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Biomedical subjects

A D Struthers

Publications and source records attributed to A D Struthers.

At least 253 records · Page 14Linked to original sources
PubMed1988

The effect of atrial natriuretic factor on urinary albumin and beta 2-microglobulin excretion in man.

The effect of a 20-min infusion of atrial natriuretic factor (ANF) 99-126, 0.4 microgram/kg per min, on both urinary albumin and beta 2-microglobulin excretion was examined in nine normal male subjects during stable water diuresis. ANF caused a rise in urinary albumin in excretion (from 4.19 +/- 0.66 to 13.49 +/- 3.07 ng/min, P less than 0.01) without any significant change in either creatinine clearance of beta 2-microglobulin excretion. These findings suggest that ANF may enhance glomerular permeability to albumin in man.

Adult↗
PubMed1987

Adrenaline causes potassium influx in skeletal muscle and potassium efflux in cardiac muscle in rats: the role of Na/K ATPase.

Previous in vitro evidence suggests that adrenaline causes K influx in skeletal muscle by stimulating a ouabain sensitive Na/K ATPase membrane pump. However in rabbits, adrenaline induced hypokalaemia was not significantly altered by pretreatment with digoxin (50 micrograms/kg). Rats were infused with adrenaline or saline after being given a tracer dose of 42KCl. Adrenaline caused a highly significant uptake of 42K in skeletal muscle and a decrease in 42K uptake in ventricle. Rats were also studied after receiving a high dose of digoxin (1.4 mg/kg) which by itself produced a significant increase in plasma K, a decrease in plasma Na and a decreased uptake of 42K in ventricle and lung. These results suggest that adequate widespread Na/K ATPase inhibition had been achieved by this dose of digoxin but despite this, adrenaline still caused hypokalaemia and also still caused significant 42K tissue uptake by skeletal muscle. These results suggest that adrenaline causes K influx by skeletal muscle and K efflux by cardiac tissue. Furthermore, the former mechanism was not inhibited by pretreatment with digoxin.

Animals↗
PubMed1987

Evidence in humans for a postsynaptic interaction between noradrenaline and angiotensin II with regard to systolic but not diastolic blood pressure.

Much animal evidence exists to suggest that there is an interaction between noradrenaline (NA) and angiotensin II (AII). We have now sought evidence for a postsynaptic AII/NA interaction. Ten normotensive volunteers were infused with dextrose/saline, All/saline, dextrose/NA or AII/NA in a randomized single-blind fashion. The respective increases in systolic blood pressure (SBP) were -4 +/- 6, -2 +/- 9, 4 +/- 6 and 14 +/- 16 mmHg at comparative time intervals while the corresponding increases in diastolic blood pressure (DBP) were 2 +/- 4, 6 +/- 7, 9 +/- 6 and 14 +/- 8 mmHg. ANOVA confirmed that AII and NA had a synergistic interaction (P less than 0.05) in elevating SBP while there was merely an additive effect in elevating DBP. Plasma NA and AII levels were unchanged by the coincidental presence of AII and NA, respectively, which excludes a generalized pharmacokinetic interaction between AII and NA. This study provides evidence for a postsynaptic AII/NA interaction with regard to SBP but not DBP although the precise location of this interaction remains uncertain. Therefore, in considering the pathogenesis of SBP abnormalities, concomitant measurements of both NA and AII may be important.

Analysis of Variance↗
PubMed1987

The effect of angiotensin II on endogenous noradrenaline release in man.

1. Considerable data from animal studies suggest that angiotensin II exerts a facilitatory effect on noradrenaline release. We sought evidence for such an effect in man by examining how a subpressor dose of angiotensin II (1.5 ng kg-1 min-1) influences the haemodynamic and plasma noradrenaline responses to physiological stimulation of the sympathetic nervous system. 2. The physiological stimuli investigated were a cold pressor test, the response to standing from lying, bicycle exercise and forearm isometric exercise. 3. The presence of the angiotensin II infusion had no effect on the systolic blood pressure, diastolic blood pressure, heart rate or plasma noradrenaline responses to stimulation of the sympathetic nervous system. 4. We have therefore found no evidence to support the enhancement of noradrenaline release by this low dose of angiotensin II in man.

