Distension-induced gastric accommodation in functional dyspepsia: effect of autonomic manipulation.

Functional dyspepsia (FD) is associated with impaired gastric accommodation and autonomic dysregulation. The aim of this study was to investigate the effects of autonomic manipulation on distension-induced gastric accommodation in subjects with and without FD, using a newly developed gastric barostat paradigm. Twelve healthy subjects (HS) and 18 subjects with FD had four barostat examinations each: no intervention, intravenous atropine (1 mg), vagal stimulation (mental relaxation with deep breathing) and acute stress stimulation (serial subtraction task). Intrabag pressure increased from 1 to 15 mmHg in 5 min (ramp phase), and was maintained at 15 mmHg for 5 min (tonic phase). Volume responses were analysed using predefined parameters. There were no significant group differences in accommodation variables between HS and subjects with FD. The FD group could be subdivided into two distinct subgroups: subgroup 1 (n = 7, 38%) with low maximum volume and accommodation rate, and subgroup 2 with normal accommodation (n = 11). In subgroup 1, but not in subgroup 2 atropine increased maximum volume and accommodation rate substantially. Neither mental stress nor mental relaxation changed any of the accommodation variables. In a subgroup of subjects with FD, impairment of distension-induced gastric accommodation can be improved by cholinergic blockade, but not by acute physiological autonomic manipulation.

Altered neuroendocrine response and gastric dysmotility in the Flinders Sensitive Line rat.

In the search for animal models that can replicate some features of functional dyspepsia (FD) patients, we turned our interest to the Flinders Sensitive Line (FSL) rat. Gastric motility disturbances prevalent in FD patients as well as urine corticosterone and plasma prolactin were measured following buspirone challenge. Flinders Resistant Line (FRL) rat was used as control. The results show that the FSL rats have a disturbed gastric motility, reflected as both an increased gastric accommodation rate and gastric volume during gastric distension as well as a delayed gastric emptying, the latter possibly as a consequence of the former. Lipid administration resulted in a significant increase in maximal gastric volume only in the FRL rats. Both the corticosterone response to buspirone and the 24-h urinary output of corticosterone were normal in FSL rats. Similar to FD patients, the FSL rat showed supersensitivity to buspirone in the increase in prolactin release. Although FSL rats show some features similar to a subset of FD patients, the increased gastric accommodation contrasts to the reduced accommodation often seen in FD patients. Further studies are warranted to determine the relevance of this rat strain as a model for FD.

Omeprazole and ranitidine, antisecretagogues with different modes of action, are equally effective in causing hyperplasia of enterochromaffin-like cells in rat stomach.

Female rats were treated for 28 days with high doses of the gastric acid secretion inhibitors omeprazole and ranitidine. Omeprazole, which is long-acting, was given orally once daily. Ranitidine, which is short-acting, was given by continuous infusion (via osmotic minipumps, implanted subcutaneously). The aim was to produce a similar degree of acid inhibition with the two drugs. The inhibition of acid secretion over the day and night was more pronounced in the omeprazole-treated rats (maximal inhibition 100%, minimum 85%) than in those receiving ranitidine (mean 70%). In both groups, there was a great increase in plasma gastrin, somewhat greater after omeprazole than after ranitidine. The gastrin concentration in the antrum was almost doubled by both treatments and there was a moderate increase in the number of antral gastrin cells in the omeprazole-treated rats. The number of enterochromaffin-like (ECL) cells (per visual field) increased in the oxyntic mucosa to the same extent (greater than 100%) in the ranitidine- and omeprazole-treated rats. Apart from the gastrin cells in the antrum and the ECL cells in the corpus no other gastric endocrine cell type seemed to respond to treatments with antisecretagogues. We conclude that, regardless of the type of antisecretagogue used, effective and long-term suppression of gastric acid secretion results in sustained hypergastrinemia and increased number of ECL cells. Conceivably therefore, the ECL cell hyperplasia reflects the trophic effect of gastrin.

Gastrin and somatostatin in the rat antrum. The effect of removal of acid-secreting mucosa.

