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Biomedical subjects

A H Soll

Publications and source records attributed to A H Soll.

At least 19 recordsLinked to original sources
PubMed1995

Different effects of indomethacin and nabumetone on prostaglandin-mediated gastric responses to central vagal activation in rats.

Intracisternal injection of a stable thyrotropin-releasing hormone (TRH) analog increases gastric prostaglandins release and mucosal resistance to injury through central vagal pathways. The effects of two nonsteroidal anti-inflammatory drugs, indomethacin (INDO) and nabumetone on intracisternal injection of various doses of TRH-induced gastric acid secretion and changes in mucosal resistance were investigated in urethane-anesthetized rats. Doses of INDO (5 mg/kg) and nabumetone (13.75 mg/kg) producing similar acute anti-inflammatory response in the carrageenin-induced paw edema were injected i.p. in all studies. INDO potentiated the acid secretion induced by intracisternal injection of TRH at 25, 50 and 200 ng by 5.1-, 1.9- and 1.4-fold, respectively, whereas nabumetone did not modify the secretory response to TRH. Moderate erosions were observed in 100% of rats treated with the combination of INDO and TRH (200 ng) whereas no erosions were observed when TRH or INDO were given alone or TRH in combination with nabumetone. TRH at 7 ng reduced mucosal damage induced by intragastric administration of ethanol (60%, 1 ml/kg) by 63%. The mucosal protective action of TRH was abolished by INDO but not altered by nabumetone pretreatment. These data indicate that at comparable anti-inflammatory doses, nabumetone, unlike INDO, neither blocks the protection against ethanol injury induced by low doses of TRH injected intracisternally nor potentiates the gastric acid secretion or lesions induced by higher dose of TRH. We speculate that these differences reflect reduced inhibition of gastric prostaglandins by nabumetone.

Animals↗
PubMed1994

Somatostatin is released in response to cholecystokinin by activation of type A CCK receptors.

Cholecystokinin is a principal mediator of intestinal fat-induced inhibition of gastric acid secretion, indicating that it is an important physiological enterogastrone. Cholecystokinin has been shown to inhibit acid secretion by activation of type A CCK receptors and through a mechanism involving somatostatin. In the present study, we investigated the possibility that these two mechanisms are directly related such that activation of type A CCK receptors by CCK causes the release of somatostatin. We tested this hypothesis in vivo in a study of CCK-stimulated release of somatostatin in dogs and in vitro in a study of CCK-stimulated release of somatostatin from an enriched culture of canine fundic D cells. In dogs, IV infusion of CCK (50 pmol/kg/h, IV) significantly increased circulating somatostatin concentrations above basal. Further, systemic administration of somatostatin MAb F(ab)1 fragments of a somatostatin monoclonal antibody prevented most of CCK-induced inhibition of meal-stimulated acid secretion. In canine fundic D cells in culture, CCK-stimulated somatostatin release was blocked in a dose-dependent fashion by application of a type A CCK receptor antagonist. This study indicates that CCK activates type A CCK receptors to release somatostatin from canine fundic mucosal D cells, and accounts for somatostatin-dependent CCK-induced inhibition of acid secretion.

Acids↗
PubMed1994

Effects of prostaglandins on gastrin release from canine antral mucosal cells in primary culture.