Adult↗
PubMed1987

Renal effects of angiotensin II, atrial natriuretic peptide and their interaction in man.

There is now much evidence that atrial natriuretic peptide (ANP) is important in the control of sodium balance. There is also evidence that ANP interacts with the renin-angiotensin system at several levels. In this study we investigated a further possible interaction between ANP and angiotensin II (ANG II) in the control of renal water and electrolyte excretion. In normal male volunteers, ANP caused urinary sodium excretion to rise significantly from baseline (+80 +/- 44 mumol/min) whereas ANG II was potently antinatriuretic (-125 +/- 36 mumol/min). When ANP was administered against a nonpressor background infusion of ANG II, urinary sodium excretion rose from a new lower level (-93 +/- 22 mumol/min) to a rate not significantly different from control (-22 +/- 25 mumol/min). In contrast to that of sodium, potassium excretion and urinary volume remained significantly below baseline levels when ANP was administered against a background infusion of ANG II. These results suggest that ANP and ANG II interact within the kidney in the control of water and electrolyte excretion.

Adult↗
PubMed1987

The interaction between noradrenaline and angiotensin II in man: evidence for a postsynaptic and against a presynaptic interaction.

Recent evidence from animal studies suggests an interaction between the renin-angiotensin system (RAS) and the sympathetic nervous system (SNS). We sought evidence for a similar interaction in man, to determine whether this interaction is presynaptic, whereby angiotensin II (ANG II) facilitates noradrenaline (NA) release, or postsynaptic, whereby ANG II facilitates the effect of NA. In our first study, a subpressor dose of ANG II was infused and NA release stimulated by physiological tests. The haemodynamic responses and plasma NA responses to SNS stimulation were not augmented by ANG II. In the second study normal volunteers were infused with either saline, ANG II, or a combination of ANG II and NA. Analysis of variance showed that ANG II interacts synergistically with NA to increase systolic blood pressure (SBP). Plasma NA and ANG II levels were not altered by the coincidental presence of NA or ANG II. These results suggest that there is a pharmacodynamic interaction between NA and ANG II which acts synergistically at a postsynaptic site to maintain SBP.

Analysis of Variance↗
PubMed1986

Epinephrine-induced hypokalemia: the role of beta adrenoceptors.

Epinephrine was infused intravenously in 9 normal volunteers to plasma concentrations similar to those found after acute myocardial infarction. This study was undertaken on 3 occasions after 5 days of treatment with placebo or the beta-adrenoceptor antagonist, atenolol, which is relatively beta 1 selective, or timolol, which blocks both beta 1 and beta 2 receptors. Epinephrine increased the systolic blood pressure (BP), decreased the diastolic BP and increased the heart rate modestly. These changes were prevented by atenolol. However, after timolol the diastolic BP rose by +19 mm Hg and heart rate fell by -8 beats/min. Epinephrine caused the corrected QT interval to lengthen (0.36 +/- 0.02 to 0.41 +/- 0.06 second). No significant changes were found in the corrected QT interval when subjects were pretreated with atenolol or timolol. The serum potassium decreased from 4.06 to 3.22 mmol/liter after epinephrine. Serum potassium decreased to a lesser extent to 3.67 mmol/liter after atenolol and actually increased to 4.25 mmol/liter after timolol. In a further study with a similar design another nonselective beta blocker propranolol also increased potassium after epinephrine. While atenolol also prevented hypokalemia in this study, it did not block the beta 2-receptor mediated decrease in diastolic BP. Epinephrine-induced hypokalemia results from stimulation of a beta-adrenoceptor linked to membrane sodium/potassium adenosine triphosphatase causing potassium influx. This appears to be predominantly mediated by beta 2 receptors although beta 1 receptors may also play a part.

Adult↗
PubMed1986

The effect of atrial natriuretic peptide on plasma renin activity, plasma aldosterone, and urinary dopamine in man.

