Sympathetic discharge to mesenteric organs and the liver. Evidence for substantial mesenteric organ norepinephrine spillover.

This study using sampling of blood from the portal vein, in addition to arterial and hepatic sites, to estimate separately spillovers of norepinephrine from mesenteric organs and the liver in seven patients undergoing upper abdominal surgery. Conventional measurements in arterial and hepatic venous plasma provided a measure of net hepatomesenteric NE spillover (403 pmol/ml) that indicated a 13% contribution of these organs to total body spillover of NE into systemic plasma (3,071+/-518 pmol/min). The net hepatomesenteric spillover of NE into systemic plasma was much lower than the spillover of NE from mesenteric organs into portal venous plasma (1,684+/-418 pmol/min). This and the hepatic spillover of NE into systemic plasma (212+/-72 pmol/min) indicated a considerable combined spillover of NE from hepatomesenteric organs (1,896+/-455 pmol/min). The sum of the latter estimate with the difference between total body and net hepatomesenteric NE spillovers provided an adjusted total body spillover of NE into both systemic and portal venous plasma (4,564+/-902 pmol/min). Mesenteric organs made a 37% contribution, and the liver made a 5% contribution to the adjusted total body spillover of NE. Thus, a substantial proportion of total body sympathetic outflow is directed towards mesenteric organs; this is obscured by efficient hepatic extraction of NE (86+/-6%) when measurements are restricted to arterial and hepatic venous plasma.

Assimilation of triglycerides in subcutaneous and intraabdominal adipose tissues in vivo in men: effects of testosterone.

To determine the effects of testosterone (T) on lipid assimilation in different adipose tissue depots, T (250 mg, im) was given to 17 middle-aged men 5 days before abdominal surgery. Twenty-four hours before surgery, 10 microCi labeled oleic acid in 80 g milk fat were administered orally. Lipid radioactivity was measured in adipose tissue biopsies from abdominal ac, omental, and retroperitoneal adipose tissues. Subcutaneous, visceral (omental plus mesenteric), and retroperitoneal adipose tissue masses were determined using computerized tomography scans at 22 levels. Sixteen men who were not treated with T served as controls. T administration was followed by an increase in serum concentrations from 17.7 +/- 1.1 to 32.6 +/- 1.8 nmol/L (P < 0.001) and a marked (> 50%) reduction compared with controls in lipid radioactivity in omental and retroperitoneal adipose tissues, but not in sc adipose tissue. In controls, sc, visceral, and retroperitoneal adipose tissues assimilated 59.2 g (73.4%), 16.9 g (20.9%), and 4.6 g (5.7%), respectively, of the orally administered fat. In the T-treated men, this was changed to 73.5 g (88.8%), 6.4 g (7.7%), and 2.9 g (3.5%), respectively. It was concluded that T inhibits triglyceride assimilation in intra-abdominal depots and apparently directs this lipid to sc fat in men.

Biliary excretion of intravenous [14C] omeprazole in humans.

We have studied the biliary excretion of [14C] omeprazole in humans. The study was performed in eight healthy subjects and the technique used was based on multiple marker dilution principles with double-lumen tubes placed in both the stomach and intestine. The results obtained show a 16% biliary excretion of [14C] omeprazole. These data suggest a minimal "spillover" of omeprazole from the gastric mucosa into the gastric lumen in humans. The results also agree with previous data of the fecal recovery of radiolabeled omeprazole that suggest that the fecal excretion of intravenous omeprazole in humans is entirely accounted for by biliary excretion.

Metabolism of adipose tissue in intraabdominal depots in severely obese men and women.

In groups of obese men and women with an abdominal type of fat distribution, we measured fat cell size, lipoprotein lipase (LPL) activity and lipolysis stimulated by norepinephrine (NE) or isoproterenol (ISO) or inhibited by insulin, in subcutaneous abdominal and retroperitoneal (nonportal), as well as in omental and mesenteric (portal) adipose tissues. Both men and women had large intraabdominal adipocytes. No differences were found between the two groups of obese subjects in fat cell size or LPL activity in the different adipose tissue regions. Women had as high NE- or ISO-stimulated lipolysis in the portal as in nonportal fat tissues, equally high as that found in men. In comparisons with a previous study in nonobese men and women, these results show an increased fat cell size in all tissues in obese women and an increased lipolysis in portal tissues in obese women and in nonportal tissues in obese men. Taken together, these results might mean that obese men and abdominally obese women have a large potential to release free fatty acids (FFA) from intraabdominal depots. This might be followed by metabolic derangements seen in such groups of obese subjects.

