuretic response to tyramine in man.

Adult↗