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Biomedical subjects

B I Hirschowitz

Publications and source records attributed to B I Hirschowitz.

At least 73 records · Page 4Linked to original sources
PubMed1988

Partial agonist activity of the bombesin-receptor antagonist [Leu14-psi-CH2-NH-Leu13]-bombesin in frog peptic cells.

The pseudopeptide [Leu14-psi-CH2NH-Leu13]-bombesin inhibited 125I-GRP binding to membrane preparations of frog cerebrum and peptic cells, rat cerebral cortex and pancreas with IC50's of 44-250 nM (using 180 pM 125I-GRP). It was unable to stimulate amylase release from rat pancreatic acini, but antagonized competitively BB stimulated amylase release with an IC50 of 130 nM. By contrast the pseudopeptide stimulated pepsinogen secretion from frog esophageal peptic cells with an efficacy relative to bombesin of 36%, and with an EC50 of 30 nM. By virtue of its partial agonist activity it inhibited submaximal BB stimulated responses to a level equal to the pseudopeptide alone. Thus [Leu14-psi-CH2NH-Leu13]-BB differentiates certain BB receptors by exhibiting selective intrinsic efficacy.

Amylases↗
PubMed1988

Basophilic leukemia and the hypersecretion of gastric acid and pepsin.

A 48-yr-old man with chronic myelogenous leukemia and basophilia developed a duodenal ulcer and hemorrhage. Gastric analysis revealed basal hyper-secretion of acid (33.1 mEq/h) and pepsin (44.5 x 10(-4) peptic units/h). Blood, serum, and urine histamine was elevated and serum gastrin was normal. Although acid output was markedly suppressed with ranitidine (50 mg i.v.), pepsin secretion was only inhibited 63% and had returned to basal levels by the sixth hour. Maximal acid output does not suggest a trophic effect of histamine in this patient. The previously reported cases of basophilic leukemia and gastric hypersecretion or duodenal ulcer disease are reviewed.

Basophils↗
PubMed1988

Pepsinogen secretion from perifused frog peptic glands: rapid transients detected with a modified pepsin assay.

In order to define the early transient responses of peptic cells to stimulation, we have modified the acidified hemoglobin substrate digestion method for pepsin to provide a very sensitive, linear (10-250 ng/ml), reproducible, inexpensive (less than 3 cents/sample) and simple semi-automated assay. Using a specially designed perifusion chamber, this method was used to accurately measure secretion at 1 min intervals from approximately 3 mg of isolated peptic glands from the esophageal peptic organ of R. catesbeiana, containing approximately 150 micrograms pepsinogen. Responses to carbachol applied for 1, 2 and 4 min could be described in discrete 1 min intervals. Secretion stimulated by carbachol (1-2 min) peaked at 200-300% of basal and upon withdrawal decayed with t1/2 approximately 3 min. Atropine added to continuous carbachol stimulation inhibited secretion with t1/2 approximately 4 min, indicating rapid metabolism of activated messengers.

Animals↗
PubMed1988

Antacids reduce Campylobacter pylori colonization without healing the gastritis in patients with nonulcer dyspepsia and erosive prepyloric changes.

Antral biopsy specimens from 89 consecutive patients with nonulcer dyspepsia and erosive prepyloric changes included in a prospective, randomized, double-blind 4-wk study of the effect of an aluminum-magnesium antacid (120 mmol/day) or pirenzepine (50 mg b.i.d.) vs. placebo were examined histologically. Campylobacter pylori (CP) was found by light microscopy of silver-stained sections in 25 patients (28%). Campylobacter pylori-positive patients were on average older than CP-negative patients (p = 0.02). There was a strong association between CP colonization and acute inflammation (p less than 0.001), both being rare in the absence of chronic inflammation. During treatment with antacids, the density of CP decreased (p less than 0.001) without any improvement of the inflammatory reaction. On the contrary, the number of patients with gastritis tended to increase after antacids as compared with placebo (p less than 0.10). A separate analysis showed no symptomatic effect of the drugs. Thus, neither nonulcer dyspepsia nor erosive prepyloric changes are strongly associated with antral CP colonization or acute inflammation. Aluminum-magnesium antacids may suppress antral CP infection without healing the gastritis or relieving symptoms.

