1. Conventional and germ-free rats were fed a fibre-free elemental diet with or without the addition of fermentable dietary fibres. We have previously reported that fibre was associated with greatly increased epithelial cell proliferation, but only in the conventional group, implying that it is the breakdown of fibre by the colonic microflora that is the main determinant of mucosal proliferation in the hind gut. The relationship of these changes to various plasma hormones implicated in intestinal growth control are described in this paper. 2. The most dramatic finding was that plasma levels of enteroglucagon and peptide YY were greatly increased in the germ-free groups. The response of these rats to fibre differed in that fibre decreased levels of enteroglucagon and peptide YY in the germ-free animals, but increased them in the conventional rats. Gastrin and insulin levels were significantly lowered in the fibre-supplemented groups, but were not affected by the microflora. 3. These results corroborate our previous findings that the effects of fibre and its fermentation are dynamically complex, and demonstrate that, like proliferation, direct effects and indirect fermentation-derived effects on plasma hormones also coexist.

1. Neuropeptide Y is a potent appetite stimulant and has been found to modulate glucose metabolism when given chronically. The acute effects of neuropeptide on peripheral glucose handling have not been studied in detail. We have studied the acute effects of central nervous system injection of neuropeptide on glucose metabolism in vivo in the rat. 2. Rats implanted with chronic cannulae in the third cerebral ventricle were injected with either neuropeptide Y or saline and peripheral insulin sensitivity was assessed during a hyperinsulinaemic euglycaemic clamp. The effect of centrally injected neuropeptide Y on post-absorptive glucose metabolism was studied using a constant infusion of [6- 3 H]glucose. 3. Infusion of neuropeptide Y resulted in a 18% increase in glucose requirement during the clamp, suggesting increased peripheral tissue responsiveness to insulin. Neuropeptide Y injection in 10 h fasted rats increased plasma glucose (area under curve 9.9 ± 0.2 versus 9.1 ± 0.1 mmol h −1 I −1 , P < 0.01), insulin (103 ± 23 versus 33 ± 8 pmol/l, P < 0.01, at 30 min) and glucagon (5.5 ± 0.5 versus 3.1 ± 0.3 pmol/l, P < 0.05, at 30 min). The increase in plasma glucose was due to an initial increase in the rate of appearance, which peaked between 20 and 30 min after neuropeptide Y infusion; over the entire 90 min 16% more glucose entered the systemic circulation in the neuropeptide Y-treated rats than in control rats, and the total quantity of glucose removed was also greater. 4. Neuropeptide Y in the central nervous system influences glucose metabolism by altering secretion of islet hormones, hepatic glucose production and the peripheral response to insulin.

1. The effects of intravenous and intra-arterial infusion of the peptides derived from prepro-vasoactive intestinal peptide, vasoactive intestinal peptide, peptide histidine methionine and peptide histidine valine, were examined in six healthy volunteers. 2. Vasoactive intestinal peptide given intravenously caused a significant increase in heart rate and a decrease in diastolic, but not systolic, blood presure, whereas peptide histidine valine caused an increase in heart rate alone, despite higher achieved circulating peptide concentrations. Peptide histidine methionine did not affect heart rate or blood pressure. Forearm blood flow was increased by vasoactive intestinal peptide and peptide histidine valine when infused locally intra-arterially, although vasoactive intestinal peptide was more potent than peptide histidine valine. 3. Plasma concentrations of cardiodilatin (the N -terminal peptide derived from pro-atrial natriuretic peptide) were increased by intravenous infusion of vasoactive intestinal peptide, but were unaffected by peptide histidine methionine or peptide histidine valine. Circulating plasma concentrations of adrenaline and noradrenaline did not change during infusion of vasoactive intestinal peptide, peptide histidine methionine or peptide histidine valine. 4. Peptide histidine valine had a long half-life when compared with peptide histidine methionine and vasoactive intestinal peptide. 5. We conclude that peptide histidine valine is active in the human cardiovascular system and has a similar, though less potent, vasodilating action to vasoactive intestinal peptide. The higher circulating levels of peptide histidine valine found in man suggest that it may be important in modulating vascular tone.

