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Biomedical subjects

I M Modlin

Publications and source records attributed to I M Modlin.

At least 235 records · Page 13Linked to original sources
PubMed1987

Somatostatin inhibition of intrinsic factor secretion from isolated guinea pig gastric glands.

The aim of our study was to examine the direct effect of somatostatin on histamine- and pentagastrin-stimulated intrinsic factor (IF) release in collagenase-dispersed guinea pig gastric glands. The effect of somatostatin (10(-11) M to 10(-6) M) on half-maximal doses of histamine (10(-6) M), pentagastrin (10(-6) M), and both histamine and pentagastrin together was tested. All tested concentrations of histamine significantly stimulated IF release. Pentagastrin (10(-10) M to 10(-6) M) inconsistently stimulated IF release. The quantity of IF release stimulated by histamine and pentagastrin together was approximately the additive sum of that produced by either agent alone. Somatostatin (10(-6) M) inhibited histamine-stimulated (10(-6) M) IF release by 69.9 +/- 7.2% and the combination of histamine (10(-6) M) and pentagastrin (10(-6) M) by 64.2 +/- 9.1%. This is the first in vitro demonstration that somatostatin inhibits IF release.

Animals↗
PubMed1987

Asperlicin: a unique nonpeptide cholecystokinin antagonist.

The lack of a potent and specific cholecystokinin (CCK) receptor antagonist has greatly hampered studies of the role of CCK in controlling pancreatic growth, enzyme release, pancreatitis, and pancreatic carcinoma. Asperlicin, a newly described, CCK antagonist, has been shown to be a potent, competitive inhibitor of CCK-induced gallbladder and ileal muscle contraction. In this study, the effects of asperlicin on CCK- and carbachol-stimulated pancreatic enzyme release from dispersed guinea pig acini were investigated. Cholecystokinin caused a dose-dependent release of amylase and lipase. Half-maximal release of amylase (17.9% +/- 2.1%, mean +/- SEM, percent of total content) and lipase (27.3% +/- 2.1%) was seen with CCK 10(-11) mmol/L) both p less than 0.01). Asperlicin (10(-11) to 10(-4) mmol/L) caused a substantial inhibition (10(-11) mmol/L) of CCK-induced amylase release with a 50% maximal effective inhibitory dose of 10(-9) mmol/L (p less than 0.01) and maximum inhibition at 10(-6) mmol/L. Asperlicin was approximately 1000-fold more potent than proglumide (a previously described CCK receptor antagonist) which had a 50% effective inhibitory dose of 10(-6) mmol/L) and a maximal effect at 10(-4) mmol/L. Asperlicin (10(-10) to 10(-4) mmol/L) failed to alter carbachol-induced amylase release. Asperlicin is a new, potent CCK antagonist for pancreatic CCK receptors and should prove useful as an investigational tool. Such receptor antagonists may have therapeutic potential.

Amylases↗
PubMed1987

Somatostatin analogue inhibition of isolated parietal cell secretion.

Somatostatin, somatotropin release-inhibiting factor (SRIF), is a regulatory peptide that has proved to directly inhibit parietal cell acid secretion. However, the therapeutic usefulness of SRIF has been limited by a brief plasma half-life. Several analogues of SRIF that are effective in suppressing acid secretion in vivo have been developed. This study was undertaken to compare the effects of SRIF and two analogues, SMS 201-995 and L-363,568, on in vitro acid secretion. We used isolated rabbit parietal cells prepared by collagenase digestion and counterflow elutriation. Acid secretion was assessed by the accumulation of 14C-aminopyrine within the cells. Two types of secretagogues were utilized: histamine (10(-6) mol/L), a membrane receptor agonist which acts by means of adenylate cyclase and cyclic AMP, and forskolin (10(-6) mol/L), a direct activator of adenylate cyclase. SRIF, SMS 201-995, and L-363,568 (10(-11) to 10(-7) mol/L) all significantly inhibited histamine-stimulated 14C-AP uptake (p less than 0.001). On a molar basis, SMS 201-995 was 10 times more potent and L-363,568 was 40 times more potent than SRIF. SRIF, SMS 201-995, and L-363,568 significantly inhibited forskolin-stimulated 14C-AP uptake (p less than 0.005). The inhibitory effects of SRIF and both analogues on forskolin-stimulated acid secretion was, however, significantly less than that observed with histamine (p less than 0.05). These results demonstrate increased in vitro potency of SRIF analogues compared with the native peptide. The data are consistent with the hypothesis that SRIF and its analogues function at more than one site within the parietal cell.