Female rats were subjected to operations aimed at reducing the amount of oxyntic gland mucosa draining its acid secretion to the antrum. The rats were provided either with Heidenhain or Pavlov pouches reducing the oxyntic mucosa draining its secretion to the antrum by about 50% or subjected to various degrees (75, 90 and 100%) of fundectomy. Ten weeks following surgery, plasma levels of gastrin and somatostatin were assayed. At the same time, antral mucosal content of gastrin and somatostatin was determined as well as the mucosal density of these hormone-producing cells. There was a relationship between the amount of acid-secreting mucosa removed and the ensuring plasma concentration of gastrin. Thus, a stepwise increase in plasma gastrin was found with the highest levels obtained in rats subjected to 90 or 100% fundectomy. The somatostatin concentration in plasma was reduced only in rats subjected to fundectomy with the most sustained decrease in animals in which all oxyntic gland mucosa had been removed. There was also a relationship between the amount of acid-secreting mucosa removed and the gastrin content of the antral mucosa. An inverse relationship seemed to exist between antral gastrin and somatostatin concentrations. However, a significant decrease in somatostatin concentration of the antral mucosa was seen only in rats subjected to a fundectomy. The number of gastrin cells in the antral mucosa was increased in fundectomized rats only, with the largest density seen in rats deprived of all oxyntic mucosa. A corresponding decrease in the number of somatostatin cells was noticed. Our results would suggest an apparent functional relationship between antral gastrin and somatostatin cells, where the antral acid load (or pH) appears to be the major factor of physiological significance.

Bicyclic phosphates increase the cyclic GMP level in rat cerebellum, presumably due to reduced GABA inhibition.

Isopropyl bicyclic phosphate (IPTBO) (0.06 mg/kg i.p.) increased the content of cyclic GMP in rat cerebellar cortex 4-fold. Pretreatment with the nicotinamide antagonist 3-acetylpyridine (3-AP) 65 mg/kg i.p. 48 h before), which destroys the climbing fibers, did not antagonize the induced increase. In contrast, GABA (15 mumol intraventricularly) and muscimol (3 mumol and 10 mumol i.p.) abated the IPTBO induced increase of cyclic GMP. The Na+-independent receptor binding of GABA to synaptosomal membranes, as well as uptake and release of GABA in synaptosomes, were unaffected by IPTBO, but the binding of dihydropicrotoxinin to brain membranes was blocked by IPTBO (IC50 = 1 X 10(-6) M). Glutamate (3.75 or 7.5 mumol intraventricularly) increased the level of cyclic GMP in the cerebellum, but the glutamate level in the cerebellum was not affected by IPTBO (0.06 mg/kg). The present results suggest that the elevation of cerebellar cyclic GMP caused by the bicyclic phosphates is not due to activation of the climbing fibers but rather due to a GABA antagonistic effect. The mechanism of action of the bicyclic phosphates is possibly similar to that of picrotoxinin.

Inhibition and stimulation of rapid axonal transport in vitro by sulfhydryl blockers.

The effects of sulfhydryl blocking agents have been studied on the rapid axonal transport in vitro of [3H]leucine-labelled proteins in the frog sciatic nerve. The transport was inhibited in the presence of low concentrations of N-ethylmaleimide (NEM) (greater than or equal to 10(-5) M), p-chloromercuribenzene sulfonic acid (PCMBS) (greater than 10(-5) M) or ions of heavy metals, Cd2+ (greater than or equal to 5 X 10(-5) M), Hg2+ (greater than or equal to 5 X 10(-6) M) and Cu2+(greater than or equal to 10(-4) M). Both the amount and the rate of transported radioactivity were reduced. Transport inhibiting concentrations of these agents also inhibited the binding of colchicine in rat brain or frog nerve supernatants. The amount of transported proteins was increased at an unchanged transport rate by a very low concentration of NEM (10(-6) M), PCMBS (10(-6) M) and Cd2+ (10(-6)M), which did not affect the binding of colchicine. The present results suggest that stimulation of axonal transport can be achieved through an interaction with sulfhydryl groups.

Omeprazole provides protection against experimentally induced gastric mucosal lesions.

Omeprazole, given orally to rats, protects the gastric mucosa against various necrotizing agents, in doses (ED50 values 12-40 mumol/kg) which inhibit acid secretion. However, the protection is due to reduced acid secretion since omeprazole given intravenously in doses which completely inhibit acid secretion is not protective. The mechanism of the protective effect of omeprazole is unknown, but does not seem to be due to stimulation of the endogenous synthesis of prostaglandins since the effect was not blocked by indomethacin.

Effects of in vivo treatment with isoprenaline or prenalterol on beta-adrenoceptor mechanisms in the heart and soleus muscle of the cat.

