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Biomedical subjects

D W Mercer

Publications and source records attributed to D W Mercer.

At least 37 records · Page 2Linked to original sources
PubMed1996

Cholecystokinin-induced protection against gastric injury is independent of endogenous somatostatin.

Cholecystokinin (CCK) prevents macroscopic injury to the stomach from luminal irritants by an unknown mechanism. The present study was undertaken in conscious rats to ascertain what role gastric mucosal blood flow, sensory neurons, and endogenous somatostatin play in CCK-induced gastric protection. Subcutaneous administration of CCK (10-100 micrograms/kg) significantly reduced macroscopic injury to the acid-secreting portion of the stomach caused by 1 ml of orally administered acidified ethanol (150 mM HCl, 50% ethanol) and augmented gastric mucosal blood flow (fluorescent microspheres) in a dose-dependent fashion. However, although the protective response to CCK (100 micrograms/kg) was still present at 2 h, the blood flow response had returned to baseline by 45 min. Ablation of capsaicin-sensitive afferent neurons with capsaicin (125 mg/kg sc) did not negate CCK-induced protection. Pretreatment with exogenous somatostatin (1 pmol-1 nmol/kg sc) failed to prevent the damaging effects of acidified ethanol to gastric mucosa. Immunoneutralization of endogenous somatostatin with somatostatin monoclonal antibody (2 mg ip) did not reverse the protective actions of CCK. Thus the data suggest that although CCK may prepare the gastric mucosa to withstand a damaging insult by augmenting gastric mucosal blood flow, its protective mechanism is independent of intact sensory neurons and endogenous somatostatin.

Animals↗
PubMed1995

Cholecystokinin is a potent protective agent against alcohol-induced gastric injury in the rat. Role of endogenous prostaglandins.

Cholecystokinin is a gastrointestinal hormone known to physiologically regulate pancreatic protein secretion and gallbladder contractility. Some evidence suggests that cholecystokinin is also involved in the maintenance of gastrointestinal mucosal integrity. This study was undertaken to ascertain whether cholecystokinin could prevent the gastric mucosal injury induced by acidified ethanol and what role prostaglandins, and type A and type B cholecystokinin receptors might play in this process. Conscious, fasted rats were given subcutaneous saline or cholecystokinin octapeptide (10-100 micrograms/kg) 30 min before a 1-ml oral gastric bolus of acidified ethanol (150 mM HCl/50% ethanol). Five minutes later, rats were sacrificed and the total area of macroscopic injury quantitated (square millimeters). In additional experiments using a similar protocol, 1 ml of either the cyclooxygenase inhibitor, indomethacin (5 mg/kg), a type A cholecystokinin receptor antagonist, L-364,718 (0.01-1 mg/kg), or the type B cholecystokinin receptor antagonist, L-365,260 (12.5-25 mg/kg) was given intraperitoneally 30 min prior to pretreatment with cholecystokinin octapeptide. Cholecystokinin octapeptide dose-dependently prevented mucosal injury from acidified ethanol (corroborated by histology). The protective effect of cholecystokinin octapeptide was completely negated by L-364,718 and partially reversed by indomethacin, while L-365,260 had no discernible effect in this process. In a further study, cholecystokinin was unable to prevent the damaging effects of aspirin and the inhibition of endogenous prostaglandins. This, it appears that cholecystokinin is able to maintain mucosal integrity in the face of a damaging insult by activation of type A cholecystokinin receptors, an effect mediated, at least in part, through the release of endogenous prostaglandins.

Animals↗
PubMed1995

Isoproterenol-induced gastric mucosal protection from bile acid. Role of endogenous prostaglandins.

Topical isoproterenol is a potent protective agent against bile acid-induced gastric mucosal injury in hypotensive and normotensive rats. This study was undertaken to ascertain what role endogenous prostaglandins and gastric mucosal blood flow play in isoproterenol-induced protection. Accordingly, anesthetized, fasted rats were given the cyclooxygenase inhibitor, indomethacin (5 mg/kg subcutaneously), 30 min prior to topical pretreatment with 3 ml of intragastric saline, isoproterenol (3 microM), or 16,16-dimethyl prostaglandin E2 (3 microM) for 15 min. Gastric injury was induced with topical 5 mM acidified taurocholate and damage assessed by measuring net transmucosal ion fluxes, the appearance of DNA into the gastric lumen, and histology of the gastric epithelium. In a separate set of experiments, the effects of topical isoproterenol on gastric mucosal blood flow (laser Doppler flowmetry) and luminal PGE2 concentrations (125I radioimmunoassay) were examined. Pretreatment with topical isoproterenol or 16,16-dimethyl prostaglandin E2 significantly decreased bile acid-induced net luminal ion fluxes and DNA accumulation, suggesting mucosal protection. The protective effect of isoproterenol, but not 16,16-dimethyl prostaglandin E2, was negated by indomethacin (corroborated by histology). Further, isoproterenol did not significantly alter gastric mucosal blood flow, but did augment luminal PGE2 concentrations, an effect also abolished by indomethacin. Thus, isoproterenol appears to protect the gastric mucosa from the damaging effects of bile acid through a mechanism that requires the synthesis and release of cytoprotective endogenous prostaglandins.