Adult↗
PubMed1988

Effect of tranexamic acid on gastric bleeding in rats.

Bleeding from an induced gastric mucosal wound was monitored for 2 h in a rat model, in which normal hemostasis was disturbed mechanically by perfusing the lesion with saline. The hemorrhage was characterized by continuous bleeding and/or episodes of spontaneous rebleeding, as often seen in patients with gastric hemorrhage. The antifibrinolytic agent, tranexamic acid, significantly reduced total bleeding volume and number of rebleeding episodes, suggesting that plasmin-induced fibrinolysis might aggravate gastric mucosal hemorrhage.

Animals↗
PubMed1988

Effect of platelet-activating factor and its receptor antagonist, SRI 63-675, on gastric bleeding in rats.

Gastric bleeding from an induced mucosal wound was monitored for 2 h in a rat model in which the normal haemostasis was disturbed mechanically by perfusing the lesion with saline. The bleeding pattern was characterized by continuous and/or rebleeding episodes. Intravenous infusion of platelet-activating factor (PAF) in a dose of 25 ng/kg/min reduced the blood loss by 92% without affecting the bleeding pattern or the macroscopic appearance of the mucosa significantly. Concomitant administration of the PAF receptor antagonist SRI 63-675 in a dose of 50 micrograms/kg/min completely reversed the effects of PAF. The bleeding was unchanged after PAF receptor antagonist alone, suggesting that endogenous PAF might not participate in the in vivo haemostasis after an acute gastric mucosal lesion.

Animals↗
PubMed1988

Muscarinic cholinergic receptor subtype on frog esophageal peptic cells: binding and secretion studies.

The muscarinic receptors coupled to pepsinogen secretion on isolated frog esophageal peptic cells have been characterized using functional and radioligand binding techniques. N-[3H]methylscopolamine [( 3H]NMS) binding to intact cells was complex and indicative of a high affinity, low capacity site and a high capacity uptake site. Binding to the high capacity site was inhibited by atropine with high affinity (IC50, 3 nM) and by imipramine and propranolol with IC50 values of 70 and 270 nM, respectively. After inhibition of uptake by 30 microM propranolol, [3H]NMS bound to a single population of high affinity sites (KD, 125 +/- 16 pM), which exhibited binding site maximum of 2.1 fmol/10(6) cells, equivalent to 1260 sites/cell. Binding to these sites was reversible, stereoselective and inhibited by muscarinic receptor agonists with an order of potency: oxotremorine greater than acetylcholine greater than carbachol greater than bethanechol and by antagonists with an order of potency:atropine greater than 4-diphenylacetoxy-N-methylpiperidine methobromide greater than pirenzepine greater than AF-DX 116 (11-2[2-[[diethylamino) methyl]-1-piperidinyl]acetyl]-5, 11-dihydro-6H-pyrido[2,3-b][1,4]-benzodiazepine-6-one). Pepsinogen secretion was stimulated by the agonists with an order of potency: acetylcholine greater than or equal to carbachol greater than oxotremorine greater than bethanechol. Atropine, pirenzepine and AF-DX 116 competitively inhibited carbachol-stimulated pepsinogen secretion with pA2 values of 9.58, 7.37 and 6.68, respectively, which correlated with their log (inhibition constants) for receptor binding. By contrast, agonists with significant efficacy exhibited EC50 values which were 20 to 90 times lower than their inhibition constants for binding which suggests the possibility of "spare" muscarinic receptors. Our findings indicate that functional muscarinic receptors on peptic cells exhibit similar characteristics to the high affinity sites labeled by [3H]NMS.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1987

Divergent effects of bombesin and bethanechol on stimulated gastric secretion in duodenal ulcer and in normal men.