1. The haemodynamic and hormonal changes following glucose ingestion (1 g/kg) were determined before and after pretreatment with either placebo or the somatostatin analogue, octreotide (SMS 201-995, 50 μg sub-cutaneously), in seven patients with chronic autonomic failure 2. In the placebo phase, after glucose, there was a marked and prolonged fall in blood pressure with no change in cardiac index and peripheral blood flow. Plasma insulin and neurotensin levels increased, whereas glucagon, vasoactive intestinal polypeptide, noradrenaline and adrenaline levels were unchanged 3. Octreotide transiently raised blood pressure and prevented glucose-induced hypotension. There were no changes in cardiac index or peripheral blood flow. Plasma insulin and neurotensin levels did not rise. Plasma glucose levels increased more slowly but reached a similar level to the placebo phase 4. We conclude that in autonomic failure patients, glucose-induced hypotension was not accompanied by changes in cardiac index or peripheral blood flow, indicating a lack of compensation to probable splanchnic vasodilatation. The hypotension was prevented by the peptide release inhibitor, octreotide, with no change in cardiac index or in peripheral blood flow, suggesting an effect on the splanchnic vasculature, probably through inhibiting release of vasodilatatory pancreatic and gut peptides.

1. To investigate whether carbohydrate contributes to postprandial hypotension in autonomic failure, the cardiovascular, biochemical and hormonal effects of oral glucose and an iso-osmotic solution of oral xylose were studied on separate occasions in six patients with chronic autonomic failure. The effects of oral glucose were also studied in eight normal subjects. 2. In the patients oral glucose lowered blood pressure substantially (−34 ± 7% at 60 min, area under curve −24.9 ± 3.5%, P < 0.001) and for a prolonged period (− 25 ± 4% at 120 min). Plasma noradrenaline levels did not change. In the normal subjects blood pressure was unchanged and plasma noradrenaline rose, suggesting a compensatory increase in sympathetic nervous activity. 3. In the patients xylose caused a smaller and more transient fall in blood pressure (−15 ± 6% at 90 min, area under curve −8.9 ± 4%, P < 0.05) with a non-significant elevation in packed cell volume (36.7 ± 1.8 to 38.2 ± 1.8). It was therefore unclear if xylose was exerting osmotic effects within the bowel which contributed to the small blood pressure fall. Packed cell volume did not change in either the patients or normal subjects after glucose. 4. In the patients and normal subjects plasma insulin rose after glucose. Insulin levels were unchanged after xylose. Levels of pancreatic polypeptide and neurotensin, a potential vasodilator, rose in the patients only. The latter rose to a similar extent after both glucose and xylose, making it unlikely that neurotensin alone accounted for the hypotension. 5. These studies indicate that the carbohydrate components of a meal, and in particular those causing insulin release, contribute to postprandial hypotension in patients with autonomic failure.

1. Negative pressure breathing was one of the first physiological tools used to study the renal effects of redistribution of the blood volume from the peripheries to the thorax. The recent discovery of a putative natriuretic hormone (atrial natriuretic peptide, ANP) in cardiac atrial tissue has rekindled interest in the effect of the cardiovascular system on renal function. We have therefore studied the effects of this physiological manoeuvre on plasma ANP concentrations and renal responses. 2. Plasma concentrations of ANP, plasma renin activity and plasma aldosterone concentration were measured during an 80 min period of negative pressure breathing at −12 cmH 2 O pressure in six hydrated normal subjects. Identical control studies were performed in the same subjects at at least 1 week apart. 3. Negative pressure breathing resulted in a natriuresis and diuresis which were associated with a significant rise in plasma ANP concentration. The natriuresis occurred despite an increase in plasma renin activity and in plasma aldosterone concentration. 4. These findings, under specific carefully controlled conditions, support the previously contentious postulate that negative pressure breathing enhances sodium excretion, in addition to its well-recognized diuretic effect. They add further weight to the hypothesis that expansion of the central blood volume is an important stimulus to the release of ANP from the heart (acting by way of atrial distension), and suggest that changes of plasma ANP concentration may have induced the natriuresis which occurred in the face of a modest activation of the sodium-retaining renin-aldosterone system.

