Electrogenic ion transport in duodenal biopsies from children with coeliac disease.

BACKGROUND: The aim of this work was to study whether different degrees of duodenal mucosal damage in coeliac disease (CD) influenced secretory responses to well-known secretagogues. METHODS: Intestinal biopsies from 53 patients in different clinical phases of CD and 34 patients without CD and with normal histology were studied in a modified Ussing chamber. The electrogenic responses-with and without pretreatment with indomethacin-to prostaglandin E2, aminophylline, dibutyryl-cAMP and acetylcholine were followed by continuous measurements of potential difference (Pd). Tissue resistance and epithelial current (Im) were calculated. RESULTS: All secretagogues induced a similar pattern, with a greater increase in Pd and Im in biopsies with villous atrophy compared to controls. The electrophysiological response was correlated to the serum levels of IgA gliadin antibodies. The most prominent electrophysiological increase was found in the biopsies with partial atrophy. Indomethacin had a greater impact on the response to secretagogues in the more severely damaged mucosa. CONCLUSION: The electrogenic secretory response in the proximal small intestine was enhanced and related to serum levels of IgA gliadin antibodies and to the degree of mucosal damage in biopsies from children with active CD compared to controls.

Transcutaneous-PO2 monitoring for detection of exercise-induced right-to-left shunts in children with congenital heart defects: a case report.

UNLABELLED: A 2-y-old boy with scimitar syndrome underwent surgery involving the redirection of partial anomalous pulmonary venous return to the left atrium. Heart catheterization after the operation did not reveal any significant intra-cardiac shunts. An exercise test performed at the age of 10 y revealed a reduction in working capacity. At the age of 12 y, the patient became unconscious and experienced seizures during heavy physical exercise. EEG and Holter ECG examinations were normal. In a second exercise test, a fall in transcutaneous PO2 was demonstrated at the start of the test. A new heart catheterization revealed communication between the inferior vena cava and the left atrium owing to a misplaced patch. No right-to-left shunt was found at rest, probably as a result of drainage of the inferior vena cava to the superior vena cava by the azygous vein. An exercise test after re-operation revealed normal conditions. CONCLUSION: Haemodynamic studies during heart catheterization in children are usually performed at rest. This could result in exercise-induced right-to-left-shunts being overlooked. The use of PtcO2 monitoring during exercise tests is a non-invasive means of exposing these shunts.

Histamine provocation in young, awake children with bronchial asthma, using a fall in oxygenation as the only indicator of a bronchial reaction.

Bronchial provocation with histamine was performed in 11 boys and 6 girls, age range 2.7-7.4 y, with unspecific respiratory symptoms or bronchial asthma, using a fall in oxygenation as the only indicator of a bronchial reaction. In addition to transcutaneous oxygen tension (tcPO2), transcutaneous carbon dioxide tension (tcPCO2) was continuously monitored during the provocation procedure in order to identify possible changes in ventilation. A fall of 20% or more in the tcPO2 below a "floating" baseline value, defined as the highest tcPO2 value between the inhalations of histamine up to that point, was regarded as indicating a significant bronchial reaction. One child was excluded from the study because of an "early, false-positive" reaction due to hyperventilation during the inhalation, verified by a decrease in the tcPCO2 followed by a compensatory period of hypoventilation, resulting in a fall of more than 15% in the tcPO2 after the inhalation of saline. In the vast majority of the children, however, the tcPO2 values remained stable during the first dose stages of saline and histamine, with either a gradual fall immediately before or a distinct fall in conjunction with the reaction. The mean reaction concentration was significantly lower in the group of children with clinical asthma, 0.74 mg/ml, compared with the group of children with unspecific respiratory symptoms, 2.00 mg/ml (p = 0.03). In conclusion, a 20% fall in the tcPO2 can be used as the only indicator of a bronchial reaction during bronchial provocation tests in young, awake children. Changes in ventilation evaluated by monitoring tcPCO2, makes it possible to distinguish between a fall in oxygen tension due to an early, "false" reaction as a result of hypoventilation and a "true" bronchial reaction.