16,16-Dimethylprostaglandin E2↗
PubMed1995

Stimulation of Na(+)-K(+)-ATPase by thyrotropin in cultured thyroid follicular cells.

Thyroid-stimulating hormone (TSH; thyrotropin) produces a pleiotropic response in the thyroid gland, accelerating nearly every aspect of metabolic turnover within the follicular epithelia. We examined the effects of TSH on expression of Na(+)-K(+)-ATPase in FRTL-5 cells, a cell line derived from rat thyroid. TSH (10 mU/ml) produced a nearly twofold increase in abundance of the mRNA encoding the catalytic alpha 1-subunit within 6 h of treatment. With the four mRNAs encoding the beta 1-subunit, TSH produced a striking increase in abundance, but this regulation was discoordinate, and some species increased more than others. Similar increases in mRNA abundance were elicited by activators of the adenosine 3',5'-cyclic monophosphate second messenger system. In contrast to the alpha 1- and beta 1-mRNAs, the abundance of the mRNA encoding the beta 2-subunit was unchanged with TSH after 6 h, indicating that the effects of thyrotropin were not universal or indiscriminate. Thyrotropin also caused a 76% increase in Na(+)-K(+)-ATPase activity and a 46% increase in pump-mediated transport after 48 h. These studies suggest that the changes in metabolic turnover initiated by TSH during hormone synthesis include upregulation of the N(+)-K+ pump.

Animals↗
PubMed1995

Protective effect of a 21-aminosteroid against hemorrhage-induced ischemia-reperfusion injury in the rat stomach: role of lipid peroxidation.

We investigated the role that lipid peroxidation plays in a hemorrhage-induced ischemia-reperfusion model of gastric injury. Rats were pretreated with an inhibitor of this process, a 21-aminosteroid (U-74389G, 10 mg/kg), or an appropriate control solution intravenously 15 min prior to 20 min of ischemia, followed by 20 min of reperfusion. Results indicated that U-74389G pretreatment significantly attenuated gastric damage compared with corresponding control animals (19.8 vs. 176.8 mm2, p < .001). Enaldehyde levels (picomoles/mg protein), a biochemical index of lipid peroxidation, paralleled these injury findings (12 vs 960, p < .001). Histologically, U-74389G pretreatment almost completely prevented gastric injury compared to control stomachs. Additional studies revealed that lipid peroxidation preceded the formation of gastric damage, and injury occurred predominantly during reperfusion, because animals subjected to ischemia alone without reperfusion failed to develop appreciable injury or enhanced enaldehyde formation. Further, if U-74389G was given intravenously after ischemia, but prior to reperfusion, gastric injury and enaldehyde formation were similarly attenuated. Our findings are consistent with the hypothesis that lipid peroxidation likely plays an important role in hemorrhage-induced ischemia-reperfusion injury to the stomach.

Animals↗
PubMed1994

Topical prostaglandin E2 and isoproterenol reduce bile acid-induced gastric mucosal injury in shocked rats.

In shocked animals, topical application of bile acids at low pH to gastric mucosa results in gross mucosal injury. Both systemic prostaglandins and isoproterenol reduce this injury, but side effects may limit their clinical usefulness. The purpose of this study was to determine the effect of topical pretreatment with isoproterenol and prostaglandin E2 on gastric mucosal injury induced by low concentrations of bile acid in shocked and normotensive rats. Mucosal injury was assessed by measuring net transmucosal ion fluxes (H+,K+) and luminal accumulation of DNA (DNAE), a sensitive and specific indicator of gastric mucosal cell exfoliation. In this model of mucosal injury, pretreatment with prostaglandin E2 or isoproterenol significantly and dose dependently decreased luminal hydrogen loss, potassium gain, and DNA accumulation in both shocked and normotensive animals. Thus, both topical prostaglandin E2 and isoproterenol reduce gastric mucosal injury caused by low concentrations of bile acid in shocked and normotensive rats, findings corroborated by histology. These findings provide a physiologic basis for the possible use of these agents as prophylaxis or treatment of stress gastritis and gastroduodenal ulcer in the critically ill patient.