The acute natriuretic effect of human atrial natriuretic peptide (ANP) has been well described in man. We have now studied possible hormonal mediators of this effect. We studied six healthy volunteers on two occasions when they received either an infusion of ANP of 1.5 pmol X kg-1 X min-1 for 30 min followed by 15 pmol X kg-1 X min-1 for a further 30 min, or matching vehicle infusions in a randomized single-blind fashion. On the placebo day, plasma renin activity (PRA) rose from 1.26 +/- 0.08 to 1.57 +/- 0.14 ng A1 X ml-1 X h-1, while on the ANP study day PRA fell from 1.45 +/- 0.15 to 1.28 +/- 0.05 ng A1 X ml-1 X h-1 (p less than 0.01). No significant changes were found in plasma aldosterone concentrations or in urinary dopamine excretion. These results provide evidence that ANP suppresses renin release in man.

Aldosterone↗
PubMed1986

Human calcitonin gene related peptide: a potent endogenous vasodilator in man.

In addition to calcitonin and katacalcin, it is now known that the human calcitonin gene encodes a novel peptide called calcitonin gene related peptide (CGRP). In experimental animals, CGRP produces vasodilatation and complex changes in plasma calcium. We have now assessed its biological activity in man by infusing human CGRP (hCGRP) into six normal volunteers. hCGRP (545 pmol/min) caused the diastolic pressure to fall from 64 +/- 5 to 55 +/- 7 mmHg (P less than 0.05), the heart rate to increase from 61 +/- 7 to 87 +/- 5 beats/min (P less than 0.05) and the skin temperature to increase from 33.7 +/- 0.9 to 34.9 +/- 0.5 degrees C. Plasma noradrenaline increased from 481 +/- 126 to 835 +/- 65 pg/ml (P less than 0.05) and plasma adrenaline from 57 +/- 17 to 82 +/- 12 pg/ml (P less than 0.05). There were no significant changes in the albumin-corrected plasma calcium. hCGRP is thus a potent endogenous vasodilator in man and is in fact more potent than any other known vasodilator. Together with the observations that CGRP circulates in normal subjects at relatively high concentration (approximately 25 pmol/l) and that CGRP is present in perivascular nerves, this study suggests a possible role for CGRP in controlling peripheral vascular tone in man.

Adult↗
PubMed1986

Atrial natriuretic peptide inhibits the aldosterone response to angiotensin II in man.

We have investigated the interaction between the recently discovered natriuretic factor alpha human atrial natriuretic peptide (alpha h-ANP) and the renin-angiotensin-aldosterone system in man. Angiotensin II infused with placebo produced a significant rise of plasma aldosterone concentration (mean +/- SEM increment 352 +/- 23 pmol/l, n = 7, P less than 0.001). The infusion of alpha h-ANP together with angiotensin II largely abolished the aldosterone response (P less than 0.001). Diastolic blood pressure rose in response to the infusion of angiotensin II with placebo (mean increment 21.0 +/- 0.9 mmHg, P less than 0.001). Systolic blood pressure increased to a lesser degree (mean increment 12.5 +/- 0.7 mmHg, P less than 0.001). The infusion of alpha h-ANP together with angiotensin II significantly blunted the diastolic pressor response (P less than 0.01). This ability of alpha h-ANP to blunt the pressor effect of angiotensin II may be important in the control of systemic blood pressure. The inhibition of angiotensin II-stimulated aldosterone release demonstrates that alpha h-ANP may not only be a circulating natriuretic factor in its own right but that it may also act as a modulator of a related endocrine system.

Adult↗
PubMed1986

Effect of captopril on changes in plasma noradrenaline induced by sodium nitroprusside.

There is much animal data to suggest that angiotensin II has a regulatory role in noradrenaline release. We sought evidence for such a mechanism in man by pretreating six normal volunteers with captopril (50 mg) or placebo and then infusing them with incremental doses of sodium nitroprusside. Pretreatment with captopril had no significant effect on the mean arterial pressure, heart rate or plasma noradrenaline response to sodium nitroprusside, despite increasing plasma renin activity. This suggests that in normotensive salt replete man, normal levels of angiotensin II do not exert any tonic effect on noradrenaline release.