To further investigate differences in the responses of normals and patients with duodenal ulcer with respect to gastrin release and acid and pepsin secretion, we infused bombesin (1 microgram/kg X h) or bethanechol (40 micrograms/kg X h) during the middle hour of a 3-h infusion of pentagastrin and compared the results with a pentagastrin infusion without added drug. Pentagastrin dosage (0.1 microgram/kg X h) was set to give about half-maximal response, to detect either inhibition or further stimulation of gastric secretion, whereas the dose of bombesin was chosen to give maximal gastrin but less than maximal acid secretion. Serum gastrin and somatostatin were also measured. In all subjects tested, bethanechol produced no effects on acid, gastrin, or somatostatin release but increased pepsin output. By contrast, bombesin inhibited pentagastrin-stimulated acid output in all 6 normal men by an average of 55%, whereas it inhibited acid output in only 2 of the 9 men with duodenal ulcer. Serum gastrin increases after bombesin in duodenal ulcer were three to four times greater than in normals. Although bombesin stimulates acid only by releasing gastrin, we postulate that bombesin may also simultaneously limit acid and pepsin secretion and speculate that this effect could be mediated by bombesin-induced somatostatin release. The cause for differences between duodenal ulcer and normal remain speculative.

Adult↗
PubMed1987

Synergism between cellular messengers and agonist combinations in pepsinogen secretion.

The esophagus of Rana catesbeiana yielded 20-40 X 10(6) peptic cells that were greater than 80% pure by immunostaining, greater than 90% viable, and had low basal pepsinogen and lactic dehydrogenase (LDH) release. Cellular responses to agents that bypass receptors and act directly on cell messenger systems have been compared with receptor-mediated activation. Pepsinogen secretion was stimulated dose dependently by A23187, the phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA), and forskolin. The combination of any two or all three agents at optimum effective concentrations stimulated secretion to more than double the output of the sum of the individual responses. Incubation in Ca2+-free media reduced responses to A23187 and TPA but not forskolin. Ca2+ deprivation eliminated the synergism of messenger combinations. Secretory responses to combinations of the agonists bethanechol or bombesin with either A23187 or TPA were additive and were synergistic with forskolin. Isoproterenol plus bethanechol or bombesin produced synergistic responses that were significantly smaller than combinations of their putative messengers. The synergistic response to isoproterenol and bethanechol was dependent on extracellular Ca2+. These data suggest that although Ca2+ may function in peptic cells to stimulate secretion directly, it may also act as a gain control for synergistic interaction between other messenger pathways (protein kinase a and c).

1-Methyl-3-isobutylxanthine↗
PubMed1987

Somatostatin effects on gastric electrolytes and pepsin in dogs with various secretory stimuli.

To determine possible sites and mechanisms of action of somatostatin (SS) in gastric secretory mucosa, secretion of pepsin, H+, Cl-, Na+ and K+ was stimulated in conscious fistula dogs by i.v. infusion of bethanechol, pentagastrin and histamine in the absence and presence of SS-14. At low dose (0.5 micrograms or 300 pmol/kg/h), SS-14 potently inhibited H+ and pepsin stimulated by bethanechol (80 micrograms/kg/h) to less than 5% of control; it required 2 micrograms or 1200 pmol/kg/h of SS-14 to achieve similar inhibition of pentagastrin (1.5 micrograms/kg/h)-stimulated secretion. In both cases, gastric [K+] was depressed by SS-14 infusion and recovered before H+ and pepsin. Similar sensitivity to SS suggests a Ca++-dependent mechanism or pathway of stimulation by gastrin similar to that by cholinergic agonists. By contrast, histamine, which acts via cyclic AMP pathways, was not inhibited by a large dose of SS-14 (20 micrograms/kg/h). SS inhibition is thus agonist (or pathway)- rather than organ- or cell-specific.

Adenylyl Cyclase Inhibitors↗
PubMed1986

Bone metastases in malignant gastrinoma.