Administration, Topical↗
PubMed1994

Sensory neuron-mediated gastric mucosal protection is blocked by cyclooxygenase inhibition.

BACKGROUND: Sensory neurons have been proposed to play a critical role in the protection of the gastric mucosa from a variety of necrotizing agents. The purposes of this study were (1) to investigate the effect of topical capsaicin, a sensory neuron stimulant, on the gastric mucosal injury caused by the topical application of low concentrations of bile acid and (2) to determine whether local neuronal blockade with topical lidocaine or cyclooxygenase blockade with systemic indomethacin has any effect during pretreatment with capsaicin. METHODS: Before injury with topical 5 mmol/L acidified taurocholate (pH 1.2) rat stomachs were pretreated with either vehicle or capsaicin (160 mmol/L), both with and without prior administration of either lidocaine (1%) or indomethacin (5 mg/kg subcutaneously). Injury was assessed by measuring net transmucosal ion fluxes, the appearance of deoxyribonucleic acid into the gastric lumen, and gross and histologic injury scores. RESULTS: Pretreatment with topical capsaicin significantly (p < 0.05) decreased bile acid-induced net luminal ion fluxes and luminal deoxyribonucleic acid accumulation, an effect blocked by both lidocaine and indomethacin. CONCLUSIONS: Thus both local neuronal blockade and cyclooxygenase inhibition block the protective effect of capsaicin, findings corroborated by gross and histologic injury analysis. This study suggests that sensory neurons may mediate gastric mucosal protection from bile acid injury by increasing synthesis of endogenous prostaglandins.

Administration, Topical↗
PubMed1993

Effects of topical isoproterenol on bile acid-induced gastric mucosal injury.

Topical isoproterenol protects the gastric mucosa from the severe necrosis induced by 100 per cent ethanol. Its effect on gastric mucosal blood flow is unknown. The purpose of this study was to determine the effect of topical isoproterenol on gastric mucosal blood flow and on the less severe gastric mucosal injury caused by dilute bile acid. Prior to injury with topical 5 mM acidified taurocholate (pH 1.2), stomachs were pretreated with either saline or isoproterenol (low dose = 50 micrograms/kg; high dose = 500 micrograms/kg). Mucosal injury was assessed by measuring net transmucosal ion fluxes (H, K) and the appearance of DNA into the gastric lumen (DNAE). Gastric mucosal blood flow was determined by using laser doppler. Pretreatment with isoproterenol significantly decreased bile acid-induced net transmucosal ion fluxes and luminal accumulation of DNA, suggesting mucosal protection. Furthermore, this effect was dose-dependent on H and DNAE but not K. Pretreatment with topical high dose isoproterenol had no significant effect on gastric mucosal blood flow. Thus, topical pretreatment with isoproterenol dose dependently protects the gastric mucosa from the superficial injury caused by the application of dilute bile acid. This protective effect appears to be mediated by a mechanism other than augmentation of gastric mucosal blood flow.

Administration, Topical↗
PubMed1992

Anatomic considerations in penetrating gluteal wounds.

A retrospective study of 81 patients with penetrating gluteal wounds was performed to determine if the site of penetration was useful in predicting the likelihood of associated vascular or visceral injury. There were 53 gunshot wounds and 28 stab wounds, including one impalement. The gluteal region was divided into upper and lower zones by determining whether entry occurred above or below the greater trochanters. Sixty-six percent of all penetrating gluteal wounds entered the upper zone. Thirty-two percent of patients with upper zone penetration had associated vascular or visceral injury. Only one of 27 patients with lower zone penetration sustained major injury. The site of entry plays a critical role in determining the likelihood of serious injury associated with penetrating gluteal wounds. Wounds penetrating above the greater trochanters demand thorough evaluation, especially gunshot wounds.

Adolescent↗
PubMed1992

Do sensory neurons mediate adaptive cytoprotection of gastric mucosa against bile acid injury?