Metabolism of adipose tissue in intraabdominal depots of nonobese men and women.

Adipocyte size, lipoprotein lipase (LPL) activity, and the lipolytic response to noradrenaline and isoproterenol were studied in three intraabdominal depots (mesenteric, omental, retroperitoneal), as well as in subcutaneous abdominal adipose tissue, in nonobese groups of middle-aged men and in premenopausal and postmenopausal women. Subcutaneous adipocytes were larger than intraabdominal adipocytes in all groups. The men had large adipocytes in all intraabdominal depots as compared with the women. The premenopausal women seemed to have low LPL activity in intraabdominal depots. Two types of responses to catecholamine-stimulated lipolysis were observed: a similar response from mesenteric and omental (portal) fat depots and from retroperitoneal and subcutaneous abdominal (nonportal) fat depots. Young women had higher lipolysis in nonportal than in portal adipose tissues. In the men the reverse characteristics were found. These dissimilarities seem to be based on differences in beta-adrenergic responsiveness. Postmenopausal women showed no differences between depots. The differences in lipolytic responsiveness between these groups might be caused by sex steroid hormones.

The morphology and metabolism of intraabdominal adipose tissue in men.

Mass, morphology, and metabolism of total adipose tissue and its subcutaneous, visceral, and retroperitoneal subcompartments were examined in 16 men with a wide variation of total body fat. Computerized tomography (CT) scans showed that the intraabdominal fat mass comprised approximately 20% of total fat mass. Visceral and retroperitoneal fat masses were approximately 80% and 20% of total intraabdominal fat mass, respectively. Enlargement of intraabdominal fat depots was due to a parallel adipocyte enlargement only. Direct significant correlations were found between these adipose tissue masses and blood glucose and plasma insulin levels, blood pressure, and liver function tests, while glucose disposal rate during euglycemic glucose clamp measurements at submaximal insulin concentrations (GDR), plasma testosterone, and sex hormone-binding globulin concentrations correlated negatively. The correlations for glucose, insulin, and GDR were strongest with visceral fat mass. Adipose tissue lipid uptake, measured after oral administration of labeled oleic acid in triglyceride, was approximately 50% higher in omental than in subcutaneous adipose tissues. Adipocytes from omental fat also showed a higher lipolytic sensitivity and responsiveness to catecholamines. Furthermore, these adipocytes were less sensitive to the antilipolytic effects of insulin. Both lipid uptake and lipolytic sensitivity and responsiveness showed strong correlations (r = 0.8 to 0.9) to blood glucose and plasma insulin concentrations and also to the GDR (negative), while no such correlations were found with lipid uptake in subcutaneous or retroperitoneal abdominal adipose tissues. Taken together, these results suggest a higher turnover of lipids in visceral than in the other fat depots, which is closely correlated to systemic insulin resistance and glucose metabolism in men.

Somatostatin release induced by gastrin-releasing peptide in man. Effect of proximal gastric vagotomy and cholinergic blockade.

The influence of intragastric pH on the basal release of somatostatin has been studied in healthy controls and in duodenal ulcer patients. In addition the somatostatin response to gastrin-releasing peptide infusion has been evaluated both regarding the effect of intragastric pH and the influence of vagal innervation and muscarinic blockade. No difference was found in basal blood levels, when changing the intraluminal pH, although a slightly higher basal somatostatin concentration was noticed in patients with duodenal ulcer disease. Neither proximal gastric vagotomy nor cholinergic blockade had any effect on basal somatostatin concentrations. GRP infused in stepwise increasing doses from 20 pmol/kg/h to 400 pmol/kg/h induced a small but significant response. This effect of GRP was most evident, when the stomach was perfused with 0.1 M HCl. The small, somatostatin response to GRP infusion was not influenced by vagal denervation of the parietal cell area, neither by cholinergic blockade. Despite the previously observed effects of vagotomy and cholinergic blockade on gastrin release induced by GRP, a corresponding inverse effect on somatostatin is not apparent.