Evidence in vivo indicates that endogenous and exogenous prostaglandins can alter gastrin secretion. We have used primary cultures containing canine antral G-cells to study the cellular actions of prostaglandins on gastrin secretion, comparing the effects of prostaglandin E2 (PGE2) and its synthetic analogue enprostil. Enprostil (10(-10)-10(-6) M) inhibited gastrin secretion in response to bombesin, carbachol, and forskolin, the latter a receptor-independent activator of adenylate cyclase. This inhibition by enprostil was reversed by treatment with pertussis toxin (200 ng/ml, 8 h). However, enprostil did not inhibit the postreceptor stimuli 8-bromoadenosine 3',5'-cyclic monophosphate (10(-3) M), calcium ionophore A-23187 (10(-7) M), or 4 beta-phorbol 12-myristate 13-acetate (10(-8) M). In contrast, whereas PGE2 inhibited forskolin-stimulated gastrin release, PGE2 did not inhibit the response to carbachol or bombesin in control cultures. However, in pertussis toxin-treated cultures, PGE2 inhibition was reversed and, in contrast, the responses to bombesin, carbachol, and possibly forskolin were augmented. Indomethacin at a dose of 10(-5) M did not alter basal or bombesin-stimulated gastrin secretion. However, the somatostatin antibody CURE-S6 enhanced the response to forskolin and enhanced inhibition by PGE2, suggesting that endogenous somatostatin produced an inhibitory tone in these cultures and excluding the possibility that PGE2 acted via release of endogenous somatostatin. Our data suggest that in cultured antral cells gastrin release is regulated by inhibitory and stimulatory prostaglandin mechanisms.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylate Cyclase Toxin↗
PubMed1994

Apical acidification induces paracellular injury in canine gastric mucosal monolayers.

We used primary monolayer cultures of enzyme-dispersed canine oxyntic mucosal cells mounted in Ussing chambers to characterize the apical barrier to H+. [3H]mannitol flux (MF) and [14C]inulin flux (IF) were used as size probes for tight junctions. Apical H+ produced a three-phase effect. In phase 1, as the apical pH was decreased from 7 to about 2.5, resistance (R) increased, but short-circuit current (Isc) did not change. In phase 2, an increased paracellular permeability developed at pH below 2.5-1.7, evidenced by decreased R and increased MF but not IF. Size sieving and monolayer integrity were preserved, and this paracellular leak was either fully reversed or stabilized by apical neutralization, depending on the duration of the paracellular leak. In phase 3, after sustained exposure to an apical pH below approximately 2, transepithelial integrity was lost; R decreased to fluid R, and both MF and IF increased. Basolateral acidification below pH 5.5 produced rapid monolayer disruption. Low concentrations of cytochalasin D (CD) decreased R and increased MF but not IF; apical acidification to pH 4 after CD increased R and decreased the MF, indicating reduced paracellular permeability by apical H+. Apical amiloride did not alter Isc; however, after 48 h of treatment with hydrocortisone and insulin, an amiloride-sensitive Isc component became evident. Our data indicate that the increase in R observed with apical acidification reflects decreased paracellular permeability and that the earliest injury with apical acidification is a selective paracellular leak.

Animals↗
PubMed1994

Future directions for reductionistic research in gastric secretion and defense.

Our theme centers on the complex processes that constitute and regulate the function of the gastric mucosa. Although some investigators promote the critical importance of a given element, such as acid, blood flow, or mucus, it is clear that both gastric secretory function and mucosal defense and repair mechanisms are multifactorial and are regulated by redundant control circuits. While it is true that critical studies can be performed in vivo with intact mucosa, at the same time it is frequently difficult, using these methods, to define the specific cellular elements involved in the regulation of secretion, defense, and repair. We now recognize that ulcer disease does not occur simply when this balance is thrown off. To the contrary, ulcer disease commonly occurs when the normal mucosal mechanisms are perturbed by Helicobacter pylori-associated gastro-duodenitis or nonsteroidal anti-inflammatory drugs. In the absence of such perturbation, the redundancy of the regulatory mechanisms underlying gastric secretion and the multiple lines of defense and healing would render ulcer disease rare indeed.

Epithelium↗
PubMed1994

Multiple pathways controlling acid secretion.

A simple balance exists between factors that promote ulcer disease (e.g., acid and pepsin secretion) and factors that protect the stomach from ulcer disease (e.g., mucosal defense mechanisms). These factors are regulated and control the integrity of the gastric mucosa. Some of the newest discoveries in the area of regulation of acid secretion are related to the cellular localization of physiologically relevant receptors for acid secretagogues and acid inhibitors. The ability to isolate and culture histamine-containing ECL cells and somatostatin-containing "D" cells, and the ability to clone genes encoding for specific receptors has greatly enhanced our understanding of the physiological role and the regulation of various cell types within the gastric mucosa.

