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Biomedical subjects

B I Hirschowitz

Publications and source records attributed to B I Hirschowitz.

At least 109 records · Page 6Linked to original sources
PubMed1983

Effects of pirenzepine and atropine on vagal and cholinergic gastric secretion and gastrin release and on heart rate in the dog.

To characterize and quantitate pathways of stimulation of gastric secretion via vagal excitation induced by 2-deoxy-D-glucose, we used graded doses of the two muscarinic antagonists, atropine and pirenzepine. Studies were performed in four conscious gastric fistula dogs with antral vagotomy to eliminate the gastrin release component of the vagal response. To further localize the site of action of the antagonists, both were tested against bethanechol, which stimulates secretion at postganglionic sites. Acid and pepsin secretion stimulated by either bethanechol or the vagus were inhibited in a dose-responsive manner by both atropine and pirenzepine, which displayed similar potencies. These data indicate that: 1) the vagus acts on the gastric fundus solely via muscarinic receptors; 2) the muscarinic receptors controlling gastric secretion are of the high-affinity (M-1) subtype; and 3) the vagus is very sensitive to atropine with D50 less than 1.4 nmol/kg. Heart rate was increased up to 120 beats/min above the resting rate by atropine; half-maximal increase was calculated to occur at 10 nmol/kg (ED50). Pirenzepine had a much less potent effect on the heart; the ED50 was 200 to 300 times greater than that for atropine. These data indicate that heart rate is affected by a mechanism acting via a muscarinic receptor pathway that has a low affinity for pirenzepine (M-2 receptor subtype).

Animals↗
PubMed1983

Anticholinergic potency of diphenhydramine (Benadryl) measured against bethanechol in the gastric fistula dog.

We quantitated the gastric secretory anticholinergic effect of diphenhydramine (Benadryl) against graded doses of bethanechol, a cholinergic agonist, which was used to stimulate acid and pepsin secretion. Anticholinergic potency of diphenyhydramine was 10,000 times less than that reported for atropine and was 1,000 times less than the reported potency of diphenhydramine antagonism of histamine H-1 effects.

Animals↗
PubMed1982

A unique "mini" pepsinogen isolated from bullfrog esophageal glands.

The evolutionary homology of pepsinogens was further evaluated by isolating and characterizing the pepsinogen of the esophageal glands of Rana catesbeiana. Like other pepsinogens, this esophageal enzyme was activated by acid; the resulting pepsin was optimally active between pH 1.4 and 2.0, and was irreversibly denatured above pH 7.0. Chromatography on DEAE-cellulose at pH 7.0 separated four acid protease fractions corresponding to pepsinogens B, D, A, and C. Hydroxylapatite chromatography of the major peptic fraction, pepsinogen A, followed by rechromatography on DEAE-cellulose at pH 8.5 yielded pure pepsinogen A which was free of detectable contaminants. Estimation of molecular weight by gel filtration on Sephadex G-75, by polyacrylamide gel electrophoresis in 0.1% SDS and by sedimentation equilibrium gave values of 31,500, 33,500, and 33,700, respectively. These studies suggest that the difference between bullfrog and other pepsinogens is located in a 90 to 110 amino acid (Mr 9,000 to 11,000) region of the molecule which must be remote from the catalytic and immunogenic sites. This lower molecular weight pepsinogen should thus provide a simpler molecular model for study of the catalytic and immunogenic properties. The pepsinogen from bullfrog gastric mucosa was found to have similar properties which suggested that gastric and esophageal pepsinogens of bullfrog are derived from a common ancestral origin. This archetypic pepsinogen may have undergone deletions late in evolution to render modern bullfrog pepsinogen structurally dissimilar from other described pepsinogens. The modern bullfrog enzyme has retained peptic enzymatic activity despite these evolutionary changes.

Amino Acids↗
PubMed1982

Effects of fundic vagotomy and cholinergic replacement on pentagastrin dose responsive gastric acid and pepsin secretion in man.

The effects of fundic vagotomy on acid and pepsin secretion in 12 patients (10 males, two females; nine duodenal ulcer, three gastric ulcer) were studied using a pentagastrin dose response before and after Vagotomy. In the intact stage H, Cl, and pepsin output all had the same ED50, 120-127 pmol/kg/h. Vagotomy reduced basal output of acid by 78%, Cl- by 50%, and pepsin by 62%. Postvagotomy basal outputs were not related to preoperative levels, while maximum acid output was reduced by an average of 35%, proportionally to the preoperative output (r = 0.94). Vagotomy uncompetitively (ED50 increase, Vmax decrease) inhibited the pentagastrin dose response of acid, chloride, and pepsin output. Postoperatively, a six-fold greater dose of pentagastrin (450 vs 76 pmol/kg/h) was required to stimulate acid to 50% of its preoperative maximum output. For pepsin secretion the increase was 12-fold (185 vs 15 pmol/kg/h). In five of the nine duodenal ulcer patients pentagastrin dose responses were repeated with a background infusion of urecholine, 20 micrograms/kg/h. Urecholine increased basal and peak acid, pepsin, and chloride outputs, and the ratio of basal: maximal almost to prevagotomy levels; it also restored the sensitivity to pentagastrin. Serum gastrin was not significantly changed by urecholine or by vagotomy. We conclude that the level of basal acid and pepsin secretion in ulcer patients, which is largely eliminated by vagotomy, is dependent on the vagus and not on serum gastrin. The effects of vagotomy are functional, are due to cholinergic withdrawal, and usually can be restored by cholinergic replacement.