Do enkephalins participate in vagal activation of gastric acid secretion in man?

The effects of the anticholinergic drug benzilonium bromide and the opiate receptor blocker naloxone, given alone or in combination, on the acid secretory response and on plasma gastrin releasing peptide (GRP) response to sham feeding was tested in eight duodenal ulcer (DU) patients. Naloxone alone had no effect on the acid secretion after sham feeding. Benzilonium reduced basal acid secretion and the acid response to sham feeding but did not abolish the response. The combination of benzilonium and naloxone was not more effective than benzilonium alone. Neither drug, nor the combination had any effect on plasma GRP following sham feeding. It is concluded that enkephalins are unlikely to participate in the acid response to sham feeding in patients with DU.

Analysis of the actions of cimetidine and metiamide on gastric acid secretion in the isolated guinea pig gastric mucosa.

Cumulative dose-response curves for histamine were determined on acid secretion from the isolated guinea pig gastric mucosa. Two H2-receptor antagonists-metiamide and cimetidine-behaved like competitive antagonists to histamine on gastric acid secretion in vitro. The isolated guinea pig gastric mucosa seems to be a suitable in vitro model for analysing the action of compounds on receptors involved in acid secretion.

Primary Roux-Y gastrojejunostomy versus gastroduodenostomy after antrectomy and selective vagotomy.

One hundred twenty-one patients with prepyloric ulcer disease entered a randomized clinical trial comparing gastroduodenostomy with Roux-Y gastrojejunostomy after antrectomy and selective gastric vagotomy. The postoperative course and morbidity were quite similar in the two study groups, as was the postoperative infectious complication rate. Forty-four of the patients with a Billroth I reconstruction and 52 of those with a Roux-Y reconstruction were followed up with a clinical assessment at least 6 months after the operation. The postgastrectomy symptoms were quite frequent, but did not differ between the two study groups. Seventy-five percent of the patients with a Billroth I gastroduodenostomy had symptoms corresponding to Visick grades 1 and 2, compared with 81% of those with Roux-Y reconstruction. Although the latter procedure was very effective in preventing bile reflux to the gastric remnant, no difference was observed in the gastric emptying rate after the two operations.

[When is H pylori a cause of duoenal ulcer? Hypersecretion of gastric acid, active duodenitis and reduced bicarbonate secretion are links in the chain]. / När ger H pylori ulcus duodeni? Hypersekretion av syra, aktiv duodenit och nedsatt bikarbonatsekretion är länkar i kedjan.

Helicobacter pylori infection engaging mainly the gastric antrum causes hypersecretion of gastric acid. The increased duodenal acid load gives rise to islands of gastric mucosa in the proximal duodenum. As these bacteria thrive only on gastric mucosa it presents an opportunity for Helicobacter pylori to colonize the duodenum. A much higher density of virulent Helicobacter pylori has been found in the duodenum of duodenal ulcer patients in comparison to infected subjects without duodenal ulcer. The high density of virulent Helicobacter pylori in the proximal duodenum results in a strong inflammatory reaction with active duodenitis and impaired bicarbonate secretion. These characteristics of duodenal ulcer patients, together with the acid hypersecretion, seem to be the key factors in evoking a duodenal ulcer.

Basal and stimulated human gastric bicarbonate secretion.

The mucus-bicarbonate barrier on the gastric mucosa is regarded as a first-line of defence against acid. Both mucus and bicarbonate originate from the mucus cells in the gastric mucosa. Bicarbonate is secreted actively by Cl-/HCO3- exchange at the luminal cell membrane. A computer based system with continuous measurement of pH and PCO2 in a gastric perfusion system was used to determine human gastric bicarbonate secretion. The rate of basal gastric bicarbonate secretion in 24 healthy subjects was 386 +/- 31 mumol/h (mean +/- SEM). The 95% confidence interval for basal bicarbonate output was 103-669 mumol/h. Vagal stimulation by sham feeding increased the bicarbonate output by 63% and instillation of 16,16 dimethyl prostaglandin E2 increased the bicarbonate output by 214%. The response to vagal stimulation was independent of intragastric pH. The sham feeding response was abolished by premedication with anticholinergics. Basal and vagally stimulated bicarbonate secretion was unaffected by prostaglandin biosynthesis blockade.