Animals↗
PubMed1987

Pepsinogen. Prolate ellipsoid or unrecognized pathogen?

Pepsin is a potent proteolytic enzyme stored and secreted by chief cells in an inactive precursor form, pepsinogen. Its secretion is modulated by both cAMP and calcium-dependent mechanisms. Abnormalities in levels of pepsinogen and its various isozymogens have been linked clinically, epidemiologically, and experimentally to peptic ulcer disease and gastric carcinoma. The ulcerogenesis of pepsin stems from its ability to breach gastroduodenal mucosal barriers. Furthermore, certain isozymogens seems abundant and hyperactive in patients with peptic ulcer disease. The etiology and significance of low pepsinogen levels with disproportionate elevations of pepsinogen II and pepsin 5 in gastric cancer and its precursors is less clear. Further exploration of the patho-physiologic role of pepsin is likely to be of considerable importance in initiating further advances in the understanding and treatment of upper gastrointestinal disease.

Animals↗
PubMed1987

Gastric epithelioid leiomyomatous tumors.

Gastric epithelioid leiomyomatous tumors can present in three patterns; intramural, endogastric and exogastric based upon the relation to the gastric muscular wall. Patients may experience no symptoms from this tumor or may complain of symptoms suggesting peptic ulcer disease. Upper gastrointestinal tract series are the most reliable diagnostic tests but important additional information can be obtained by ultrasound and abdominal computerized tomography. The overwhelming majority of epithelioid leiomyomatous tumors are found in the gastric antrum. Round or polygonal cells are seen histologically. Often these cells have a clear zone that surrounds the nuclei. The origin of these tumors is debated. Less than one-third of these tumors metastasize. Complete surgical excision can often achieve cure. The exogastric lesions are the ones most readily cured by resection. Prognosis also correlates with clinical parameters including size of tumor, duration of symptoms and weight loss. Adjuvant therapy has not proved beneficial.

Humans↗
PubMed1987

Gastric epithelioid leiomyosarcoma: a curable gastric neoplasm.

This is the first case report of the preoperative diagnosis of a gastric epithelioid leiomyosarcoma by percutaneous needle biopsy. Preoperative diagnosis facilitated curative surgical resection. Patients may present without symptoms or may report symptoms of peptic ulcer disease or gastrointestinal bleeding. Upper gastrointestinal series is the most useful radiological tool for detecting these lesions. Ultrasound and CT play a useful role in documenting the origin of these large masses, as well as their spread. Endoscopy is being used with increasing frequency, but because these are submucosal lesions diagnosis cannot easily be made through the endoscope. Pathologically, these tumors can be subdivided histologically into a benign epithelioid leiomyoma and two varieties of malignant epithelioid leiomyosarcoma. Prognosis correlates with histological features. Complete surgical resection is the treatment of choice. Chemotherapy or radiotherapy have no proven efficacy in treating epithelioid leiomyosarcoma. Unlike most other gastric malignancies, a favorable prognosis follows successful resection.

Aged↗
PubMed1986

Forskolin (cyclic adenosine monophosphate)-dependent protein phosphorylation in isolated gastric glands.

Improved management of peptic ulcer disease requires elucidation of cellular processes underlying gastric secretion. The intracellular execution of regulatory commands to secretory cells involves protein phosphorylation. We studied cyclic adenosine monophosphate (cAMP)-dependent phosphorylation in isolated gastric glands (IGGs) using forskolin, which directly stimulates adenylate cyclase. Forskolin stimulated secretion by both parietal and chief cells. In a separate set of studies, IGGs were incubated for 45, 90, and 105 minutes in modified Ham's F-10 medium containing orthophosphate labeled with phosphorus 32. The forskolin (10(-4) M) was added to some IGG preparations at 90 minutes. The reaction was terminated with sodium dodecyl sulfate and boiling. The proteins were resolved on sodium dodecyl sulfate-polyacrylamide gels, stained with Coomassie blue, and autoradiographed. Incorporation of phosphorus 32 increased progressively at 45, 90, and 105 minutes. Forskolin enhanced phosphorylated bands around 92 kilodaltons. These results are consistent with the major role of cAMP in the regulation of gastric cellular function. The study of cAMP-stimulated phosphorylation may be an important tool in the elucidation of intracellular regulatory mechanisms of gastric secretion. Modulation of these mechanisms may be the ideal therapeutic modality for treatment of acid-secretory disorders.

Aminopyrine↗
PubMed1986

Rectal carcinoma in a renal transplant patient. Long-term complication of immunosuppression?

