Pure red cell aplasia and protein-losing enteropathy in a patient with systemic lupus erythematosus.
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Adult↗
Biomedical subjects
B I Hirschowitz
Publications and source records attributed to B I Hirschowitz.
An update on histamine receptors and the gastrointestinal tract.
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Animals↗
Bombesin and G-17 dose responses in duodenal ulcer and controls.
Gastric acid and pepsin secretion and serum gastrin concentrations were measured in nine patients with uncomplicated duodenal ulcer (DU) and 10 normal controls in the fasting state and in response to graded doses of bombesin, a tetradecapeptide gastrin releaser, and, for reference, synthetic gastrin G-17. Serum gastrin with bombesin stimulation was significantly greater in duodenal ulcer (maximum 467 pg/ml) than in controls (153 pg/ml), while in seven of the DU group tested gastrin levels after a meal were not different from that seen in five of the normal controls. Gastric acid concentrations and outputs were greater in duodenal ulcer with both stimuli. Secretory responses were then related to serum gastrin levels; despite increasing gastrin levels with bombesin stimulation, peak outputs achieved with bombesin were only 50% of G-17 maximum in normals and up to 90% of maximum in duodenal ulcer. Up to the point of peak response to bombesin, acid and pepsin outputs were the same with exogenous and endogenous gastrin, ie, bombesin acted only via G-17. Furthermore, in direct comparison of duodenal ulcer and normals with G-17 infusion, acid and pepsin outputs related to serum gastrin were congruent up to 75% of duodenal ulcer maximum, at which point normals reached their maximum level. These data have shown that duodenal ulcer patients are not more sensitive to either exogenous or endogenous gastrin; we have also shown regulatory defects in duodenal ulcer patients not previously described: an exaggerated release of gastrin with bombesin stimulation, and a defective inhibition of acid and pepsin secretion with higher doses of bombesin.
Adult↗
Mediation of muscarinic stimulation of pepsinogen secretion in the frog.
The in vitro release of pepsinogen secretion by the isolated esophagus of the American bullfrog was studied with an improved model system. The tissue was mounted in a double chamber that preserves mucosal polarity and provides both control and test segments, each 1 cm2 from the same tissue. Pepsinogen secretion was severalfold higher than previously found with mucosal strips and could be sustained for several hours. Bethanechol (BCh) caused concentration-dependent (0.1-50 microM) pepsinogen secretion with a Vmax of 74 +/- 12 micrograms X mg prot-1 X h-1 or 50-60% of total pepsinogen; Km was 3 microM and 500 microM BCh stimulated at less than the Vmax value. Atropine specifically blocked BCh and pA2 = 9.3. In the presence of 100 microM isobutylmethyxanthine, BCh produced a dose-dependent increase in tissue cAMP but not cGMP. BCh remained effective in Ca2+-free medium. In calcium-free medium EGTA concentration dependently (0.2-5 mM) suppressed the pepsinogen response to BCh. The evidence thus far suggests that cholinergic stimulation of pepsinogen secretion in the tissue acts via both cAMP and Ca2+. More specific studies would be required for absolute confirmation of either or both apparent mechanisms and to resolve how they interact.
1-Methyl-3-isobutylxanthine↗
Interaction between stimuli and their antagonists on frog esophageal peptic glands.
The peptic glands, which are located in the mucosa of the distal esophagus in the frog, respond to multiple stimuli. In vitro studies were performed, using mucosal sheets of the esophagus of Rana catesbeiana, during the summer months when the glands are fully responsive to determine whether the receptors for the stimuli [cholinergic, beta-adrenergic, and peptidergic (bombesin but not cholecystokinin)] are specific to the stimuli. Through the use of three classes of antagonist, we found that 1) atropine defined the muscarinic nature of the bethanechol stimulation, 2) propranolol defined the beta-adrenergic nature of stimulation by isoproterenol, and 3) the substance P analogue [D-Arg1,D-Pro2,D-Trp7,9,Leu11]substance P was specific for the peptide bombesin. No cross-inhibition was seen, and dibutyryl cGMP did not inhibit any of the three stimuli. Moreover, any two of the three stimuli in combination stimulated more pepsinogen than either alone but the same as the sum of the two individual responses. Both lines of evidence indicate that there are at least three independent receptor pathways for stimulation of pepsinogen secretion in these glands.
Animals↗
Histamine and the gut.
The role of histamine in the gut is reviewed in relation to gastric secretion of acid, pepsin and intrinsic factors. Species-dependence of some of these actions are also discussed. Interactions with other agonists and antagonists in intact and isolated systems provide the basis for models of the role of histamine in control of gastric secretion. This review deals further with histamine H1 and H2 effects on gastrointestinal circulation and musculature including sphincters. The most dramatic application of the development of histamine H2 antagonists has been in the treatment of duodenal ulcer. The use of H2 antagonists in the treatment of duodenal and gastric ulcer, gastrinoma, gastritis, and esophagitis is critically evaluated.