Six patients (4 women, 2 men) with malignant gastrinoma developed multiple bone metastases; osteolytic as well as osteoblastic lesions occurred. All lesions involved the central skeleton, most caused symptoms, and, in 2 cases, there was associated hypercalcemia with normal serum parathormone levels. Poor responses were observed after treatment with cytotoxic drugs, but good symptomatic responses occurred after radiotherapy in 2 of the 4 patients in whom it was used. The peptic ulcer component of the disease was well controlled in all patients by cimetidine with or without anticholinergic supplements or by ranitidine alone in doses of 300-600 mg daily. Five of the 6 patients died with a mean survival after diagnosis of Zollinger-Ellison syndrome of 3.3 yr (range 1.0-7.0 yr), suggesting that bone metastases are associated with a poor prognosis in metastatic gastrinoma.

Adult↗
PubMed1986

A multicenter study of ranitidine treatment of duodenal ulcers in the United States.

Treatment of duodenal ulcer with the histamine H2-receptor antagonist, ranitidine, was assessed in a double-blind, randomized, multicenter trial in which patients were treated for two consecutive 4-week periods with ranitidine 150 mg b.i.d. or a placebo. All patients were allowed to take antacids as necessary for symptoms. Three hundred eighty-two patients were entered and 355 completed the first 4-week trial period. Ranitidine significantly improved healing at 2 weeks (37 versus 19%, p less than 0.01) and at 4 weeks (73 versus 45%, p less than 0.01), with better relief of pain and lower use of antacids. In the second 4-week trial period, 124 unhealed patients from the first 4 weeks were re-randomized. Ranitidine treatment resulted in a greater healing rate regardless of previous treatment (p less than 0.05). In this trial, side effects were uncommon and not different between placebo and the tested drug. One case of hepatitis in the ranitidine treated group was presumed on the evidence to be non-A non-B. Ranitidine is effective and appears to be safe in the treatment of duodenal ulcer and its symptoms.

Adult↗
PubMed1986

Treatment of benign chronic gastric ulcer with ranitidine. A randomized, double-blind, and placebo-controlled six week trial.

A randomized, multicenter, double-blind, placebo-controlled study was conducted to determine whether ranitidine 150 mg b.i.d. for 6 weeks would expedite endoscopic healing or relief of symptoms in patients with benign gastric ulcer. Of 203 patients enrolled, 101 received ranitidine and 102 received placebo. Endoscopic evaluations were conducted at baseline and at 2 and 6 weeks. At 6 weeks 68% of the patients treated with ranitidine had healed compared with 53% in the placebo group (p = 0.02). In those patients who had not healed by 6 weeks, ranitidine provided greater relief from pain than placebo. More patients in the placebo group dropped out of the study because of worsening symptoms (13 versus 4, p = 0.04). No differences in laboratory abnormalities or incidence of adverse events were detected between the two study groups. These results indicate that ranitidine 150 mg b.i.d. is superior to placebo in the treatment of benign gastric ulcer.

Adult↗
PubMed1986

Cellular messengers of stimulants of pepsinogen secretion from isolated frog esophageal mucosa.

The messenger roles of Ca2+ and cyclic nucleotides in the stimulation of pepsinogen secretion by three classes of stimuli [muscarinic (bethanechol), peptidergic (bombesin), and adrenergic (isoproterenol)] were studied in vitro using the peptic gland-bearing esophageal mucosa from the American bullfrog, Rana catesbeiana. Pepsinogen secretion was stimulated in a dose-dependent manner by the calcium ionophore A23187, by dibutyryl cAMP (DBcAMP), and by isobutylmethylxanthine (IBMX), a phosphodiesterase inhibitor. Isoproterenol and bethanechol increased the tissue cAMP content in the presence of IBMX. IBMX, which by itself stimulated secretion, was potentiating in combination with bombesin, additive with bethanechol, and less than additive with isoproterenol. Omission of Ca2+ from the bathing medium did not alter basal pepsinogen secretion nor the response to maximally effective doses of isoproterenol but partly inhibited the secretory responses to bethanechol and bombesin. Ca2+-free medium with 1 mM EGTA reduced pepsinogen secretion under all basal and stimulated (including A23187- but not DBcAMP-stimulated) conditions, indicating a critical role for Ca2+ in the secretion of pepsinogen secretion. A23187 by itself produced only an initial (15-20 min) release of pepsinogen, whereas IBMX and DBcAMP produced a delayed sustained secretion. The combination of A23187 with either IBMX or DBcAMP mimicked the responses to bethanechol or bombesin. These results indicate that both calcium and cAMP may be obligatory and interacting intermediates in the full stimulation of pepsinogen secretion by frog esophageal peptic glands with at least cholinergic and peptidergic stimuli.