1. Atrial natriuretic peptide (ANP) levels were measured in cardiac tissues and in plasma from adult rats exposed to chronic alveolar hypoxia for periods of 2 h, 24 h and 7 days. Levels were also measured in rats that were maintained in hypoxia for 7 days and then returned to air for 24 h. 2. Plasma ANP was not altered at 2 h but was significantly increased at both 24 h and at 7 days. Plasma ANP in animals exposed to hypoxia for 7 days was normal 24 h after returning to air breathing, despite the persistence of indices of pulmonary hypertension. 3. No significant right atrial hypertrophy was observed under these conditions of chronic hypoxia. A reduction in right atrial ANP content was found at 24 h and was accompanied by a decrease in the number of electrondense granules per right atrial muscle cell. After exposure to hypoxia for 7 days, right atrial ANP and granule number was not different from control, and no alteration was found in right atrial ANP level after removal from the hypoxic environment. 4. No significant right ventricular hypertrophy was produced by exposure to hypoxia for 2 or 24 h. In the former group ventricular ANP had decreased significantly compared with control. Right ventricular hypertrophy was found in both the hypoxic groups after exposure for 7 days, when selective increases in right ventricular ANP content were found. 5. These findings are consistent with the hypothesis that ANP release occurs on exposure to chronic hypoxia and is independent of the associated cardiac hypertrophy and pulmonary vascular remodelling. The findings may have relevance to the natriuresis and reported changes in the renin-angiotensin-aldosterone axis under hypoxic conditions.

1. The objective of this study was to see whether another proliferative stimulus could modify the marked proliferative effect of human epidermal growth factor (urogastrone-epidermal growth factor, URO-EGF) on the gastrointestinal epithelium. 2. The response of the gastrointestinal tract to URO-EGF was investigated in rats maintained on total parenteral nutrition (TPN) with or without 75% small bowel resection. 3. Continuous infusion of 60 μg of recombinant β-urogastrone/day per rat increased proliferation in the stomach by over four times ( P < 0.01), doubled proliferation in the small intestine ( P < 0.001) and increased it by four and a half times in the colon ( P < 0.001) in the control group. No significant effect of urogastrone was observed in the stomach of the resected groups, but proliferation was also increased in the small intestine by one and a half times ( P < 0.001) and by nearly four times in the colon ( P < 0.001). 4. Two-way analysis of variance showed that resection had a significant effect ( P < 0.01) on proliferation below the anastamosis and in the ileum. However, the response of the ileum was only half that observed in orally fed rats, which confirms the importance of ‘luminal nutrition’ in the response to resection. 5. Intestinal resection in the TPN rat was associated with a small rise in plasma enteroglucagon levels, suggesting that this hormone may be implicated in the adaptive response of the small intestine to resection. However, the proliferative effects of URO-EGF were not associated with increased plasma enteroglucagon and thus the two agents probably exert their proliferative effects via separate mechanisms. 6. There was no evidence for a significant positive interaction between the effects of URO-EGF and resection. Thus loss of intestinal mass had no influence on the susceptibility of the intestine to the effects of URO-EGF. Although URO-EGF significantly increased intestinal epithelial cell proliferation, it could not entirely compensate for the lack of luminal contents.

1. The effect of insulin-induced hypoglycaemia on gastro-jejunal motility was studied in five, healthy, male subjects using tethered, pressure sensitive, radiotelemetry capsules. 2. Thirty minutes after the intravenous injection of soluble insulin (0.15 unit/kg body weight), a significant reduction in blood glucose concentration (control: 5.26 ± 0.19 sem mmol/l; insulin: 1.48 ± 0.44 mmol/l; P < 0.001) was associated with a rise in heart rate (mean peak rise 29 ± 8 beats/min, P < 0.05), systolic arterial blood pressure (mean peak rise 28 ± 4 mmHg, P < 0.01) and plasma pancreatic polypeptide concentration (control: 20 ± 7 pmol/l; insulin: 287 ± 66 pmol/l; P < 0.01). These events coincided with a short period of jejunal motor activity, which was not associated with gastric motor activity nor with raised plasma motilin concentrations. 3. During the control study, there were no changes in blood glucose concentration, heart rate, arterial blood pressure or plasma pancreatic polypeptide concentrations, and there was no jejunal motor activity. 4. The interval between successive gastric migrating motor complexes (MMC) was not significantly different in the insulin and control studies (control: median interval 110 min, range 108–148 min; insulin: median interval 124 min, range 115–125 min), suggesting that the fasting gastro-jejunal MMC and jejunal motor activity arose independently. 5. Insulin-induced hypoglycaemia is accompanied by jejunal motor activity, which may underlie the abdominal symptoms associated with hypoglycaemia.