Animals↗
Autonomous cholesterol biosynthesis in murine hepatoma. A receptor defect with normal coated pits.
These studies indicate that autonomous cholesterol biosynthesis by hepatocellular carcinoma may result from absent or defective receptors for chylomicron remnants on the surface of the malignant hepatocytes. In vivo, DAB2 hepatoma or liver were perfused with chylomicron remnants labeled with tritiated palmitic acid. Normal liver had chylomicron remnant uptake/gm tissue that was ten times that of hepatoma. In vitro studies using isolated hepatocytes and cultured DAB2 hepatoma cells showed similar results. Uptake of chylomicron remnants labeled with 3H-palmitic acid by normal hepatocytes during a 4-hour period was ten times that of hepatoma cells. Both in vivo and in vitro differences were statistically highly significant (P less than 0.005). Since many surface receptors are related to the coated pits, the cellular membranes of both neoplastic and normal liver cells were examined by electron microscopy. Coated pits were present in both the hepatoma and normal liver cells and occupied 2.61% and 2.65% of the cell surface, respectively. The defective uptake of chylomicron remnants by DAB2 hepatoma appears to be related to the chylomicron remnant receptor and not to the coated pit-internalization mechanism.
Animals↗
Towards a rational treatment of duodenal ulcer.
This review concerns itself with the current understanding of the control of gastric secretion and the application of this knowledge to the design of treatment for duodenal ulcer through the reduction of acid and pepsin load on the duodenal bulb. The control of gastric secretion is described under the headings: (i) neurohormonal; (ii) endocrine; (iii) paracrine; (iv) luminal; and (v) cellular. This discussion is followed by a description of the pathophysiology of gastric secretion in duodenal ulceration. The strategies of treatment are discussed under four headings: (i) postsecretory treatments; (ii) destruction of the gastric mucosa; (iii) alteration of neurohormonal controls; and (iv) modification or inhibition of the cellular mechanisms of acid and pepsin secretion. Several currently useful and potentially important new lines of treatment are described.
Benzimidazoles↗
Effects of very low doses of atropine on basal acid and pepsin secretion, gastrin, and heart rate in normals and DU.
Muscarinic mechanisms in basal acid and pepsin secretion in man were quantitated by graded intravenous doses of atropine (1-16 micrograms/kg). Secretion was dose-responsively inhibited in six healthy controls. For the mean dose response, maximum inhibition (Imax) was 100%, and D50 (dose inhibiting 50%) was 0.31 +/- 0.06 and 0.93 +/- 0.13 micrograms/kg, respectively, for acid and pepsin. In 24 patients with duodenal ulcer (DU), calculated Imax was also 100%, and D50S were 1.2 +/- 0.27 and 1.7 +/- 0.3 micrograms/kg, respectively. The low D50 values and the 100% calculated maximum inhibition indicated that in both groups basal secretion was largely or completely cholinergic dependent. We also found that atropine raised heart rate in controls by 44 +/- 1 beats per min (bpm) (D50 = 6 +/- 1.1 micrograms/kg), while the mean maximum increase in DU was only 23 +/- 2 bpm (P less than 0.01) with (D50 = 5.3 +/- 1.0 micrograms/kg (NS)). In DU atropine increased fasting serum gastrin from 62 to 82 pg/ml (P less than 0.05); the increase in normals from 32 to 38 pg/ml was not significant. Thus, while both normals and DU exhibited the same qualitative responses to muscarinic receptor antagonism by atropine with respect to gastric secretion, gastrin levels, and heart rate, there were quantitative differences in all three parameters.
Acetylcholine↗
Apparent and intrinsic sensitivity to pentagastrin of acid and pepsin secretion in peptic ulcer.