Cells, Cultured↗
PubMed1993

Endogenous somatostatin inhibits histamine release from canine gastric mucosal cells in primary culture.

The effects of somatostatin on histamine release were studied using primary cultures of canine oxyntic mucosal cells in which mast cell content was reduced by density gradient. The S6 monoclonal antibody to somatostatin, but not control antibodies, enhanced gastrin-stimulated histamine release. In the presence of S6, the somatostatin analogue SMS-201-995 (10(-7) M) inhibited gastrin-stimulated histamine release by 95%. The dose producing 50% inhibition for this inhibition was approximately 3 x 10(-10) M and was completely reversed by pertussis toxin treatment. In contrast to somatostatin, epinephrine failed to inhibit this gastrin stimulation. However, the lectin concanavalin A (ConA) also stimulated histamine release from these cultures, and this response was inhibited by epinephrine but not by somatostatin. Thus somatostatin selectively inhibited the gastrin-responsive histamine pool, which presumably is stored in oxyntic mucosal endocrine cells. In contrast, epinephrine selectively inhibits histamine release from the ConA-sensitive pool, which is presumably stored in mast cells. Furthermore, enhancement of gastrin-stimulated histamine release by immunoneutralization of somatostatin indicates an important role for endogenous somatostatin as a paracrine inhibitor of non-mast cell histamine release.

Animals↗
PubMed1992

Gastrin induction of histamine release from primary cultures of canine oxyntic mucosal cells.

Using enzyme-dispersed canine oxyntic mucosal cells, we studied regulation of histamine release from fractions in which mast cells were largely removed by density gradient. Histamine-like immunoreactivity was demonstrated using peroxidase-anti-peroxidase immunohistochemistry. Histamine-containing cells in the small cell elutriator fractions (SCEF) were further separated by albumin step density gradients. Approximately 2.5% of cells in the low density fraction (LDF) contained histamine-like immunoreactivity; this fraction was largely depleted of the more dense mast cells (0.5%). These two fractions were cultured for 48-64 h on a Matrigel substrate. The cell content of histamine and release into the medium were measured by radioenzymatic assay. Gastrin, carbachol, and forskolin increased histamine release from the LDF. The induction of histamine release by gastrin was evident within 5 min and was sustained for at least 60 min. The response to gastrin was dose dependent between concentrations of 10(-11) and 10(-8) M. In contrast, in the mast cell-enriched SCEF, basal release was higher and gastrin was without effect; however, concanavalin A stimulated and epinephrine inhibited histamine release indicating that histamine-release mechanisms were intact in this fraction. Our methods provide a preparation of low density oxyntic mucosal histamine cells that demonstrate gastrin-responsive histamine release; we speculate that enterochromaffin-like cells account for this gastrin response.

Animals↗
PubMed1991

Nonsteroidal anti-inflammatory drugs and peptic ulcer disease.

Evidence has accumulated that nonsteroidal anti-inflammatory drugs (NSAIDs) cause clinically important gastroduodenal ulcers. The pathogenesis, which involves the impairment of mucosal resistance to injury in an acid-peptic environment, is multifactorial and controversial. Ulcers caused by NSAIDs can occur either in mucosa inflamed because of infection with Helicobacter pylori or in histologically normal mucosa. The use of these drugs has been linked to an unexpectedly high incidence of ulcer complications, and a history of peptic ulcer disease is common in such cases. Nonsteroidal anti-inflammatory drugs thus appear both to exacerbate an underlying peptic diathesis and to cause de novo ulcers. The association between the use of these drugs and ulcer complications is supported by ulcer prevalence data from cross-sectional studies, and by data from case-controlled and cohort studies, and from randomized, experimental trials. Drug-induced gastric ulcers have been prevented by misoprostol, but not by H2 blocker therapy. Several therapies have been reported to promote ulcer healing despite continued use of NSAIDs, but adequate controlled trials have not been done. Small gastric and duodenal ulcers readily heal, whereas larger gastric ulcers require vigorous and prolonged therapy. The relative efficacies of various therapies in preventing ulcers, healing ulcers, or preventing complications remain to be established.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1991

Mitogenic response of canine fundic epithelial cells in short-term culture to transforming growth factor alpha and insulinlike growth factor I.

