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Biomedical subjects

J D Gardner

Publications and source records attributed to J D Gardner.

At least 181 records · Page 10Linked to original sources
PubMed1983

Pepsinogen secretion from dispersed glands from rabbit stomach.

In dispersed glands from rabbit stomach, pepsinogen secretion was stimulated by carbamylcholine, the C-terminal octapeptide of cholecystokinin (CCK-8), and structurally related peptides physalaemin and A23187 but not by bombesin or histamine. Reducing the incubation temperature from 37 degrees to 4 degrees C or adding carbonyl cyanide m-chlorophenylhydrazone reduced basal as well as stimulated pepsinogen secretion. Dibutyryl cGMP inhibited the stimulation of pepsinogen secretion caused by cholecystokinin but not that caused by carbamylcholine; atropine inhibited the stimulation of pepsinogen secretion caused by carbamylcholine but not that caused by cholecystokinin. Each cholecystokinin-related peptide had the same efficacy for stimulating pepsinogen secretion. In terms of the concentration that caused half-maximal stimulation of pepsinogen secretion, the relative potencies of cholecystokinin-related peptides were caerulein greater than CCK-8 greater than [desSO3]CCK-8 greater than gastrin. Removing extracellular calcium did not alter basal or cholecystokinin-stimulated pepsinogen secretion. These results illustrate that dispersed glands from rabbit stomach constitute a suitable preparation for examining the actions of various agents on pepsinogen secretion in vitro.

Animals↗
PubMed1983

Use of 125I-secretin to identify and characterize high-affinity secretin receptors on pancreatic acini.

We prepared 125I-secretin and studied the kinetics, stoichiometry, and chemical specificity with which the labeled peptide binds to dispersed acini prepared from guinea pig pancreas. Iodinated secretin retained intrinsic biological activity in that it was as effective but 2.5-times less potent than native secretin in its ability to bind to pancreatic acini and to increase cellular cAMP. Scatchard analysis of binding of 125I-secretin indicated that each pancreatic acinar cell has approximately 93,000 binding sites, half of which are occupied by 11 nM iodinated secretin. Binding of 125I-secretin was rapid, reversible, saturable, specific, and temperature dependent. Binding of 125I-secretin was inhibited by secretin, vasoactive intestinal peptide, PHI, and Gila monster venom but not by glucagon, gastric inhibitory polypeptide, cholecystokinin, caerulein, gastrin, bovine pancreatic polypeptide, somatostatin, neurotensin, leucine-enkephalin, methionine-enkephalin, carbachol, bombesin, litorin, eledoisin, physalaemin, or substance P. With agonists (secretin, vasoactive intestinal peptide, PHI, or Gila monster venom), as well as antagonists (C-terminal fragments of secretin), there was a close correlation between their relative potencies for inhibiting binding of 125I-secretin and their relative potencies for increasing cAMP (agonists) or inhibiting the secretin-induced increase in cAMP (antagonists). For a given agonist, however, a 40-fold higher concentration was required for half-maximal inhibition of binding of 125I-secretin than was required to produce a half-maximal increase in cellular cAMP. Thus, maximal stimulation of cellular cAMP occurs when approximately one-third of the secretin receptors are occupied by an agonist.

Animals↗
PubMed1983

Potentiation of pepsinogen secretion from dispersed glands from rat stomach.

In the present study we examined the actions of various agents alone and in combination on pepsinogen secretion from dispersed gastric glands prepared from rat stomach. Potentiation of pepsinogen secretion occurred with secretin or vasoactive intestinal peptide plus carbamylcholine or cholecystokinin. The pattern of action of secretin and vasoactive intestinal peptide could be reproduced by 8-bromo-cAMP, and the pattern of action of carbamylcholine and cholecystokinin could be reproduced by the calcium ionophore A23187. A phosphodiesterase inhibitor, isobutylmethylxanthine, increased pepsinogen secretion, increased the potency but not the efficacy of the action of secretin on pepsinogen secretion, and potentiated the action of carbamylcholine on pepsinogen secretion. These results suggest that, in dispersed gastric glands from rat stomach, secretagogue-induced pepsinogen secretion can be stimulated by two different mechanisms: one mechanism is mediated by cAMP and the other is mediated by changes in cellular calcium. Secretagogues whose actions are mediated by one mechanism potentiate the actions of those secretagogues whose actions are mediated by the other mechanism.