1-Methyl-3-isobutylxanthine↗
PubMed1986

Seasonal fluctuations in pepsinogen secretion from frog esophageal peptic glands.

The seasonal activity of pepsinogen secretion in the Rana catesbeiana was studied by use of peptic gland bearing esophageal mucosa mounted in a perfused double chamber. The amount of the basal pepsinogen secretion during hibernation (winter) and breeding (spring) periods was approximately 25 and 55% of basal secretion during the active (summer) period. The circumannual variation of basal secretion was highly correlated (r = 0.88, n = 37) with the pepsinogen content of the mucosa. The fractional rate of basal secretion (approximately 2% of content per hour) remained essentially constant, and pepsinogen as a fraction of total protein remained at between 20 and 25%. The results indicate that the decrease in absolute basal secretion from frog peptic glands during winter is a consequence of decreased content and hence synthesis of protein, including pepsinogen, by the mucosa. In addition, stimulated secretory responses to both bethanechol and bombesin, as a multiple of basal rate, were reduced during both hibernation and breeding periods, whereas the response to isoproterenol was entirely abolished during the hibernation period. By contrast, the secretory response to isobutylmethylxanthine remained constant (approximately 200% of basal) through all seasons, suggesting that mechanisms responsible for enzyme translocation and secretion remained intact. Reduced basal and secretagogue-stimulated secretion during hibernation and breeding seasons is thus likely due to a combination of reduced protein synthesis and decreased number or function of agonist receptors in peptic cells of the frog.

1-Methyl-3-isobutylxanthine↗
PubMed1986

Desensitization within and between secretagogues of canine gastric acid and pepsin secretion.

Two types of desensitization, autodesensitization and cross-desensitization, of gastric secretory responses to cholinergic (bethanechol and vagal excitation) and noncholinergic stimuli (histamine and pentagastrin) were studied in groups of three to six conscious dogs with gastric fistula. Autodesensitization was manifested as fade of both acid and pepsin secretory responses by 10 to 20%/hr from peak output with all stimuli, histamine, pentagastrin and bethanechol. At the end of 4 hr of pentagastrin, 1.5 micrograms/kg X hr, doubling the dose of pentagastrin for 75 min reversed partly the trend of the acid fade, whereas adding an equipotent dose of histamine was much more effective, i.e., pentagastrin does not desensitize the stomach to histamine. When the three stimuli were given in sequence in random order for 2.5, 1.5 and 1.5 hr, respectively, to study cross-desensitization, histamine and pentagastrin reduced markedly the response of the parietal cells to either direct (bethanechol) or indirect (vagal) subsequent cholinergic stimulation. However, the parietal cells unresponsive to bethanechol remained fully responsive to histamine or pentagastrin, i.e., cholinergic stimulation did not desensitize the stomach to noncholinergic stimuli. From present and published data, neither auto- nor cross-desensitization is due to general, e.g. electrolyte and water depletion, or local, e.g. pH or osmolality, homeostatic consequences of secretion or to the drugs used, e.g. fall in blood pressure with histamine, but to cellular events. Inasmuch as the cell unresponsive to one stimulus may respond to another, a working hypothesis involving receptors is presented.

Animals↗