The occurrence of a rectal adenocarcinoma in a 48-year-old man 11 years after he received a cadaveric renal transplant is reported. Since his operation, the patient had been receiving prednisone and azathioprine for immunosuppression. The occurrence of rectal carcinoma in this patient at an early age, after a decade of immunosuppression, suggests an association between the malignancy and his altered immunologic state. Although an increased incidence of skin and reticuloendothelial malignancies in the first five years following renal transplantation has been well documented, few colorectal carcinomas have developed in these patients. Follow-up of transplant patients, however, is only now passing ten years in large numbers of patients. This case suggests that there may be a ten year latency period before transplant patients develop colorectal carcinoma. Such a time course would be similar to that seen in patients with chronic ulcerative colitis, in whom colorectal carcinomas are found. Surveillance colonoscopy for transplant patients beginning ten years after surgery may be necessary.

Adenocarcinoma↗
PubMed1986

Perforated appendicitis and obstructing colonic carcinoma in the elderly.

Two patients admitted with perforated appendicitis and obstructing colonic cancers are presented. The first patient, a 75-year-old man, developed a persistent fecal fistula following appendectomy. Barium enema demonstrated an obstructing hepatic flexure carcinoma. The second patient, a 62-year-old man, recovered uneventfully following appendectomy. Persistent occult blood was found in his stools during follow-up examinations. Three months after surgery, diagnostic colonoscopy revealed a nearly obstructing sigmoid carcinoma. Obstruction of the appendiceal lumen by such lesions as fecaliths, carcinoid tumors, lymphoid hyperplasia, or cecal carcinoma accounts for appendicitis in the majority of patients. These two patients illustrate a less common cause. As many as 3 percent of patients over 40 years of age presenting with appendicitis also have obstructing colonic carcinomas. Elderly patients with appendicitis should be evaluated for colonic neoplasms at a clinically suitable time.

Aged↗
PubMed1986

Squamous cell carcinoma in situ in condyloma acuminatum.

This is the 14th case report of squamous cell carcinoma in situ developing in perianal condyloma acuminata. A 72-year-old nonhomosexual man suffered this lesion 11 months after his condyloma was first fulgurated. The lesion was excised locally. He received no local or systemic chemotherapy. Random biopsies on several occasions since that time have not shown any evidence of local recurrence. Squamous-cell carcinoma in situ in perianal condyloma must be distinguished from Bowen's disease and extramammary Paget's disease of the perianal skin, both of which have associated skin rashes. Although Bowen's disease and extramammary Paget's disease frequently are associated with either local or distant malignancies, no such association has been found for squamous cell carcinoma in situ in condyloma unless the patient also has the acquired immunodeficiency syndrome (AIDS). Since this lesion is a premalignant lesion like Bowen's disease and extramammary Paget's disease, squamous cell carcinoma in situ in condyloma is treated by local excision. If the margins are free of tumor, the resection is curative. No local or systemic recurrence of this condition has been reported following adequate local resection. Patients with condyloma acuminata should undergo treatment to eliminate all of the warts. When the condylomata recur, or when the patient has AIDS, the lesions should be examined histologically for evidence of premalignant or malignant degeneration.

Aged↗
PubMed1986

Vasoactive intestinal peptide augmentation of cholecystokinin-8-stimulated pepsinogen secretion: evidence for dual modulation of chief cell function.

Pepsinogen (PPG) secretion from chief cells (CC) is dually modulated by adenosine 3':5'-monophosphate (cAMP) and calcium second messenger systems. Vasoactive intestinal peptide (VIP) stimulates cellular function by elevating intracellular levels of cAMP. In contrast, cholecystokinin-8 (CCK-8) acts by producing a rise in intracellular calcium concentration. Consequently, it was the purpose of this study to test whether VIP (acting through cAMP-mediated systems) could augment CCK-8 (acting through calcium-dependent systems)-stimulated PPG secretion. Collagenase dispersed rabbit isolated gastric glands (IGG) were incubated alone (unstimulated) or with secretagogues for 30 min. VIP in graded doses of 10(-11) to 10(-7) M was used alone or in combination with CCK-8 (10(-9) M). PPG levels were determined using an assay based on pepsin hydrolysis of [14C]methemoglobin. Results are expressed as percentage of total pepsinogen (within the IGG) secreted above unstimulated levels. VIP alone (10(-11) to 10(-7)) or CCK-8 alone (10(-9)) did not significantly stimulate PPG secretion (P greater than 0.05). The combination of CCK-8 (10(-9) M) plus VIP (10(-7) M) significantly stimulated PPG secretion above unstimulated levels (P less than 0.05). Thus, the combination of VIP and CCK-8 produced greater PPG secretion than either secretagogue alone. These data support the hypothesis that secretagogues acting through either cAMP or calcium-mediated systems contribute to the regulation of PPG secretion from CC and that the two second messenger systems act in concert achieving at least additive effects.