1-Methyl-3-isobutylxanthine↗
PubMed1983

Effects of inhibitors of cyclic nucleotide phosphodiesterase on actions of cholecystokinin, bombesin, and carbachol on pancreatic acini.

In dispersed acini from guinea pig pancreas two inhibitors of cyclic nucleotide phosphodiesterase, Ro 20-1724 and 3-isobutyl-1-methylxanthine (IBMX), augmented the increase in amylase secretion caused by supramaximal concentrations of cholecystokinin but did not alter the stimulation of enzyme secretion caused by bombesin. The augmentations of the action of cholecystokinin caused by Ro 20-1724 or IBMX could be reproduced by 8-bromo-cAMP. When tested alone or with theophylline, cholecystokinin did not alter cAMP in pancreatic acini; however, with Ro 20-1724 or IBMX, concentrations of cholecystokinin that were supramaximal for stimulating amylase secretion caused a significant increase in cellular cAMP. These findings indicate that Ro 20-1724 and IBMX augment the action of cholecystokinin on enzyme secretion by inhibiting cyclic nucleotide phosphodiesterase and allowing a significant cholecystokinin-induced increase in cellular cAMP. IBMX but not Ro 20-1724 caused a parallel rightward shift in the dose-response curve for the stimulation of amylase secretion caused by carbachol. IBMX also caused a parallel rightward shift in the dose-response curve for the stimulation of outflux of 45Ca caused by carbachol. These results indicate that IBMX, but not Ro 20-1724, can function as a muscarinic cholinergic antagonist.

1-Methyl-3-isobutylxanthine↗
PubMed1983

Action of natural glucagon on pancreatic acini: due to contamination by previously undescribed secretagogues.

In dispersed acini from guinea pig pancreas, natural glucagon caused a two- to threefold increase in amylase secretion, and this natural glucagon-induced increase was augmented by theophylline. Natural glucagon also caused a sixfold increase in cellular cAMP but did not alter cellular cGMP or outflux of 45Ca. Natural glucagon caused detectable changes in cAMP and amylase secretion at a concentration of 1 microM, half-maximal stimulation at 10 microM, and maximal stimulation at 100 microM. Natural glucagon potentiated the increase in enzyme secretion caused by secretagogues that act by causing mobilization of cellular calcium but did not alter the increase in enzyme secretion caused by secretagogues that increase or mimic the action of cellular cAMP. At concentrations up to 100 microM, natural glucagon did not inhibit binding of 125I-vasoactive intestinal peptide. The potency with which glucagon stimulated amylase release and augmented the increase in amylase release caused by cholecystokinin or carbachol was the same with acini from rat or mouse pancreas as it was with acini from guinea pig pancreas. Biologically active synthetic glucagon did not increase enzyme secretion. On reverse-phase, high-pressure liquid chromatography of natural glucagon, the ability to stimulate enzyme secretion migrated differently from the glucagon. Natural glucagon, at concentrations that stimulated cAMP accumulation, did not react with vasoactive intestinal peptide or secretin radioimmunoassays. Neither insulin nor pancreatic polypeptide, which are known to contaminate natural glucagon preparations, increased enzyme secretion from pancreatic acini. Trypsin treatment abolished the ability of natural glucagon to increase enzyme secretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Amylases↗
PubMed1983

Zollinger-Ellison syndrome: current concepts and management.