The full agonist isoprenaline (5.3-6.6 nmol/kg . min) and the partial beta-adrenoceptor agonist prenalterol (10.6-13.3 nmol/kg . min) were administered to cats continuously via osmotic minipumps (i.p.). After seven days the functional and adenylate cyclase responsiveness to the agonists, as well as the beta-adrenoceptor-binding characteristics, were studied in cardiac and soleus muscle preparations in vitro. After isoprenaline pretreatment, the papillary muscles and soleus muscle strips wer 15-18 times less sensitive to isoprenaline compared with muscles from control cats. The stimulatory potency (pD2) of prenalterol in the papillary muscle was not changed significantly. The affinity of the agonists to the beta-adrenoceptors was unaffected in both tissues by the pretreatment, but the densities of beta-adrenoceptors were significantly reduced, by 36% (myocardium) and 47% (soleus) respectively. In the cat papillary muscle the intrinsic sympathomimetic activity (ISA) of prenalterol on contractile parameters was reduced from 84 (Tmax), 69 (dT/dtmax) and 71% (dT/ dtmin ) in control animals, to 33, 22 and 28%, respectively in the animals pretreated with isoprenaline. Prenalterol pretreatment did not induce any marked changes, either in the stimulatory potency or affinity of the agonists in the two tissues or in the maximal response (ISA) of prenalterol in the papillary muscle. The marked reduction in the stimulatory potency of isoprenaline and the reduced ISA of prenalterol in the myocardium after isoprenaline pretreatment can not be explained by the reduction in beta- adrenoceptor density alone. Since the affinity to the beta- adrenoceptors is unaffected, a reduced efficiency in the signal transmission must be the main cause.(ABSTRACT TRUNCATED AT 250 WORDS)

beta 1-and beta 2-adrenoceptor stimulatory effects of prenalterol.

Prenalterol, previously characterized as a functionally cardioselective partial beta-adrenoceptor agonist, was shown to relax K+ -elicited contractures in the uterine muscle from progesterone pretreated rats (pD2 7.7) and to increase beating rate in the rat right atrium (pD2 8.0) at about the same concentrations with maximal effects corresponding to 94 and 82% respectively of those of isoproterenol. Terbutaline, with equal maximal effects as isoproterenol, was 50 times more potent in the uterus (pD2 7.8) than in the right atrium (pD2 6.1). Both tissues displayed a high sensitivity to isoproterenol (pD2 9.1 in both tissues) indicating large receptor reserves for the full agonist. The maximal relaxing effect of prenalterol in the uterus was obtained at about a three-fold increase of the cyclic AMP content, which is similar to that obtained with isoproterenol at a corresponding relaxation. The effects in the uterine muscle of all three agonists were mediated through beta 2-adrenoceptors since beta 2-adrenoceptor blockers (ICI 118, 551 and IPS 339) antagonized the effects in concentrations which had only marginal effects on the atrial responses of the agonists. The beta 1-antagonists pafenolol and pamatolol in concentrations higher than those, which blocked the effects of the agonists on beating rate, were devoid of inhibitory effects in the uterus. These results indicate that prenalterol possesses the ability to elicit a functional response by stimulation of either beta 1-or beta 2-adrenoceptors provided that the tissue has a large spare receptor reserve for full agonists.

Changes in gastric mucosal permeability induced by haemorrhagic shock in the anaesthetized rat: modulation by acid.

Gastric mucosal damage induced by haemorrhagic shock in the anaesthetized rat has been evaluated by studying changes in capillary-to-lumen clearance of fluorescein isothiocyanate (FITC)-labelled dextran. Haemorrhagic shock (20 min ischaemia + 20 min reperfusion) induced a significant increase in blood-to-lumen permeability to FITC-dextran of different molecular weight (10,000, 40,000 and 70,000) without modifying the macroscopic integrity of the gastric mucosa. The increase in vascular permeability was dependent on the time of administration of the tracer and was correlated with an elevation of the protein content of the gastric lumen. Intravenous administration of the secretagogue pentagastrin (20 or 50 micrograms kg-1 h-1) did not significantly modify the vascular permeability to dextran in control animals or in animals subjected to haemorrhagic shock. When the intraluminal pH was reduced by intragastric administration of acidic saline solution, only pH 1, which itself induced the appearance of macroscopic mucosal lesions, significantly increased vascular permeability to dextran, both in control animals and in animals subjected to haemorrhagic shock. These findings suggest that stress induced by haemorrhagic shock increases vascular gastric permeability to dextran, by an acid-independent mechanism, without affecting the macroscopic integrity of the gastric mucosa.