The sensitivity to stimuli of gastric acid and pepsin secretion in duodenal and gastric ulcer was studied using a pentagastrin dose response that was analyzed by an exponential model. By this model, maximum secretory rate (Vmax), the dose of administered pentagastrin giving 50% of Vmax (D50), and the threshold equivalent dose responsible for basal secretory rate are calculated. Using only individual tests in which the data adequately fitted the model, we report on 171 subjects, 120 with duodenal ulcer, 22 with gastric ulcer, and 29 controls. Among the possible influences on secretion, sex and weight were significant, whereas age and activity or duration of ulcer disease were not. Men secreted more acid per kilogram body weight than women in each group, and men with duodenal ulcer secreted more acid and pepsin than normal men or those with gastric ulcer. Because basal secretion in men with duodenal ulcer was a higher proportion of maximum, D50 (the measure of apparent sensitivity) was 25% lower (p less than 0.01) in patients with duodenal ulcer than in controls; when examined by sex, men with duodenal ulcer had a lower D50 than women with duodenal ulcer, men with gastric ulcer, and male controls. D50 in all patients was very much lower for pepsin than for acid. Km, the dose that would be required to stimulate secretion to 50% of maximum if basal = 0 (intrinsic sensitivity), was not different between groups or sexes. Thus the difference in sensitivity between duodenal ulcer patients and controls was seen only in the apparent, and not in the intrinsic sensitivity indices; this was largely a phenomenon of males and could be explained by a higher ratio of basal to maximal secretion. Neither the observed increase of basal nor the maximal rates of acid and pepsin secretion in duodenal ulcer patients could be explained by an increased sensitivity to gastrin.
Adult↗
Histamine H1 and H2 effects on gastric acid and pepsin, heart rate and blood pressure in humans.
Gastric acid and pepsin secretion, heart rate and blood pressure were studied simultaneously during an infusion of histamine in eight patients with peptic ulcer or esophagitis. We found that histamine equally stimulated both acid and pepsin via H2 receptors. No evidence for any gastric H1 effect was found. Heart rate was increased modestly (12 beats/min) and this effect was reversed by diphenhydramine, an H1 antagonist, which did not by itself or in combination with the H2 antagonist cimetidine modify the hypotensive effect of histamine. The histamine effects in humans contrasts with those in the conscious dog where histamine inhibits pepsin secretion and strongly stimulates heart rate. The results emphasize major species and organ differences in both gastric and cardiac histamine effects.
Adult↗
Gastrin release in fistula dogs with solid compared to nutrient and nonnutrient liquid meals.
Using conscious gastric fistula dogs, gastrin release stimulated by a 360-g meat-based solid meal was compared to that stimulated by two isocaloric (1 kcal/g), hypertonic (approximately 700 mosm/kg) nutrient liquids (Sustacal and Vivonex) and by two nonnutrient, hypotonic (60 mosm/kg) liquids (mannitol and coffee). Serum gastrin levels were measured at 15- to 30-min intervals over 120 min. Without a meal, serum gastrin levels remained stable. Effectiveness in stimulating gastrin release was coffee = mannitol less than Sustacal = Vivonex less than solid food; 2-hr integrated gastrin responses were 1.2, 2.6, 4.3, 5.6, and 12.2 ng/ml/min, respectively. The greater gastrin responses produced by nutrient liquids and meat meals could be explained by slower emptying and delayed acidification of gastric contents. We conclude that solid meals are preferable to liquid meals in studies of antral gastrin release.
Animals↗
Lessons from the U.S. multicenter trial of ranitidine treatment for duodenal ulcer.
In duodenal ulcer, acid and pepsin in greater amounts and at higher concentration enter the duodenum and specific treatment should be directed towards correcting this abnormality. Such treatment is provided by the histamine H2-receptor antagonists. We discuss the first U.S. multicenter trial of the new nitrofuran-based antagonist, ranitidine, in which 382 patients were treated for 4 weeks with either ranitidine 150mg b.i.d. (195 pts.) or placebo (187); both groups were allowed to use antacid for pain. Those treated with ranitidine had significantly less pain and used less antacids than the placebo-treated patients; after 2 weeks, 37% vs 19% were healed, and after 4 weeks, 73% vs 45% were healed (p less than 0.01). After 4 weeks, 124 unhealed patients were randomized to ranitidine vs placebo for another 4 weeks. Ranitidine treatment again produced a greater healing rate (p less than 0.01), regardless of prior treatment. The 3 subsets of the data which contained more than 34 patients were analyzed separately. Each showed 1 or more significant deviations (type I and type II errors) from the overall study, which was in all respects similar to the aggregate results of all similar studies overseas. We emphasize the need for studies of adequate size.
Antacids↗
Effect of cimetidine on histamine-stimulated gastric acid and electrolytes in dogs.