Over the last few years the approach to managing patients with the Zollinger-Ellison syndrome has changed dramatically. The establishment of gastrin hypersecretion by a non-beta islet cell tumor as responsible for the gastric acid hypersecretion, and the subsequent development and widespread availability of gastrin radioimmunoassays have changed the criteria generally used for diagnosis and have led to an increased understanding of syndromes that can mimic Zollinger-Ellison syndrome. With the availability of histamine H2-receptor antagonists, gastric acid hypersecretion can be controlled medically in almost all patients with Zollinger-Ellison syndrome, obviating routine total gastrectomy. With the reduced mortality from gastric acid hypersecretion, increased attention is being focused on the natural history of the gastrinoma. Newer methods of localizing tumors are being investigated with a view to surgical removal of the gastrinoma, and the importance of developing an affective chemotherapeutic regimen is becoming increasingly apparent.

Adolescent↗
PubMed1983

Reliability of symptoms in assessing control of gastric acid secretion in patients with Zollinger-Ellison syndrome.

In the present study we explored whether the presence or absence of symptoms could provide a reliable way of assessing the adequacy of control of gastric secretion in patients with Zollinger-Ellison syndrome who were treated medically. Over a 5-yr period, 26 Zollinger-Ellison syndrome patients were entered into a prospective study which examined the presence or absence of symptoms that are associated with gastric hypersecretion, the presence of absence of upper gastrointestinal pathology, and the degree of control of gastric acid secretion. During their last admission, 15 of the 26 patients (58%) were symptomatic, but post-drug gastric acid secretion for the 2 h before the next dose of medication was not significantly different from that in asymptomatic patients. This lack of correlation between the presence or absence of symptoms and post-drug gastric acid secretion was evident for the group as a whole, as well as for 8 to 12 patients who underwent multiple admissions. Of 23 patients who underwent upper gastrointestinal endoscopy of x-ray, or both, on their last admission, 12 had pathology. Post-drug gastric acid secretion was less in patients without pathology than in those with pathology. Furthermore, in patients in whom post-drug gastric acid secretion was less than or equal to 10 mEq/h, the criterion of acceptable control used in this study, pathology did not occur. These findings demonstrate that the presence or absence of symptoms cannot be used to assess the adequacy of medical control of gastric acid secretion in patients with Zollinger-Ellison syndrome. In our opinion, maintenance of post-drug gastric acid secretion less than or equal to 10 mEq/h for the 2 h before the next dose of medication is an acceptable criterion for long-term control of gastric secretion in patients with Zollinger-Ellison syndrome.

Adult↗
PubMed1983

Characterization of receptors for gastrointestinal peptides.

Acinar cells from guinea pig pancreas possess six different classes of receptors that mediate the actions of various secretagogues on enzyme secretion. Two classes of receptors stimulate enzyme secretion by causing activation of adenylate cyclase and increased cellular cyclic AMP; four classes of receptors stimulate enzyme secretion by causing mobilization of cellular calcium. This paper summarizes the results of studies that have employed radiolabeled secretagogues of high specific activity and have measured directly the interaction of secretagogues with their receptors on pancreatic acinar cells.

Adenylyl Cyclases↗
PubMed1982

Mechanism of action of ATP on intestinal epithelial cells. Cyclic AMP-mediated stimulation of active ion transport.

ATP, ADP and AMP but not adenosine increased cyclic AMP in dispersed enterocytes prepared from guinea pig small intestine. This action of ATP was augmented by IBMX and was reproduced by App(NH)p or App(CH2)p. ATP also increased the formation of cyclic [14C]AMP in enterocytes that had been preincubated with [14C]adenine. Gpp(NH)p and NaF each caused persistent activation of adenylate cyclase in plasma membranes from enterocytes and ATP caused significant augmentation of this persistent activation. In addition to increasing cellular cyclic AMP and augmenting Gpp(NH)p and NaF-stimulated persistent activation of adenylate cyclase, ATP increased the Isc across mounted strips of small intestine and inhibited net absorption of fluid and electrolytes in segments of everted small intestine. These results indicate that intestinal epithelial cells possess a receptor that interacts with ATP and other adenine nucleotides and that receptor occupation by ATP causes activation of adenylate cyclase, increased cyclic AMP and changes in active ion transport across intestinal mucosa.