Adult↗
PubMed1986

Exercise-induced increases in plasma catecholamines and growth hormone are augmented by selective alpha 2-adrenoceptor blockade in man.

A specific alpha 2-adrenoceptor antagonist (idazoxan) was used in man to examine the neuroregulation of growth hormone (GH) release and the effect of alpha 2-adrenoceptors on noradrenaline release. In the first study, GH-releasing factor (GRF)-induced GH release was unaffected in 6 normal volunteers by the prior administration of idazoxan, suggesting that the alpha 2-receptors involved in GH release are not operative at pituitary level. In the second study, 6 normal volunteers performed a bicycle exercise test with and without prior treatment with idazoxan. The exercise-induced GH response (to 13 +/- 5 mU/l) was significantly augmented by idazoxan (to 20 +/- 7 mU/l) which contrasts with the current view of GH release being regulated by stimulatory hypothalamic alpha 2-adrenoceptors and suggests that these alpha 2-adrenoceptors are capable of exerting a dual effect on GH release. The exercise-induced increase in plasma noradrenaline (to 1.45 +/- 0.19 micrograms/l) and in heart rate (to 142 +/- 5 beats/min) were also augmented by idazoxan (to 2.24 +/- 0.23 micrograms/l and 152 +/- 6 beats/min). A similar augmentation of the plasma adrenaline response to exercise was also found, whereas the blood glucose, plasma insulin and potassium response to exercise was unaffected by idazoxan. These results suggest that during exercise in man, alpha 2-adrenoceptors exert a tonic inhibitory influence on noradrenaline release which also serves to limit the exercise-induced tachycardia.

Adult↗
PubMed1985

Central nervous system mechanisms in blood pressure control.

Much of our knowledge about the CNS control of blood pressure is derived from animal studies using techniques such as intracerebroventricular administration of drugs, stereotactic ablation of specific brain nuclei, and biochemical analysis of these nuclei. These methods have identified numerous specific brain nuclei in the brain stem and a meshwork of interconnecting neurones involved in cardiovascular control. The main neurotransmitter involved is noradrenaline but recent interest has focused on several laterally situated nuclei which are capable of synthesizing adrenaline. Centrally acting antihypertensive drugs are thought to act by stimulating central alpha 2-adrenoceptors either by the parent drug itself (clonidine) or via the formation of an active metabolite (alpha-methyldopa). This leads to decreased peripheral sympathetic activity and a hypotensive response but the latter is often attained at the expense of central side-effects such as drowsiness or dry mouth. The mechanism of the antihypertensive effect of beta-blockers remains uncertain although the balance of evidence is against a central effect. The central administration of propranolol causes decreased peripheral sympathetic activity in animals, but plasma catecholamine levels are little altered by beta-blockers in man. In equipotent antihypertensive doses, central alpha-agonists cause a much greater reduction in plasma noradrenaline than beta-blockers.

Adrenergic beta-Antagonists↗
PubMed1985

Metabolic and haemodynamic effects of alpha 2-adrenoceptor stimulation and antagonism in man.

Six healthy volunteers received a 60 min infusion of guanfacine (alpha 2-agonist) on two occasions, preceded by either idazoxan (alpha 2-antagonist) or vehicle. Idazoxan elevated blood pressure by 8/7 mmHg, but there was no change on either day during guanfacine infusion. Guanfacine reduced plasma noradrenaline by approximately 30%, and this was not antagonized by idazoxan. By contrast, the 30-fold increase in plasma growth hormone caused by guanfacine was almost completely blocked by idazoxan. Guanfacine caused a two- to three-fold increase in plasma glucagon and a similar reduction in plasma insulin. Only the latter was antagonized by idazoxan. No consistent changes in plasma ACTH were observed after either idazoxan or guanfacine. Idazoxan itself elevated plasma noradrenaline up to twice baseline values, but did not affect the other metabolic measurements. alpha 2-Adrenoceptor stimulation plays a minor role in control of hormone release but has a greater physiological role in regulating release of the neurotransmitter, noradrenaline.