1. The administration of exogenous atrial natriuretic peptide (ANP) causes a natriuresis and diuresis in man, but this has, to date, only been demonstrated at plasma ANP concentrations within the high pathological or pharmacological ranges. Evidence that ANP acts physiologically requires the demonstration of a natriuretic effect when it is infused to recreate plasma concentrations similar to those observed after physiological stimuli. 2. We infused human α-ANP (1–28) at a calculated rate of 1.2 pmol min −1 kg −1 for 3 h into seven water-loaded normal subjects, achieving plasma ANP concentrations within the upper part of the physiological range. The subjects' resting plasma ANP concentration increased from 3.8 ± 1.5 to 20.9 ± 1.9 pmol/l. 3. The infusion of ANP caused a 60% increase of mean urinary sodium excretion from 111 ± 18 to 182 ± 30 μmol/min ( P < 0.001) and a 28% increase of mean water excretion from 10.8 ± 0.8 to 13.8 ± 1.6 ml/min ( P < 0.01). 4. The infusion suppressed mean plasma renin activity from 1.55 ± 0.10 to 1.17 ± 0.06 pmol of ANG I h −1 ml −1 ( P < 0.001). Mean plasma aldosterone concentration (242 ± 16 basally and 215 ± 15 pmol/l at the end of ANP infusion) did not change significantly. Pulse rate and blood pressure were unchanged throughout the study. 5. No significant change in any of the variables mentioned above occurred during the infusion of the vehicle alone on a separate study day. 6. The demonstration that recreation of plasma concentrations of ANP within the physiological range by intravenous infusion induces a natriuresis provides new evidence supporting the role of ANP as a natriuretic hormone.

1. Coeliac patients are known to have an expanded bile salt pool which recirculates slowly due, at least in part, to impaired gall bladder contractility. We have investigated the possibility that delayed small bowel transit of chyme and bile may also contribute to this sluggish recycling. 2. Plasma cholylglycine, total bile acids and cholecystokinin concentrations were measured after a lactulose-labelled test meal whose mouth-caecum transit time (M–C TT) was assessed by the breath hydrogen technique. 3. Overall there were no significant differences in plasma bile acid profiles between seven healthy controls and a group of 25 coeliac patients. However, when subjects were divided according to their M–C TT, the 10 with the slowest transit were found to have significant elevation of fasting levels when compared with the 10 with the fastest transit, fasting total bile acids being 3.4 ± 1.3 versus 0.7 ± 0.6 μmol/l ( P < 0.02) and fasting cholylglycine being 0.43 ± 0.17 versus 0.06 ± 0.04 μmol/l ( P < 0.05) respectively. 4. Peak bile acid levels did not differ significantly between subjects with fast or slow transit. However, subjects with slow transit were found to have a delay in the return of plasma bile acid levels to fasting levels so that the 4 h postprandial levels were significantly elevated when compared with those observed in the subjects with fast transit (total bile acids 3.6 ± 1.2 versus 0.19 ± 0.1 μmol/l and cholylglycine 0.70 ± 0.13 versus 0.24 ± 0.07 μmol/l respectively, both P < 0.01). 5. We conclude that M–C TT is an important variable determining the postprandial plasma bile acid response, which should be considered when comparing different disease groups in whom gut motility may differ.

1. Thermoneutral water immersion produces a physiological increase of thoracic blood volume, raises central venous pressure and increases urinary sodium excretion by a hitherto ill-understood mechanism. We have investigated whether this enhanced sodium excretion could be mediated by the recently discovered natriuretic factor, atrial natriuretic peptide (ANP). 2. During water immersion there was a highly significant ( P < 0.001) twofold increase of the mean plasma ANP concentration and a doubling of the mean urinary sodium excretion. Both were unchanged during the control experiments. 3. These results are consistent with the hypotheses (a) that ANP is released into plasma in response to central blood volume expansion and (b) that it functions as a natriuretic hormone in normal man under physiological conditions.