We report methods allowing the culture of rapidly dividing gastric epithelial cells to investigate the regulation of mucosal cell replication. Cells from canine fundic mucosa were dispersed by enzyme treatment, enriched by filtration and elutriation, and cultured on collagen gel in DMEM/F12 medium. After 48 h, greater than 95% of the cells displayed immunoreactivity with antibody to cytokeratin, an epithelial marker. The cells formed confluent monolayers by 72 h with a transmembrane resistance of 1,600 ohm.cm2 when mounted in a Ussing chamber indicating retention of epithelial cell characteristics. Calf serum (0.1-2%) produced a dose-dependent mitogenic effect evident by increases in [3H]-thymidine incorporation into acid-precipitated material and in cell number. After an 18-24-h incubation with [3H]-thymidine, approximately 55% of the cells cultured in 2% serum showed evidence of DNA synthesis by autoradiography and all of the replicating cells were cytokeratin positive. Using comparable culture conditions, a similar proportion of cells incubated for 18-24 h with bromodeoxyuridine displayed nuclear anti-bromodeoxyuridine immunoreactivity, thus indicating that over half of the cells in these cultures synthesized DNA during this period. As with serum, epidermal growth factor and transforming growth factor alpha (TGF alpha) (10 pM to 1 nM), insulin (10 nM to 1 microM) and insulinlike growth factor-I (IGF-I, 1-100 nM) increased [3H]-thymidine uptake. The greater potency of IGF-I, compared to insulin, suggests the presence of IGF-I receptors. We conclude that this culture preparation is composed of fundic mucosal epithelial cells and contains a predominance of dividing epithelial cells. EGF/TGF alpha and IGF-I are potential factors directly regulating proliferation of fundic mucosal cells.

Animals↗
PubMed1991

Gastrin-histamine interactions: direct and paracrine elements.

The receptors mediating the physiologic actions of gastrin on acid secretion and growth have thus far not been localized to specific cells or fully characterized. Studies in canine fundic mucosa indicate that gastrin receptors are present on several cell types, including parietal cells and somatostatin cells. There is also increasing evidence for a gastrin-inducible pool of histamine in the fundic mucosa which is presumably stored in histamine-enterochromaffin-like cells. From the vantage point of studies in the canine fundic mucosa, the issue is no longer which cell type has the gastrin receptor but to sort out the mechanisms by which the effects of the gastrin receptors on endocrine/paracrine (histamine and somatostatin) cells and exocrine (parietal) cells are integrated to regulate secretory function and mucosal growth and differentiation.

Animals↗
PubMed1990

Dual modulation by adenosine of gastrin release from canine G-cells in primary culture.

The effects of adenosine on gastrin release were studied in enzymatically dispersed canine antral cells after 24-36 h in primary culture. We found two contrasting actions for adenosine: inhibition of forskolin-stimulated gastrin release and potentiation of bombesin-stimulated gastrin release. These actions appeared to be mediated by A1 and A2 receptors, respectively. Forskolin-stimulated gastrin release was reduced by adenosine and the A1-selective agonist N6-(L-2-phenylisopropyl)adenosine (L-PIA) but not by the A2-selective agonist 2-phenylaminoadenosine (CV 1808). This inhibition by adenosine was reversed by the preferential A1-receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) as well as by the nonselective adenosine receptor antagonist 8-phenyltheophylline (8-PT). Incubation of the cells with pertussis toxin (200 ng, 8 h) reversed the inhibition by adenosine. In contrast, bombesin stimulation of gastrin release was potentiated by adenosine and CV 1808 but not altered by L-PIA. This effect was enhanced by DPCPX and was not altered by treatment of cells with pertussis toxin. In the absence of exogenous adenosine, 8-PT and DPCPX produced a small increase in basal and stimulated gastrin release. These data suggest dual modulation by adenosine of G-cell function. A1 receptors inhibit adenosine 3,5'-cyclic monophosphate (cAMP)-mediated gastrin release via a pertussis toxin-sensitive mechanism, whereas A2 receptors potentiated the response to cAMP-independent stimuli of gastrin release. Enhancement of gastrin release by adenosine antagonists suggests functional restraint by endogenous adenosine.