Animals↗
PubMed1986

Paradoxical effect of trifluoperazine, a calmodulin antagonist, on pepsinogen secretion.

Pepsinogen secretion (PS) is modulated at the intracellular level by both cAMP and calcium ion. Cholecystokinin octapeptide (CCK-8), a potent stimulus for PS, is believed to act through calcium. The most extensively studied pathway for calcium-mediated modulation involves the formation of calcium/calmodulin complexes, leading to activation of calmodulin. We have therefore examined the hypothesis that an inhibitor of calmodulin might inhibit PS stimulated by CCK-8. The phenothiazine derivative trifluoperazine (TFP) was chosen as a calmodulin antagonist. We measured in vitro secretion of pepsinogen by isolated gastric glands as a function of TFP concentration 10(-6) M-5 X 10(-4) M), in the presence and absence of a maximal concentration of CCK-8 (10(-7) M). Cellular viability was determined by measurement of release of the enzyme lactate dehydrogenase (LDH) into the medium. TFP did not significantly inhibit PS stimulation by CCK-8 at any concentration (P greater than 0.05). At 10(-4) M, TFP actually augmented PS stimulation by CCK-8 (P less than 0.05). TFP alone significantly stimulated PS (P less than 0.05) at 5 X 10(-5) M and above. TFP did not raise cAMP levels at any concentration tested (P less than 0.05), in contrast to the adenylate cyclase activator forskolin, 10(-5) M, which caused a 6- to 37-fold increase (P less than 0.05). TFP, 2 X 10(-4) did not increase LDH levels significantly (P less than 0.05). Thus a calmodulin inhibitor, TFP, paradoxically stimulates PS. This stimulatory effect of TFP is not cAMP-dependent and is not accompanied by a nonspecific release of LDH into the medium.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Proton pump inhibition--the ultimate control of acid secretion?

The cellular mechanisms of acid secretion by the parietal cell (PC) include stimulation of membrane receptors, increases in cytosolic cyclic AMP levels, and activation of protein kinase systems. These events culminate in stimulation of a membrane-based proton pump. This consists of a non-electrogenic H+-K+-ATPase which transports H+ ions into the secretory canaliculus of the PC in exchange for the cation K+. It has been proposed that blockade of this proton pump would result in inhibition of acid secretion by all classes of acid secretagogues. Thus, the effects of membrane receptor agonists as well as any agents which augment cellular cAMP levels should be inhibited. Substituted benzimidazoles are weak bases which prevent acid secretion by blocking the H+-K+-ATPase system. In order to test the above hypothesis, we investigated the effects of the substituted benzimidazole H168/68 and cimetidine (C) on histamine (H) and 8B-stimulated acid secretion. The rabbit isolated gastric gland (IGG) model was used and acid secretion assessed by the accumulation of 14C-labeled weak base aminopyrine (AP) within the IGG in response to secretagogue stimulation. H168/68 and C both inhibited H (5 X 10(-5) M)-stimulated [14C]AP accumulation in a concentration-dependent manner (P less than 0.05). H168/68 inhibited both H- and 8B-stimulated [14C]AP accumulation (P less than 0.05), while C inhibited only H-stimulated [14C]AP accumulation (P less than 0.05). H168/68 suppressed [14C]AP below even unstimulated levels of [14C]AP accumulation. These results support the hypothesis that H168/68 inhibits the PC distal to cAMP stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1986

Evidence for dual modulation of pepsinogen secretion using isoproterenol, carbachol, CCK-8, forskolin, 8 bromo-cAMP, and A23187 probes.