Adrenergic alpha-Agonists↗
PubMed1985

Peripheral alpha 2 adrenoceptor stimulation contributes to the sympatholytic effect of guanfacine in humans.

Guanfacine 3 mg was infused into six volunteers over 1 h on two occasions to investigate whether its sympatholytic effect is centrally or peripherally mediated. On one occasion, the central effects of guanfacine were blocked by prior administration of idazoxan 0.2 mg/kg i.v. (45 min preguanfacine); central alpha 2-blockade was confirmed by inhibition of the guanfacine-induced rise in plasma growth hormone. Rapid disappearance of idazoxan from the circulation prevented antagonism of peripheral alpha 2 receptor effects of guanfacine (confirmed by suppression of plasma insulin by guanfacine on both occasions). Idazoxan elevated plasma noradrenaline concentration by 0.26 +/- 0.018 ng/ml; however, guanfacine caused a similar (approximately 30%) reduction in plasma noradrenaline after both idazoxan and vehicle. Idazoxan elevated systolic and diastolic blood pressure, but no change was observed after guanfacine on either occasion. Thus, the reduction in plasma noradrenaline caused by guanfacine appears to be peripherally mediated but is not due to baroreceptor activation. This is consistent with stimulation of presynaptic alpha 2 receptors.

Adult↗
PubMed1985

The plasma noradrenaline and growth hormone response to alpha-methyldopa and clonidine in hypertensive subjects.

The mechanism of the antihypertensive effect of alpha-methyldopa was compared with clonidine by administering equipotent single doses of clonidine (0.2 mg) and alpha-methyldopa (750 mg) to nine hypertensive patients. Plasma noradrenaline was followed for 8 h thereafter as an index of peripheral sympathetic activity. alpha-Methyldopa and clonidine produced the same hypotensive response at 6 and 8 h after dosing with a similar fall in plasma noradrenaline levels at these times. Linear regression analysis between the systolic blood pressure fall and the corresponding plasma noradrenaline fall, showed that the slopes of the two regression lines were similar for alpha-methyldopa as for clonidine. Equipotent doses of alpha-methyldopa and clonidine produce the same fall in plasma noradrenaline. This supports the current hypothesis that an alpha-methyldopa metabolite acts centrally, like clonidine, to reduce peripheral sympathetic activity.

Adult↗
PubMed1985

The physiological and pharmacological role of presynaptic alpha- and beta-adrenoceptors in man.

Two studies were performed each in six normal volunteers in order to find evidence of either a physiological or pharmacological role of presynaptic alpha- and presynaptic beta-adrenoceptors in man. In Study 1 subjects received a 60 min infusion of guanfacine 3 mg (alpha 2-adrenoceptor agonist) preceded by either idazoxan (alpha 2-adrenoceptor antagonist) or vehicle. Guanfacine reduced plasma noradrenaline concentration by approximately 30% and this fall was not antagonised by the alpha 2-receptor antagonist. The 30-fold increase in plasma growth hormone, measured as a marker of the central action of guanfacine, was almost completely blocked by idazoxan. A comparison of the drug concentrations of idazoxan and guanfacine, together with their relative affinities for alpha 2-adrenoceptors, suggested that the idazoxan could not block the peripheral actions of guanfacine and that these were responsible for the fall in plasma noradrenaline concentration. In Study 2 adrenaline 0.05 micrograms kg-1 min-1 was infused for 80 min preceded by either idazoxan or vehicle. After vehicle, adrenaline caused no change in plasma noradrenaline concentration whereas it rose approximately 25% after administration of idazoxan. This was probably due to unmasking of presynaptic beta-adrenoceptor stimulation by adrenaline when the opposing inhibitory autoreceptor was blocked.

Adrenergic beta-Antagonists↗