Adenosine↗
PubMed1989

Canine enteric submucosal cultures: transmitter release from neurotensin-immunoreactive neurons.

A culture system of dispersed submucosal neurons from canine ileum has been developed. The neuronal nature of over 80% of the cells in culture was confirmed by positive staining with a neurofilament antibody. In this culture system, neurotensin-immunoreactive neurons constituted greater than 50% of the total cell population. Neurotensin immunoreactivity in these cells was chromatographically characterized as a single molecular form coeluting with synthetic neurotensin (1-13). We have assessed the release of immunoreactive neurotensin by stimulatory and inhibitory transmitters, and by post-receptor activators of cell function. Forskolin (10 microM), the calcium ionophore A23187 (100 nM), and the active phorbol ester beta-12 myristrate 13-acetate (10 nM), each significantly increased neurotensin release compared with basal peptide secretion. The concomitant application of ionophore and phorbol ester resulted in a marked increase in neurotensin release and this stimulatory response was inhibited over 70% by somatostatin (100 nM). Substance P (0.1-100 nM) caused a dose-dependent increase in neurotensin release. Somatostatin (100 nM) reduced maximal stimulation with 100 nM substance P by 79%. Our results suggest that this submucosal culture system represents an entirely new model for characterizing transmitter release from enteric neurons.

Animals↗
PubMed1989

Ulcers, nonsteroidal antiinflammatory drugs, and related matters.

This overview is intended to provide perspectives drawn from the proceedings of the Ulcer-Epidemiology Symposium reported in this supplement. This meeting was designed to review the epidemiology and risk factors underlying the development of acid/peptic diseases and to highlight the natural history and therapy of these disorders. These topics served as a focus for the meeting. A second goal was to consider the topics in the context of ulcer complications resulting from use of nonsteroidal antiinflammatory drugs. Although nonsteroidal antiinflammatory drugs are well known to cause gastric damage and ulcers and to lead to complications of preexisting peptic ulcers, the frequency and severity of the clinical problems resulting from their use and the efficacy of different modalities for prevention and treatment have only recently begun to be the subjects of careful analysis.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1989

Beta-adrenergic and prostanoid inhibition of canine fundic mucosal mast cells.

We examined regulation of histamine release from canine hepatic and fundic mucosal mast cells in short-term culture. We found that beta- but not alpha-adrenergic agonists markedly inhibited concanavalin A (ConA)-stimulated histamine release. Inhibition by epinephrine was reversed by the beta-antagonist propranolol, but not by the alpha-adrenergic antagonists phentolamine or yohimbine. The beta 2-selective antagonist ICI 115881 reversed the effects of epinephrine, whereas the beta 1-antagonists practolol and betaxolol had little effect. Prostaglandin E2 (PGE2), but not its analogue enprostil, inhibited ConA-stimulated histamine release. This difference may relate to the ability of PGE2, but not enprostil, to stimulate adenosine 3',5'-cyclic monophosphate (cAMP) production. Forskolin, cAMP analogues, and the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine also effectively inhibited ConA-stimulated histamine release. Neither adrenergic agonists nor PGE2 inhibited histamine release stimulated by the combination of phorbol 12-myristate-13-acetate plus the calcium ionophore A23187. These data suggest that inhibition was mediated via cAMP-dependent mechanisms and was exerted on primary cell activation, rather than on postreceptor activating events.

1-Methyl-3-isobutylxanthine↗