Electrogenic ion transport along the human duodenum in childhood.

BACKGROUND: To find reliable sites to study the effects of different secretagogues on electrogenic ion secretion, we investigated the secretion pattern in different parts of duodenum. METHODS: Histologically normal routine intestinal biopsy specimens from children were mounted in a modified Ussing chamber. The secretory responses to prostaglandin E2 (PGE2), aminophylline, dibutyryl cyclic adenosine 5'-monophosphate (cAMP), and acetylcholine (ACh) were studied with continuous measurements of the potential difference. Tissue resistance and generated current were calculated. RESULTS: ACh induced secretion in the whole of duodenum, although the secretory response was augmented distally. PGE2 and cAMP induced significant secretion only in the distal duodenum. CONCLUSIONS: The ACh-induced, calcium-mediated, electrogenic secretion was expressed along the whole duodenum, whereas the cAMP-mediated secretion was only seen in the distal part. The fully expressed electrogenic chloride secretion was only seen at or distal to the duodenojejunal flexure. Our study shows that it is important to carefully define the localization of physiologic studies performed in the duodenum.

Wheezing bronchitis reinvestigated at the age of 10 years.

We have reinvestigated 92/101 children aged 10, who before the age of 2 years were admitted to a paediatric ward due to wheezing bronchitis. At the present time, 70% are symptom-free without medication, 20% have mild asthma, 8% moderate and 2% severe asthma. Persistent asthma correlated significantly to the presence of some other atopic disease in recent years, to early start of wheezing during infancy and to intense obstructive disease as a young child, while initial respiratory syncytial virus infection did not. A clear-cut relationship between smoking in the home in infancy and persistent asthma emerged (not visible at a preschool follow-up). The histamine challenge results correlated to the clinical picture. A normal histamine challenge was seen in 63%, mild hyperresponsiveness in 19%, moderate in 12% and pronounced hyperresponsiveness in 6%. The figures for persistent asthma and bronchial hyperresponsiveness are high compared with the prevalence of asthma in the overall population of schoolchildren.

Small intestinal fluid absorption in the rat during haemorrhage and its importance for plasma refill.

Small intestinal net fluid absorption and its importance for plasma volume restitution during a slow, stepwise haemorrhage was studied in rats. A continuous administration of a Krebs-glucose solution into the intestinal lumen increased the tolerated maximal bleeding volume from 31 to 70% of initial total blood volume. The 'small intestinal' autotransfusion rate, i.e. the rate of fluid mobilized from the intestinal lumen into the vascular compartment, was calculated to 2.3 ml h-1 100 cm-2 small intestinal serosal surface. 'Small intestinal' autotransfusion is proposed to be an important mechanism in the defence line against hypovolaemia. Haemorrhage induced a 40% increase in small intestinal net fluid absorption. This increase was abolished after pretreatment with Captopril, an angiotensin-converting enzyme blocker. Post-ganglionic denervation of the small intestine reduced, but did not abolish, the stimulatory effect of haemorrhage on net fluid absorption. These results indicate that both a direct nervous component and the renin-angiotensin system are of importance for the increase in small intestinal net fluid absorption observed after haemorrhage.

Intestinal fluid and electrolyte transport in man during reduced circulating blood volume.

The effect on intestinal net transport of fluid and electrolytes of a reduced circulating blood volume was studied in the human jejunum with the triple lumen perfusion technique. The blood volume was reduced by changing the lower extremities from an elevated to a dependent position combined with a venous stasis. The tilting manoeuvre, probably resembling a bleeding of about 600-800 ml, significantly increased net absorption of fluid, sodium and chloride while glucose transport was unaffected. Concomitantly the blood flow decreased and vascular resistance increased in the forearm vascular bed. The results are consistent with the hypothesis that activity in the sympathetic nervous system initiated from unloading of the cardiopulmonary volume receptors enhances intestinal absorption of fluid and electrolytes. The results also indicate that the human intestines are an important target organ in the compensatory mechanisms activated during hypovolaemia due to - for example, haemorrhage.