Adult↗
PubMed1982

Incremental and decremental kinetics of gastric responses to infused gastrin in dogs.

Acid and pepsin secretion was stimulated by graded doses of synthetic human gastrin I (G-17-I) and pentagastrin (G-5) in six conscious gastric fistula dogs, three with intact vagi and three with fundic vagotomy. Metabolic clearance rate of G-17 was 15.2 ml.kg-1.min-1 and volume of distribution was 15.8%. Gastrin levels decayed in two slopes: t1/2 of 6.8 min and 25-35 min, respectively. These were compared with other published data. Vmax was higher in intact stomachs and at doses or blood levels of gastrin about three to four times smaller. G-17 was almost four times more potent (molar basis) than G-5. Responses were log linearly related to G-17 dose and to serum G-17 during infusion (incremental) and after stopping infusion (decremental). Normalized decremental curves were congruent in all dogs but displaced fivefold (625 vs. 130 pmol/l) to the right at midpoint. Vagotomy changed only association (incremental) kinetics (Km = 352 pmol/l). The previously undescribed difference between blood concentration-effect relationship during drug administration and withdrawal may be important in situations in which blood levels are used as therapeutic guide.

Animals↗
PubMed1982

Analysis of the 2-deoxy-D-glucose-induced vagal stimulation of gastric secretion and gastrin release in dogs using methionine-enkephalin, morphine and naloxone.

Gastric acid and pepsin secreted in 3 hr and antral gastrin released in response to vagal excitation induced by 2-deoxy-D-glucose (2DG), 625 mumol/kg i.v., were studied in six conscious trained gastric fistula dogs. During a 2-hr infusion, Met-enkephalin (96 nmol/kg/hr; delta receptor) reduced the 2DG response by 50%; when the enkephalin was stopped there was a rapid rebound to peak values. Met-enkephalin also blocked the release of gastrin in the first 15 min. By itself, Met-enkephalin did not stimulate secretion and slightly depressed gastrin. By contrast, morphine (96 nmol/kg/hr; mu receptor) augmented and sustained the 2DG gastric acid secretory response. This effect was blocked by naloxone. Morphine alone caused a small rise in serum gastrin after 90 min, followed by a delayed gastric acid secretion of about 30% of the peak 2DG response. Naloxone, a mu opiate antagonist (mu/delta, 27:1), also inhibited the 2DG gastric secretory response by about 50% and augmented the Met-enkephalin inhibition of secretion without blocking either the secretory rebound or the effect on gastrin release. None of the three opiates changed the direct cholinergic gastric secretory or gastrin-releasing effects of bethanechol. Thus, vagal stimulation of the stomach involves pathways which can be influenced by both mu and delta opiates, with apparently opposite effects, proximal to the level of acetylcholine action on the gastric mucosa. The central and peripheral control points in the activation of the stomach via the vagus which are sensitive to opiates have yet to be located and explained.

Animals↗
PubMed1981

A plea for clarity.

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Gastrointestinal Diseases↗
PubMed1981

Risk factors for isoniazid (NIH)-induced liver dysfunction.

We examined prospectively risk factors which might contribute to INH-induced liver damage in 113 patients taking preventive INH for at least 8 weeks. Twelve who had abnormal initial liver tests did not get worse with INH, while 19/101 with normal initial tests developed significant liver dysfunction, mostly hepatocellular, three having overt hepatitis. When 12 other patients who drank alcohol were excluded from analysis, there were still 15/89 with significant liver dysfunction, 12 of whom were slow acetylators (p less than 0.05). The only other risk factor was age. By combining acetylator phenotype with age, but excluding alcohol, we calculated the risk of INH-induced liver enzyme elevation as follows: under 35 years--fast acetylators, 3.7%, slow acetylators, 13%; over 35--fast acetylators, 13.2%, slow acetylators, 37% (p less than 0.02). Fast acetylation is thus not a risk factor for developing INH-induced liver dysfunction; indeed, the contrary seems to be the case.

Acetylation↗
PubMed1981

Postnatal physiologic hypercholemia in both premature and full-term infants.