1-Methyl-3-isobutylxanthine↗
PubMed1982

Action of cholera toxin on dispersed acini from rat pancreas. Post-receptor modulation involving cyclic AMP and calcium.

In dispersed acini from rat pancreas, cholera toxin caused a significant increase in cellular cyclic AMP but little or no change in amylase secretion. The presence of a secretagogue that causes mobilization of cellular calcium (e.g., cholecystokinin, carbamylcholine, bombesin or ionophore A23187) caused a substantial increase in the effect of cholera toxin on enzyme secretion. Cholera toxin did not alter calcium transport or the changes in calcium transport caused by other secretagogues, and secretagogues that mobilize cellular calcium did not alter cellular cyclic AMP or the increase in cyclic AMP caused by cholera toxin. These results indicate that in dispersed acini from rat pancreas there is post-receptor modulation of the action of cholera toxin by secretagogues that mobilize cellular calcium and that this modulation is a major determinant of the effect of the toxin on enzyme secretion.

Amylases↗
PubMed1982

Mycobacterium fortuitum infection: evidence of bactericidal defect due to hyperactive antigen-specific suppressor cells. Correction in vitro and in vivo by cholinergic agonist and indomethacin.

Immunologic studies in a patient with long-standing Mycobacterium fortuitum infection revealed normal numbers of T cells, T inducers, T suppressors, B cells, and monocytes, significant in vitro proliferative response to M. fortuitum antigen, and poor bactericidal activity against M. fortuitum but not against Escherhicia coli. M. fortuitum antigen-activated suppressor cells contributed to the bactericidal defect. The activity of these suppressor cells could be eliminated by the in vitro treatment of blood mononuclear cells with a combination of a cholinergic agonist and indomethacin, but not with either alone. Administration of the two drugs to the patient resulted in reversal of the bactericidal defect and dramatic clinical improvement. Systemic atypical (nontuberculous) mycobacterial infection may activate specific suppressor cells that could compromise the host's phagocytic cell function. Modulation of those suppressor cells by a combination of a cholinergic agonist and prostaglandin synthetase inhibitor could reverse this abnormality and may be beneficial to the patient.

Adult↗
PubMed1982

Synthesis and some pharmacological properties of Z-Tyr(SO3H)-Met-Gly-Trp-Met-Asp(Phe-NH2)-OH, a 32-beta-aspartyl analogue of cholecystokinin (pancreozymin) 27-33.

The heptapeptide carbobenzoxy-L-tyrosyl(O-sulfate)-L-methionylglycyl-L-tryptophyl-L-methionyl-L- aspartyl-beta-L-phenylalanine amine (Z-32-beta-Asp-CCK-27-33) was synthesized and tested for its ability to stimulate secretion from dispersed pancreatic acini in vitro, to increase protein secretion from cat pancreas in vivo, and to cause contraction of guinea pig gallbladder in situ. In increasing amylase secretion in vitro, the Z-32-beta-Asp-CCK-27-33 was equal in efficacy with but approximatively one-third as potent as the Boc-CCK-27-33, and when tested in vivo its activity is approximately 10 Ivy dog units (Idu)/microgram. In stimulation of the contraction of the gallbladder, it showed an activity lower than 1 Idu/microgram. This analogue has more pancreozyminic activity than cholecystokin-like activity. This seems to indicate different affinities for the two receptors.

Amylases↗
PubMed1982

Cyclic nucleotide antagonists of cholecystokinin: structural requirements for interaction with the cholecystokinin receptor.