Small intestinal mucosal lesions in feline septic shock: a study on the pathogenesis.

The pathogenesis of small intestinal mucosal damage in septic shock was explored in experiments on 15 cats given live E coli i.v. Villous (absorptive site) blood flow was studied by the carbon monoxide uptake technique using isolated small intestinal segments. In eight of the cats, segments were perfused intraluminally with oxygenated or nitrogenated saline. The main part of the small intestine was unperfused and served as control. Nine cats (60%) developed mucosal damage. They had significantly lower arterial blood pressure at the end of septicemia (56 +/- 6) than cats without mucosal damage (76 +/- 3 mmHg). Total intestinal blood flow was similar before or during septicemia. Villous blood flow before septicemia was 3.7 +/- 0.5 ml/min X 100 g intestine and 5.1 +/- 1.0 (n.s.) in the two groups, respectively, and remained unchanged. Intraluminal perfusion with oxygenated but not with nitrogenated saline prevented the development of mucosal damage. It was concluded that the small intestinal mucosal damage is due to hypoxia in spite of unchanged villous blood supply.

The importance of nervous and humoral factors in the control of vascular resistance, blood flow distribution and net fluid absorption in the cat small intestine during hemorrhage.

The influence of preganglionic (splanchnic) and postganglionic (periarterial) denervation of the cat small intestine on the changes in blood flow and net fluid absorption elicited by hemorrhage was investigated. The compiled data from a previous report indicate that hemorrhage induces a vasoconstriction and a redistribution of blood flow towards the absorptive part of the mucosa. The vasoconstriction was unaffected by a total postganglionic denervation whereas after a preganglionic denervation both the vasoconstriction and the redistribution of blood flow were abolished. We have also shown earlier that hemorrhage induced an increase in net fluid absorption as long as no ischemic mucosal lesions developed. This increase was reduced by postganglionic denervation, and was reversed into a small decrease after preganglionic denervation. On the basis of these findings it is proposed that the increase in vascular resistance, the redistribution of blood flow towards the absorptive part of the mucosa as well as the increase in net fluid absorption observed after hemorrhage all are effects mainly mediated via the splanchnic nerves. Furthermore, humoral factors are of major importance for the increase in vascular resistance observed after hemorrhage. The increase in net fluid absorption was shown to be induced both by direct nervous and by humoral factors.

Blood flow distribution, villous tissue osmolality and fluid and electrolyte transport in the cat small intestine during regional hypotension.

The hemodynamic reactions of the parallel coupled vascular circuits in the cat small intestine were studied before, during and after a two-hour period of intestinal hypotension induced by lowering the intestinal arterial inflow pressure by partially occluding the superior mesenteric artery during a continuous stimulation of the postganglionic nerves to the small intestine. Furthermore, fluid and electrolyte transport and villous tissue osmolality were measured. A histological examination of biopsies taken during and after the hypotensive period was also carried out. The animals were divided into two groups (undamaged and damaged) according to the histological appearance of the intestinal mucosa. The hemodynamic reactions were investigated with a method that made it possible to study total intestinal, absorptive site ("villous"), nonabsorptive site ("crypt") and muscle layer blood flow. Total intestinal blood flow was lower in the damaged group than in the undamaged group during the arterial hypotension. However, absorptive site blood flow was similar in the two groups. Consequently, a significantly larger fraction of blood flow was distributed to the "villi" in the damaged group. Moreover, absorptive site red blood cell flow was only slightly reduced despite the development of mucosal ulcerations. These findings are discussed in relation to the pathophysiology of the mucosal lesions. Net fluid, net sodium and net chloride absorption was unchanged in the undamaged group whereas in the damaged group a marked decrease was observed after lowering the perfusion pressure. The decrease in net sodium absorption was due to a decrease in the lumen to tissue transport of sodium. Thus, the capacity of the small intestine to absorb fluid and electrolytes is unchanged even during a marked arterial hypotension with a pronounced decrease of intestinal blood flow as long as no mucosal damage has developed.