Previous studies have shown that bile salt concentrations in human blood taken from the placenta at birth of term infants are in the range found in adults. A 125I-radioimmunoassay procedure and capillary gas liquid chromatography-mass spectrometry have been used in this investigation to measure serum bile salt concentrations in premature and normal term infants. It was found that the serum bile salt concentration in samples taken at birth in premature infants were also similar to that of adults. In the week after birth the serum bile salt concentration rose four- to sevenfold in each of the infant groups. The increase was independent of gestational age and the "health" of the child. A similar increase was observed in term infants. Thus, hypercholemia is physiologic in newborn infants. In conjunction with other abnormalities of the enterohepatic circulation of bile salts there are profound implications in the newborn for the metabolism and excretion of those endogenous and exogenous substances that are dependent on the secretion of bile salt by the liver. In addition, speculations concerning the role of parenteral nutrition in the induction of cholestasis in premature infants should be made with caution.

Age Factors↗
PubMed1981

Histamine H-2 receptor stimulation and inhibition of pepsin secretion in the dog.

Although low doses of histamine (less than 150 nM/kg.hr) stimulate pepsin secretion, higher doses inhibit pepsin secretion in a dose-dependent manner. To better histamine stimulation of pepsin, histamine was used at doses at the lower end of the dose-response scale in five dogs with gastric fistula. Five doses of histamine below the ED50 for acid, viz, 9, 22.5, 67.5, 90 and 112 nM/kg.hr in 45-min steps, provided values for pepsin secretion from which Ed50 = 11.4 nmol/kg.hr (i.e., about 1/12 the ED50 for acid) and calculated maximum 22,600 peptic U/30 min were calculated. To document the inhibition, pepsin secretion was first stimulated by an infusion of bethanechol (0.4 mumol/kg.hr). A super-added injection of the histamine H-2 agonist 4-methylhistamine (0.4 or 0.8 mumol/kg) produced strong additional acid stimulation and immediate 40% suppression of pepsin secretion. The ratio pepsin/acid was reduced to one-third of control for the 90 min after 4-methylhistamine. The most specific H-2 agonist impromidine had the same effects, whereas pentagastrin (1.95 nmol/kg) inhibited both acid and pepsin secretion stimulated by bethanechol. The specificity of H-2 effect of impromidine was confirmed by simultaneous tachycardia and hypotension; pentagastrin did not produce cardiovascular effects. These studies confirm the unique effect of histamine on the peptic cell of the dog in which both stimulation and inhibition are H-2 receptor-mediated effects.

Animals↗
PubMed1981

Atropine suppresses gastrin release by food intact and vagotomized dogs.

We have demonstrated that at doses lower than those used by others in dogs, atropine consistently inhibited food-stimulated gastrin release irrespective of vagal innervation of the stomach. Gastrin release induced by food placed directly into the stomach was studied in four gastric fistula dogs with intact vagi and in three other similar dogs with fundic vagotomy. The studies were repeated in dogs after conversion to truncal vagotomy. Fasting serum gastrin was lower in the intact dogs (33 +/- 1.7 pg/ml) than after fundic vagotomy (61 +/- 13 pg/ml) or truncal vagotomy (97 +/- 20 pg/ml). The same relationship held for absolute postprandial values. However, the integrated gastrin response to food over 2 h was similar in the three groups of dogs (intact 14 +/- 4.6, fundic vagotomy 10.3 +/- 4.3, truncal vagotomy 17.4 +/- 2.4 ng.min/ml). Regardless of the state of gastric vagal innervation atropine 20 microgram/kg . h reduced gastrin releases due to food by 66-76% (p less than 0.05) in all three groups. In small doubling doses (1-16 microgram/kg), atropine given i.v. at 15-min intervals, dose-responsively inhibited food-stimulated gastrin release in the four dogs with intact vagi. Assuming that the atropine effect was cumulative, kinetic analysis of the dose-response data gave a calculated maximum inhibition of 91% and an ID50 of 5.1 microgram/kg or 7.2 X 10-9 mol/kg. Findings of this study indicate a previously undescribed muscarinic cholinergic pathway leading to gastrin release by food.

Animals↗
PubMed1980

Gastrin release after truncal vagotomy in fistula dogs: hypersensitivity to bombesin but not bethanechol.

Integrated gastrin response was measured by the serial changes in serum immunoreactive gastrin after various stimuli in three dogs with gastric fistula and highly selective fundic vagotomy, who were then subjected to truncal vagotomy. Truncal vagotomy eliminated the gastrin as well as the gastric acid response to vagal excitation by 2-deoxy-glucose, but did not significantly changes the responses to bethanechol (20 or 120 micrograms/kg/hr by IV infusion). Acid output was the same with bombesin or its nonapeptide in the dogs with fundic vagotomy as it was after subsequent truncal vagotomy, but gastrin release was very much increased by truncal vagotomy. For a 3-hour infusion of bombesin integrated gastrin release was 65 and 143 ng/ml/min and for its nonapeptide 43 and 109 ng/ml/min in the dogs with fundic and truncal vagotomy respectively. The marked hypersensitivity of the gastrin response after truncal vagotomy to bombesin but not to a cholinergic agonist suggests that the antral denervation led to a post-denervation hyper-response to the putative transmitter, bombesin, and that the vagal release of antral gastrin may thus represent a peptidergic neurohormonal mechanism. Also, a long half-life of effect suggests that bombesin binds avidly to its receptors.

Animals↗