The cellular mechanisms by which pepsinogen (PNG) secretion is controlled are not understood. The aim of this study was to explore whether modulation of PNG secretion is mediated by cAMP or calcium-calmodulin (C-C). PNG secretion in isolated rabbit gastric fundic glands (IGG) was tested, using agents believed to act via cAMP or C-C. IGG were stimulated for 30 minutes with histamine (H) 10(-5) M, isoproterenol (I) 10(-5) M, carbachol (C) 10(-5) M, cholecystokinin-octapeptide (CCK-8) 10(-7) M, forskolin (F) 10(-5) M, 8 bromo-cAMP (8B) 10(-3) M, and A23187 (A) 10(-6) M. PNG levels were determined by spectrophotometric assay of hemoglobin digestion products. PNG amounts secreted were (mean per cent above basal levels of total IGG PNG units +/- SEM): H, -0.02 +/- 0.30%; I, 3.5 +/- 0.9%; C, 5.1 +/- 2.2%; CCK-8, 5.3 +/- 1.5%; F, 10.6 +/- 3.8%; 8B, 13.8 +/- 4.5%; A, 2.1 +/- 1.1%. All secretagogues except H stimulated PNG release significantly above basal levels (p less than 0.05). A primary histaminergic mechanism for pepsinogen secretion is unlikely. Since two other adenylate cyclase activators, isoproterenol and forskolin and the 3':5'-cyclic adenosine monophosphate analog 8-bromo cAMP stimulated pepsinogen secretion, cAMP-dependence is probable. Since carbachol, CCK-8, and A23187, which are believed to act via calcium-calmodulin, also stimulated pepsinogen secretion, this system, too, presumably plays a substantial role. Thus the data support a dual 3':5'-cyclic adenosine monophosphate/calcium-calmodulin modulation of pepsinogen secretion.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1986

Evidence for nongastrin-mediated somatostatin inhibition of parietal cell function.

Somatostatin (SRIF), a tetradecapeptide, has been reported to suppress gastrin release and hence inhibit acid secretion in vivo. This study was performed to determine whether SRIF has any direct effect on parietal cell (PC). Isolated gastric cells were prepared by collagenase digestion and calcium chelation of rabbit fundic mucosa. PC enrichment (75% +/- 5%) was accomplished by velocity sedimentation with an elutriator rotor. Acid, as assessed by the accumulation of 14C-aminopyrine (AP) and macromolecular (intrinsic factor [IF]) secretion were used as markers of PC function. Cells were stimulated with histamine (H) (10(-6) mol/L). SRIF (10(-10) to 10(-6) mol/L) significantly inhibited H-stimulated 14C-AP accumulation (p less than 0.05). Inhibition of H-stimulated IF release was less sensitive, occurring at 10(-8) and 10(-7) mol/L (p less than 0.05), and loss of inhibition was observed at 10(-6) mol/L (p less than 0.05). These results demonstrate a direct inhibitory action of SRIF on PC secretion. The difference in inhibitory effect on IF and proton secretion is consistent with the postulation that SRIF may function at more than one site within the PC.

Aminopyrine↗
PubMed1986

A manganese-dependent protein kinase in gastric gland cytosol.

A protein kinase activity completely dependent on Mn2+ was studied in the cytosolic fraction from rabbit-isolated gastric glands. The manganese-dependent protein kinase (MNPK) activity phosphorylated major 33 kd (pp33) and minor 140 kd (pp140) endogenous proteins. The MNPK activity displayed a Kact for Mn2+ of 7.5 mmol/L. MNPK showed no preference for adenosine triphosphate or guanosine triphosphate with a Kact of 10 mumol/L for both. The kinase was differentiated from other known kinases since calmodulin, cyclic adenosine monophosphate, and phospholipids failed to stimulate pp33 phosphorylation. Furthermore, the protein kinase inhibitors trifluoperazine, the Walsh inhibitor protein, and heparin, as well as the phosphatase inhibitor p-nitrophenylphosphate failed to alter MNPK activity. The results indicate that novel MNPK activity is present in gastric gland cytosol. Elucidation of intracellular protein kinase activities may provide insights into the regulation of gastric secretory process.

Animals↗
PubMed1985

The effects of cholecystokinin on parietal cell secretion in isolated gastric glands.

Cholecystokinin (CCK), a peptide hormone found in both gut and brain, shares amino acid homologies with gastrin and has previously been shown to stimulate gastric acid secretion in whole animal experiments. To investigate possible direct effects of CCK apart from extrinsic neural and hormonal influences, we have investigated the effects of the sulfated octapeptide of CCK (CCK-8) in rabbit isolated gastric glands using 14C-aminopyrine accumulation and intrinsic factor (IF) secretion as markers of parietal cell function. CCK-8 stimulated a significant increase (p less than 0.05) in IF secretion and 14C-aminopyrine accumulation. IF secretion was dose dependent for CCK concentrations from 10(-10)M to 10(-6)M. The combination of CCK (10(-6)M) and histamine (5 X 10(-5)M) elicited IF secretion greater than that of either agent alone. These results are similar to those observed for pentagastrin (10(-7)M), suggesting that the effects of CCK on parietal cell secretion may be due at least in part to a direct receptor-mediated parietal cell response to this agent.

Aminopyrine↗