Effects of hemorrhage on intramural blood flow distribution, villous tissue osmolality and fluid and electrolyte transport in the cat small intestine.

The hemodynamic response in the parallel-coupled vascular sections of the cat small intestine were studied before, during and after a two hour period of hemorrhage (about 30 per cent of estimated blood volume). Fluid and electrolyte transport and villous tissue osmolality were also measured. Biopsies for histology were taken at the end of all experiments. The animals were divided in two groups, undamaged and damaged, according to the degree of mucosal damage observed. The hemodynamic reactions were investigated with a method that made it possible to study total intestinal, absorptive site ("villous"), nonabsorptive site ("crypt") and muscle layer blood flows. Total intestinal blood flow was lower in the damaged as compared to the undamaged group during hypovolemia. No difference in absorptive site blood flow was observed between the two groups during hypovolemia. Furthermore, no decrease of red blood cell flow in the "villi" was recorded in either group after hemorrhage. Consequently, mucosal lesions developed despite an unchanged oxygen transport capacity to the villi. The pathophysiology of the mucosal lesions is briefly discussed. Net fluid and sodium absorption was after hemorrhage increased in the undamaged group reflecting a decrease in the tissue to lumen transport of sodium. After retransfusion net fluid and sodium absorption returned to control. In the damaged group, however, net fluid and sodium absorption was decreased after hemorrhage. The increased rate of fluid and electrolyte transport observed in the undamaged small intestine after hemorrhage, is proposed to be an important mechanism for fluid replacement after hemorrhage.

Effect of intravenous dopamine infusion on intramural blood flow distribution and fluid absorption in the feline small intestine.

The aim of the study was to investigate the effects of dopamine on the intestinal mucosal blood flow and transport function. Dopamine was infused intravenously at 20 micrograms X kg-1 X min-1 in anesthetized cats. Total and intramural blood flow in an isolated jejunal segment was measured by a combined drop-flow and 85Kr clearance technique. Net fluid transport was recorded by two independent perfusion methods. Unidirectional sodium transport was estimated from luminal 22Na disappearance. Dopamine induced a pronounced mucosal vasodilatation up to 400% of control values. Concomitantly, net fluid and sodium absorption increased by 50%. The effect on sodium transport was due to a pronounced decrease in tissue-to-lumen sodium flux, a pattern similar to the one seen on alpha-adrenergic stimulation. The effect of dopamine on blood flow was unaffected by phentolamine, 1 mg X kg-1, whereas the absorptive response was abolished. The findings indicate that dopamine induces a mucosal vasodilation via one mechanism (possibly dopaminergic) and enhances fluid transport via another mechanism, probably alpha-adrenergic.

Evidence for cardiac volume-receptor regulation of feline jejunal blood flow and fluid transport.

The aim of the study was to investigate the role of cardiac mechanoreceptors in the reflex regulation of intestinal blood flow and fluid transport. Feline cardiac mechanoreceptor activity was modified with two noninvasive techniques: positive-pressure ventilation (PPV) and inspiratory resistance breathing (IRB). A jejunal segment with intact vascular and nervous supply was isolated and exposed to cholera toxin as a model for intestinal secretion. The results revealed that PPV induced a pronounced intestinal vasoconstriction and a marked inhibition of choleraic secretion. IRB had the opposite effects. The responses were well correlated with changes in central blood volume and either markedly reduced or abolished by vagotomy, intestinal alpha-adrenoreceptor blockade, or postganglionic mesenteric denervation. The results indicate that cardiac mechanoreceptors with vagal afferents may mediate the observed reflex responses, and hence this receptor station may be of importance in the normal reflex control of intestinal hemodynamics and fluid transport.