1. We studied plasma atrial natriuretic peptide (ANP) concentrations in seven normal subjects after the acute intravenous infusion of sodium chloride/potassium chloride solution (saline). 2. Three separate infusions of 6, 12 and 18 ml of saline/kg body weight each significantly increased the circulating concentration of ANP without changes of plasma osmolality or electrolyte concentrations. 3. The mean maximal rise of the plasma ANP concentration after the three saline infusions was significantly correlated ( r = 0.74, P < 0.001) with, but occurred 10–30 min later than, the maximal atrial pressure rise. 4. These observations are in accord with the hypotheses that: (a) ANP is a circulating natriuretic factor; (b) atrial distension is an important stimulus to ANP release in man.

1. Neuropeptide Y content of the kidneys, heart, blood vessels, adrenals and brain stem was determined in both two-kidney, one-clip and one-kidney, one-clip Goldblatt hypertension in rats and compared with levels in age- and sex-matched controls. 2. Renal neuropeptide Y content was significantly reduced in the clipped kidney of rats in both Goldblatt two-kidney, one-clip and Goldblatt one-kidney, one-clip models of hypertension. The content of neuropeptide Y was also reduced but to a lesser extent in the contralateral, non-ischaemic kidney in the two-kidney, one-clip model. 3. In both models of hypertension, neuropeptide Y content in the heart was significantly reduced in the left ventricle and septum but unchanged in the atria and right ventricle wall. 4. There was no significant change in the concentration of neuropeptide Y through the vasculature (major arteries and veins), including the renal artery distal to the clip, or in adrenals and brain stem.

1. 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. 2. Angiotensin II infused with placebo produced a significant rise of plasma aldosterone concentration (mean ± sem increment 352 ± 23 pmol/l, n = 7, P < 0.001). The infusion of alpha h-ANP together with angiotensin II largely abolished the aldosterone response ( P < 0.001). 3. Diastolic blood pressure rose in response to the infusion of angiotensin II with placebo (mean increment 21.0 ± 0.9 mmHg, P < 0.001). Systolic blood pressure increased to a lesser degree (mean increment 12.5 ± 0.7 mmHg, P < 0.001). 4. The infusion of alpha h-ANP together with angiotensin II significantly blunted the diastolic pressor response ( P < 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. 5. 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.

1. A novel vasoconstrictor peptide, neuropeptide Y (NPY), has been identified in considerable quantities in the renal artery and kidney. Within the kidney, NPY was confined to the cortex and corticomedullary interface, the regions where the juxtaglomerular apparatus is most numerous. 2. In the isolated perfused rat kidney, NPY caused a prompt dose-dependent increase in perfusion pressure and reduction in flow, with only a small fall in glomerular filtration rate (GFR). In spite of the reduced renal perfusion, a dose-dependent natriuresis was observed. This response contrasts to the response of this preparation to noradrenaline, which causes sodium reabsorption. 3. The presence of a potent vasoconstrictor and natriuretic peptide within the rat renovascular system suggests that it may play a significant role in the control of renal function.

1. To test whether impaired carbohydrate tolerance in cirrhosis could be modified by dietary means ten cirrhotic patients, five of them taking insulin, took as breakfast either lentils or whole-meal bread and cottage cheese containing the same amount of carbohydrate and protein. 2. Lentils resulted in significantly diminished blood glucose, insulin (in those not on insulin) and gastric inhibitory peptide responses. 3. Enteroglucagon and neutrotensin levels were high with lentils, suggesting that absorption of lentil carbohydrate continued into the ileum with perhaps some malabsorption, so confuming the results of earlier studies in vitro. 4. However, breath hydrogen studies on a separate group of eight healthy volunteers indicated that the difference in carbohydrate malabsorption between lentil, and wholemeal bread was insignificant. 5. It is suggested that slowly digested carbo-hydrate foods, such as leguminous seeds, may minimize carbohydrate intolerance in patients with cirrhosis.