Effect of omeprazole on gastric acid secretion in man.

Omeprazole in doses of 20, 40 or 60 mg dose-dependently inhibits basal acid secretion in young healthy subjects, with almost complete inhibition by 60 mg. Omeprazole has also been shown to dose-dependently inhibit vagally stimulated and meal stimulated acid secretion. Pentagastrin stimulated acid secretion is strongly inhibited by omeprazole for 4-5 hours, with moderate inhibition remaining 24 hours after a single dose. The plasma half-life of omeprazole, however, is about 50 minutes. The inhibitory effect accumulates over the first few days of repeated administration, and the effect continues for at least 24 hours after the last dose. A relatively high dose of intravenous omeprazole is required to keep the gastric pH above 4 over the 24-hour period. Both basal and postprandial serum gastrin concentrations have been observed to increase during omeprazole treatment. These changes, however, are probably secondary to a pronounced reduction of intragastric acidity which relieves acid inhibition of gastrin release from the antrum.

Acid inhibitory characteristics of omeprazole in man.

Single-dose studies in man have shown that omeprazole is a potent inhibitor of acid secretion stimulated by betazole, pentagastrin, modified sham-feeding and peptone. The degree of inhibition is dose-dependent and correlates to the area under the plasma omeprazole concentration-time curve. The duration of action of a single oral dose is 2-3 days and not dependent on a sustained plasma concentration of omeprazole. During repeated once-daily administration the level of acid inhibition increases over the first 5 days, after which it stabilises. With once-daily omeprazole treatment it is possible to almost abolish 24-hour intragastric acidity in the majority of DU patients.

Effect of omeprazole on gastric acid secretion and plasma gastrin in man.

Single doses of omeprazole inhibit pentagastrin-stimulated gastric acid secretion and almost complete inhibition can be achieved for 4-6 hours with a single dose of 80 mg. Acid secretion then slowly returns and reaches normal levels after 3-4 days. Omeprazole also dose-dependently inhibits basal acid secretion as well as acid secretion stimulated with histamine, peptone and modified sham feeding, with similar efficiency. During repeated once-daily dosing with an enteric-coated granule capsule formulation, inhibition of acid secretion increased initially, and stabilized within about 4 days. Dose-response studies in patients with duodenal ulcers and healthy subjects have shown that 20-40 mg/day results in a peak reduction (80-100%) of pentagastrin-stimulated acid secretion 6 hours after dose. Studies of 24-hour intragastric acidity in duodenal ulcer patients have shown that 4 weeks of treatment with omeprazole, 20 mg once daily, resulted in a reduction of median intragastric acidity by 97%, which was superior to the 57% median reduction achieved with ranitidine, 150 mg b.d., for 4 weeks in the same patients. During omeprazole treatment, fasting plasma gastrin increased in relation to the degree of inhibition of acid secretion. After discontinuation of treatment, plasma gastrin normalized. Treatment with omeprazole, 20 mg, increased 24-hour plasma gastrin to the same extent as after highly selective vagotomy. Long-term treatment with omeprazole, 20-40 mg, for up to 2 years has not been associated with any progressive rise in fasting plasma gastrin.

The effect of different anticholinergics on the gastric acid response to sham feeding in man.

Modified sham feeding by the chew and spit technique stimulates gastric acid secretion at a level about 50% of peak acid output. This response is vagal and can be totally blocked by vagotomy. The effect on the acid response to modified sham feeding produced by a quaternary amine, benzilonium bromide, and a presumably more selectively acting antimuscarinic drug, pirenzepine, was compared. The drugs were given 45 min and 10 min before the start of the sham feeding, respectively. Benzilonium bromide, 1 + 1 mg, blocked 73% of the acid response to sham feeding and pirenzepine, 10 + 10 mg, blocked 48% of the response. The difference was not statistically significant. The data confirm that a part, about one third, of the acid response to sham feeding is non-cholinergic, although it is vagal.