On the mode of action of the sympathetic fibres on intestinal fluid transport: evidence for the existence of a glucose-stimulated secretory nervous pathway in the intestinal wall.

The effect of sympathetic nerve stimulation or close i.a. infusion of noradrenaline on net fluid transport was investigated on anesthetized cats. In the presence of glucose in the solution perfusing the intestinal lumen the adrenergic mechanisms increased net fluid absorption in normal intestines. Substituting glucose with mannitol in the perfusate abolished this effect of adrenergic stimulation on the net fluid uptake. Furthermore, the effect of noradrenaline on net fluid transport in normal or choleraic intestines was abolished by tetrodotoxin (TTX), a nerve conductivity blocking agent. This suggests that the sympathetic influence is dependent on intraluminal glucose and that noradrenaline exerts its effect mainly via nerves. TTX significantly increased fluid uptake from normal intestines perfused with an isotonic electrolyte solution containing glucose while a considerably smaller effect was seen in intestinal segments perfused with a solution with mannitol. Based on these findings it is proposed that glucose in some way activates intramural nervous reflex(es) in the intestinal wall. According to this hypothesis the enhancement of fluid transport induced by adrenergic stimuli is explained by an inhibition of the glucose-activated nervous secretion.

Intramural blood flow distribution in the small intestine of the cat studied by carbon monoxide uptake and 85krypton elimination.

Carbon monoxide (CO) uptake from the feline small intestine was measured to investigate if it could be used to determine blood flow in the superficial parts of the intestinal mucosa. Several observations were made that substantiated this proposal: 1) Lowering PCO in the intestinal lumen from 100 to 70 kPa did not influence the rate of CO absorption during "resting" blood flow conditions, while the same reduction of lumen PCO resulted in a decreased rate of CO uptake during isoprenaline induced vasodilatation. These observations suggest that CO uptake was flow limited during "rest" and diffusion limited during vasodilation. 2) Lowering perfusion pressure or totally occluding the intestinal vascular supply markedly reduced the rate of CO uptake. 3) The diffusion distance for CO into the tissue was calculated to be 75-225 micron, i.e. CO mainly diffused into the villous tissue. 4) The flow values calculated from the CO measurements were of the same order of magnitude as earlier reported with other techniques (microspheres, indicator dilution method). It was concluded that CO absorption mainly reflected villous blood flow during "resting" and low intestinal blood flow. Total blood flow (venous drop recorder) and muscle layer blood flow (85Kr elimination) were measured simultaneously to CO uptake. From these determinations "resting" blood flow distribution in the small intestine was calculated.

Intestinal vascular responses to dopamine during fentanyl-nitrous oxide anaesthesia, supplemented with dixyrazin.

Intestinal haemodynamics in response to continuous i.v. administration of dopamine were investigated in cats anaesthetized with fentanyl-nitrous oxide either with or without supplement of dixyrazin. A dose-dependent vasodilatation was observed in the dopamine dose range 2.5-35 micrograms . kg-1 . min-1 and the subsequent maximal intestinal blood flow increase was 121%. No net intestinal vasoconstriction was evident even at the largest dopamine doses, although the vascular response reached a plateau at 17.5 micrograms . kg-1 . min-1. Control experiments during chloralose anaesthesia gave similar results. Changes in mean arterial pressure and heart rate were small. Renal blood flow was virtually unchanged at dopamine doses below 10 micrograms . kg-1 . min-1, while renal vasoconstriction was evident following dopamine doses above that level. The addition of i.v. dixyrazin (0.15-0.30 mg . kg-1) to the fentanyl-nitrous oxide anaesthesia substantially potentiated the intestinal vasodilator response to i.v. dopamine and the maximal blood flow increase was 183% at 10-15 micrograms . kg-1 . min-1. In vitro experiments using mesenteric resistance vessels from the rat demonstrated a dose-dependent relaxation to dopamine. At very large doses this response was counteracted, but not reversed into vasoconstriction by dopamine-induced alpha-adrenergic stimulation.