Previously, we have found that, in pancreatic acini, butyryl derivatives of cGMP antagonize the action of cholecystokinin by inhibiting binding of the peptide to its membrane receptors. In the present study, we found that derivatives of cAMP and cIMP can also inhibit binding of cholecystokinin as well as its actions on acinar cell function. Moreover, the inhibition caused by cyclic nucleotide derivatives did not require the presence of a butyryl moiety, because certain 8-bromo-cyclic nucleotides also inhibited the interaction of cholecystokinin with its receptors. Cyclic nucleotide derivatives can also increase pancreatic enzyme secretion; however, for the various cyclic nucleotides tested, there was no apparent correlation between their abilities to stimulate enzyme secretion and their abilities to antagonize the actions of cholecystokinin. Finally, cyclic nucleotide derivatives also inhibited binding of 125I-cholecystokinin to antibodies that were specific for the biologically active, C-terminal region of cholecystokinin. Thus, certain cyclic nucleotide derivatives possess a conformational structural which resembles that of the biologically active portion of cholecystokinin, and this structural similarity accounts for the abilities of these nucleotide derivatives to interact with cholecystokinin receptors and, by so doing, to inhibit the action of cholecystokinin on its target tissues.

Animals↗
PubMed1982

Structural requirements for action of cholecystokinin on enzyme secretion from pancreatic acini.

Using dispersed acini prepared from guinea pig pancreas, we found that the structural requirements for cholecystokinin-induced stimulation of amylase secretion are the same as those for cholecystokinin-induced desensitization of amylase secretion. 1) The relative potencies with which various C-terminal fragments of cholecystokinin cause stimulation are the same as their relative potencies for causing desensitization. 2) With each fragment tested, desensitization occurs with peptide concentrations that are supramaximal for causing stimulation of amylase secretion. 3) Fragments of cholecystokinin less efficacious in causing supramaximal inhibition of amylase secretion are also less efficacious in causing desensitization of amylase secretion. In contrast, there is no obvious fixed relation between the ability of a cholecystokinin fragment to cause stimulation of enzyme secretion and its ability to cause residual stimulation of enzyme secretion. Cholecystokinin and its C-terminal hexadecapeptide are 25-40% more efficacious than the C-terminal decapeptide, octapeptide, and heptapeptide in causing residual stimulation, and the C-terminal pentapeptide and tetrapeptide caused no detectable residual stimulation. The C-terminal tetrapeptide, however, can prevent as well as reverse the residual stimulation caused by other cholecystokinin fragments, and the ability of the tetrapeptide to prevent cholecystokinin-induced residual stimulation is itself fully reversible.

Amylases↗
PubMed1982

Postreceptor modulation of action of VIP and secretin on pancreatic enzyme secretion by secretagogues that mobilize cellular calcium.

In dispersed acini from rat pancreas, secretagogues that act through or mimic the action of AMP [vasoactive intestinal peptide (VIP), secretin, or 8-bromo-AMP] caused a twofold increase in amylase secretion. Secretagogues that mobilize cellular calcium (carbamylcholine, C-terminal octapeptide of cholecystokinin, bombesin, or A23187) caused a sevenfold augmentation of the actions of VIP, secretin, or 8-bromo-cAMP on enzyme secretion. Carbamylcholine and the C-terminal octapeptide of cholecystokinin also augmented the action of VIP on amylase secretion from mouse pancreatic acini. Secretagogues that mobilize cellular calcium did not alter binding of 125I-VIP, cellular cAMP, or the increase in cellular cAMP caused by VIP or secretin. Similarly, secretagogues that increase cellular cAMP did not alter 45Ca outflux or the increase in 45Ca outflux caused by carbamylcholine, C-terminal octapeptide of cholecystokinin, bombesin, or A23187. These results indicate that in dispersed acini from rat pancreas there is postreceptor modulation of the actions of VIP and secretin on enzyme secretion by secretagogues that mobilize cellular calcium and that this modulation is a major determinant of the magnitude of the effect of VIP and secretin on enzyme secretion. This modulation, in turn, reflects the ability of cellular calcium, mobilized from intracellular stores, to amplify the action of cellular cAMP on the enzyme secretory process.

8-Bromo Cyclic Adenosine Monophosphate↗