Intravenous administration of cimetidine (0.25-2.0 mg X kg-1 X h-1) inhibited histamine-stimulated gastric acid secretion in both intact (Ki = 1.0 mg X kg-1 X h-1) and vagotomized (Ki = 1.75 mg X kg-1 X h-1) dogs. During histamine infusion, all doses of cimetidine reduced gastric volume output; high doses increased gastric juice pepsin and [Na+] and reduced [H+] and [Cl-]. Gastric juice [K+] was not affected during cimetidine infusion. The cimetidine-induced changes in electrolyte concentrations were qualitatively comparable with those observed on withdrawal of histamine stimulation. On termination of cimetidine infusion with continued histamine administration, gastric [K+] and volume output increased immediately, followed 30 min later by an increase in [H+] and a reciprocal decrease in [Na+]; [Cl-] did not recover. The changes in gastric juice electrolytes after termination of cimetidine, with the exception of [Cl-], mimicked the changes observed on initiation of histamine stimulation. These data indicate that the effects of cimetidine may be totally explained by its antagonism of histamine binding to the parietal cell H2-receptor, that vagotomy reduces cimetidine binding to the H2-receptor, and that cimetidine antagonism of histamine is rapidly reversed on removal of the antagonist.
Animals↗
Relation of gastric acid and pepsin secretion to serum gastrin levels in dogs given bombesin and gastrin-17.
To quantitate bombesin stimulation of gastric acid and pepsin via release of gastrin, five gastric fistula dogs were given graded doses (60-1,250 pmol X kg-1 X h-1) of bombesin tetradecapeptide and 40-2,000 pmol X kg-1 X h-1 of synthetic gastrin-17 (G-17). Acid and pepsin output and serum gastrin were proportional to the dose of stimulant. The half-maximal dose of bombesin for gastrin release was 200 pmol X kg-1 X h-1. Bombesin-stimulated acid secretion related to serum gastrin concentrations was congruent with the G-17 curve, but with a maximum of only 62% of the G-17 maximum before declining by 27% despite higher serum gastrin levels. This suggested that bombesin stimulates acid secretion only via gastrin release and inhibits at higher doses by releasing another inhibitory peptide, most likely somatostatin, which is also released by bombesin. The same mechanism could apply to supramaximal inhibition of acid and pepsin seen with high doses of G-17. Because the pepsin curve related to serum gastrin was to the left of the G-17 curve, we concluded that another secretagogue released by bombesin acts synergistically with gastrin on pepsin secretion. Therefore, bombesin stimulates gastric secretion through gastrin release, but its effects are modified by peptides coreleased to a) increase pepsin output at low doses and b) limit the output of acid and pepsin to 50-60% of the G-17 maximum.
Animals↗
Effects of KCl and insulin on benzimidazole-inhibited canine gastric secretion.
The final step in acid secretion is believed to result from the H+-K+-ATPase-mediated exchange of H+ in the parietal cell, with K+ in the lumen. To study the K+ secretion we used Picoprazole and insulin separately and together to inhibit gastric secretion stimulated in gastric fistula dogs with histamine (100 micrograms X kg-1 X h-1). Picoprazole, a substituted benzimidazole (750 mg/kg), reduced gastric H+ concentration and volume with a rise in K+ concentration [( K+]) to 20-25 meq/l. Insulin alone inhibited acid output to the same extent as Picoprazole but with a marked fall in [K+]. Insulin (0.6 U/kg) given with Picoprazole did not alter inhibition of H+ but prevented the large decrease in gastric juice [K+]. An injection of KCl (1 meq/kg) 1 h after Picoprazole did not alter the effects of the inhibitor. Pepsin secretion after insulin was delayed by Picoprazole, whereas during bethanechol chloride infusion (80 micrograms X kg-1 X h-1) pepsin output was reduced for a shorter period and to a lesser extent than acid. We concluded that insulin affects gastric H+ and K+ secretion by a mechanism not related to H+-K+-ATPase and that Picoprazole affects pepsin secretion probably indirectly via its effect on the parietal cell, where its action is quite consistent with an effect limited to inhibition of the H+-K+-ATPase of the parietal cell.
Animals↗
Effects of four H2 histamine antagonists on bethanechol-stimulated acid and pepsin secretion in the dog.
In five gastric fistula dogs, each of four H2-receptor antagonists was given (at doses roughly equal to the dose inhibiting histamine stimulation at 50%) as background infusion to graded doses of i.v. bethanechol. We measured acid and pepsin secretion and gastrin release. All four compounds noncompetitively inhibited acid secretion, reducing maximum acid outputs by 50 to 70%. Two compounds, tiotidine and cimetidine, shifted the bethanechol dose-response for pepsin secretion about 30% to the right at midpoint without reducing maximum output significantly, whereas the other two, ranitidine and metiamide, did not alter the dose-response. Dose-dependent gastrin release was unaffected by cimetidine, an imidazole compound, and augmented by tiotidine and ranitidine, the two nonimidazole compounds. Actions on pepsin and gastrin are thus not related to H2-receptor effects. The uniform effect of the four antagonists on acid secretion indicates an essential interaction between cholinergic and histamine effects on the parietal cell, although we could not distinguish between prereceptor, receptor and postreceptor sites for such interaction.
Animals↗