The effect of splanchnic nerve stimulation on blood flow distribution, villous tissue osmolality and fluid and electrolyte transport in the small intestine of the cat.

The effect of splanchnic nerve activation on intestinal fluid transport and intramural blood flow distribution was examined in the cat. Previous reports from our laboratory have demonstrated that splanchnic nerve activation increases fluid absorption. The present study was performed to elucidate the mechanisms behind this effect. The results showed an increase in net sodium and chloride transport on splanchnic nerve activation whether intestinal blood flow decreased or not. The effect on sodium transport was due to a decrease in lumen to tissue flux. The effect could not be explained by a decrease in local blood flow, as it was present despite constant blood flow in both the villous and crypt regions. No change was seen in the villous osmolality gradient on splanchnic nerve activation. On the basis of these findings, it is proposed that the in vivo effect of splanchnic nerve activation is due to a decrease in fluid and electrolyte secretion, probably occurring in the intestinal crypts.

The effect of carotid occlusion on the rate of net fluid absorption in the small intestine of rats and cats.

The effect on net intestinal fluid absorption of unloading the baroreceptors by bilateral carotid occlusion was studied in rats and cats. It was shown that net fluid uptake from the intestine increased 30-40% upon carotid occlusion. This effect was eliminated by cutting the splanchnic nerves (cats) or by severing the nerves surrounding the superior mesenteric artery (rats). In fact, these denervation procedures resulted in a decreased net fluid absorption upon carotid occlusion. Cutting the vagal nerves did not significantly influence the response to carotid occlusion. It is concluded that the arterial baroreceptors influence net fluid transport in the small intestine, a reflex compensatory mechanism that may be important in different hypotensive situations.

Intramural blood flows and flow distribution in the feline small intestine during arterial hypotension.

The vascular reactions of the parallel-coupled vascular sections of the small intestine were studied during hypotension at two different levels of intestinal arterial inflow pressure, using a 85Kr elimination technique. The regional hypotension was accomplished by partially occluding the superior mesenteric artery with a clamp and maintained for 2 h. At the higher level (50-55 mmHg) total intestinal blood flow decreased but not to the same relative extent as blood pressure due to the autoregulatory capacity of the intestinal vascular bed. The flow autoregulation was also reflected in a decreased blood flow resistance. The distribution of blood to the muscularis and mucosa-submucosa layer, respectively, did not change significantly during or after hypotension as compared to the prehypotensive level, since the relative flow decrease was the same in the mucosa-submucosa and in themuscularis. At the lower arterial pressure level (30-35 mmHg) a more marked decrease of intestinal blood flow and flow resistance was observed as compared to the experiments performed at the 50-55 mmHg pressure level. Moreover, muscularis blood flow was relatively more decreased than blood flow in the mucosa-submucosa implying the fraction of total blood flow diverted to the muscularis was significantly decreased. Despite this redistribution of blood flow, a histological damage was apparent only in the mucosa, particularly at the villous tips.

The effects of cholera toxin on intramural blood flow distribution and capillary hydraulic conductivity in the cat small intestine.

Blood flow distribution to the mucosa-submucosa and to the muscularis in the cat small intestine was investigated with a 85Kr elimination technique before and after exposing the intestinal mucosa for 30 min to cholera enterotoxin. In all experiments the toxin induced an intestinal secretion. Concomitantly, total intestinal blood flow was increased to a level 50 per cent above control 3 h after exposure. This vasodilatation reflected a doubling of mean blood flow in the mucosa--submucosa while muscularis blood flow remained unchanged. In another series of experiments the effect of cholera toxin on intestinal capillary hydraulic conductivity was investigated by determining the capillary filtration coefficient (CFC). A slight increase in CFC was noted during the 3 h observation period but this was not more pronounced than would have been expected from the concomitant vasodilatation. It is concluded that hemodynamic changes in the intestinal mucosa may be one of the several factors that probably are involved in the pathogenesis of cholera.