Pharmacology and toxicology of omeprazole--with special reference to the effects on the gastric mucosa.

Omeprazole is a long acting inhibitor of gastric acid secretion in different species including rat and dog. Due to the long duration of action, steady state inhibition at repeated once daily administration is reaches within 4-5 days in dogs and in about 3 days in rats. Daily dosing at high dose levels results in virtually complete 24-hour inhibition of acid secretion in experimental animals. The elimination of the inhibitory feedback effect of acid on gastrin secretion leads to hypergastrinaemia. Because gastrin has a trophic effect on the oxyntic mucosa, the hypergastrinaemia results in a reversible hypertrophy of the oxyntic mucosa and an increased capacity to produce acid following maximal stimulation with exogenous secretagogues after discontinuing treatment. Despite the increased capacity to produce acid, basal acid secretion seems to be unchanged. The pronounced hypergastrinaemia which occurs during long-term treatment with high doses rapidly normalizes after discontinuing treatment. The hyperplasia of the oxyntic endocrine ECL cells, and the eventual development of gastric ECL cell carcinoids after lifelong treatment of rats with high doses, can also be attributed to the hypergastrinaemia developing after almost complete elimination of gastric acid secretion in these animals.

Inhibition of gastric acid secretion by omeprazole and ranitidine. Effects on plasma gastrin and gastric histamine, histidine decarboxylase activity and ECL cell density in normal and antrectomized rats.

Female rats were subjected to various treatments for 10 weeks to study effects on plasma gastrin levels. Intact rats were treated orally with omeprazole, 10 or 400 mumol/kg, ranitidine, 175 + 175 + 350 mumol/kg, or vehicle; antrectomized rats were treated with omeprazole, 400 mumol/kg, or vehicle. In addition to plasma gastrin levels, histidine decarboxylase (HDC) activity, histamine levels and ECL cell density in the oxyntic mucosa were determined. Gastrin levels were increased in unoperated rats treated with the high omeprazole dose and with ranitidine, whereas they were lowered in antrectomized controls. A small increase in plasma gastrin was seen in the low-dose omeprazole group. In antrectomized rats treated with omeprazole, the plasma gastrin level was the same as in intact control rats. The ECL cell density, the activity of HDC and the concentration of histamine in the oxyntic mucosa were found to reflect the plasma gastrin concentration. The results suggest that the changes in ECL cell density are secondary to the changes in plasma gastrin, induced by inhibition of acid secretion or antrectomy. It is concluded that neither omeprazole nor ranitidine per se is likely to induce proliferation of ECL cells.

Partial symptom-response to proton pump inhibitors in patients with non-erosive reflux disease or reflux oesophagitis - a post hoc analysis of 5796 patients.

BACKGROUND: Although most patients with gastro-oesophageal reflux disease (GERD) benefit from proton pump inhibitor (PPI) therapy, some experience only partial symptom relief. AIM: To determine the prevalence of partial heartburn response to PPIs and its impact on health-related quality of life. METHODS: Four randomised, double-blind studies in adults with reflux disease compared esomeprazole 40 mg/day or 20 mg/day with omeprazole 20 mg/day, or esomeprazole 40 mg/day with pantoprazole 40 mg/day. Patients with heartburn on ≥4 days during the 1-week recall period at baseline were included. Partial response was defined as heartburn on ≥3 days during the last treatment week and reduced heartburn frequency after 4 weeks of treatment compared with baseline. RESULTS: The analysis included 2645 patients with non-erosive reflux disease (mean age: 48.8 years; 54.4% women) and 3151 patients with reflux oesophagitis (mean age: 50.6 years; 37.1% women). At baseline, most patients reported heartburn on 5-7 days (non-erosive reflux disease: 82.2%; reflux oesophagitis: 86.8%). Partial heartburn response occurred in 19.9% of patients with non-erosive reflux disease and 14.0% with reflux oesophagitis. Defining partial response as heartburn on ≥2 days increased these rates to 26.2% and 19.3%, respectively; defining partial response as heartburn of moderate or severe intensity on ≥3 days decreased these rates to 6.4% and 5.3%, respectively. Nonresponse to PPIs was rare (non-erosive reflux disease: 2.4%; reflux oesophagitis: 1.4%). CONCLUSION: Using our conservative definition, partial heartburn response to proton pump inhibitor therapy occurred in 14-20% of gastro-oesophageal reflux disease patients, more commonly in non-erosive reflux disease than in reflux oesophagitis.