Pretreatment with the mild irritant 1 mmol acidified taurocholate protects the gastric mucosa from the injury induced by the subsequent application of 5 mmol acidified taurocholate, a phenomenon referred to as "adaptive cytoprotection." How this occurs remains an enigma. The purpose of this study was to investigate the role of sensory neurons and mucus secretion in this phenomenon. Prior to injury with 5 mmol acidified taurocholate (pH 1.2), the stomachs of six groups of rats were subjected to the following protocol. Two groups were topically pretreated with either saline or the mild irritant 1 mmol acidified taurocholate. Two other groups received the topical anesthetic 1% lidocaine prior to pretreatment with either saline or 1 mmol acidified taurocholate. The last two groups got the mucolytic agent 10% N-acetylcysteine (NAC) after pretreatment with either saline or 1 mmol acidified taurocholate. Injury was assessed by measuring net transmucosal ion fluxes, luminal appearance of deoxyribonucleic acid (DNA), and gross and histologic injury. Pretreatment with the mild irritant 1 mmol acidified taurocholate significantly decreased bile acid-induced luminal ion fluxes and DNA accumulation, suggesting mucosal protection (corroborated by gross and histologic injury analysis). This effect was negated by lidocaine but not by NAC. Thus, it appears that sensory neurons, and not increased mucus secretion, play a critical role in adaptive cytoprotection.

Acetylcysteine↗
PubMed1992

Selective lipoxygenase inhibitor reduces bile acid-induced gastric mucosal injury.

Leukotriene receptor blockade attenuates topical bile acid-induced gastric mucosal injury, suggesting that peptidyl-leukotrienes may be mediators of this injury. The purpose of this study was to test the hypothesis that a selective 5-lipoxygenase inhibitor protects against bile acid-induced gastric epithelial injury in the rat. Prior to injury with 10 and 20 mM acidified taurocholate (pH 1.2), rat stomachs were pretreated with either vehicle or WY50295K (selective 5-lipoxygenase inhibitor, 20 mg/kg). Injury was assessed by measuring net transmucosal hydrogen ion flux, luminal appearance of DNA, and gross mucosal injury. Topical 5-lipoxygenase inhibitor significantly reduced luminal H+ ion loss, surface epithelial cell loss (as measured by luminal accumulation of DNA), and gross mucosal injury in bile acid-injured stomachs compared to controls. This study lends further support to the hypothesis that leukotrienes may be mediators of bile acid-induced gastric mucosal injury.

Acids↗
PubMed1992

Do leukotrienes mediate bile acid-induced gastric mucosal injury?

Leukotrienes C4 and D4 are potent vasoconstrictors and have been proposed as mediators of the severe gastric mucosal injury caused by a variety of necrotizing agents. The purpose of this study was to investigate the role of leukotrienes on the less severe gastric mucosal injury caused by low concentrations of bile acid. Prior to injury with 5 mM acidified taurocholate (pH 1.2), rat stomachs were pretreated with either normal saline, leukotrienes C4 or D4 (10(-6), 10(-8), and 10(-9) M), or SKF-104353 (a leukotriene D4 receptor antagonist 10(-7) M). Injury was assessed by measuring net transmucosal hydrogen ion flux, luminal appearance of DNA, and histologic injury. Topical pretreatment with LTC4 and LTD4 significantly increased bile acid-induced luminal hydrogen ion loss and DNA accumulation in a dose-dependent manner. Leukotriene receptor blockade with SKF-104353 significantly decreased these parameters. Thus, both LTC4 and LTD4 exacerbate the gastric mucosal injury caused by the application of low concentrations of bile acid while leukotriene receptor blockade reduces this injury (corroborated by histologic injury analysis). This study suggests that leukotrienes may be mediators of bile acid-induced gastric mucosal injury.

Animals↗
PubMed1991

Leukotriene receptor blockade reduces bile acid-induced superficial gastric mucosal injury.

Leukotriene C4 and D4 are putative mediators of the severe gastric mucosal injury caused by a variety of topical irritants. The purpose of this present study was (1) to investigate the effect of pretreatment with topical leukotriene C4 and D4 on the more superficial injury caused by low concentrations of bile acid and (2) to determine the effect of leukotriene receptor blockade, alone and during leukotriene pretreatment, on this injury. Prior to injury with topical 5 mM acidified taurocholate (pH 1.2) rat stomachs were pretreated with either normal saline, leukotriene C4 or D4, SKF-104353 (a leukotriene receptor antagonist), SKF-104353/LTC4, or SKF-104353/LTD4. Injury was assessed by measuring hydrogen ion flux and DNA efflux, a marker of gastric mucosal cell exfoliation. Both LTC4 and LTD4 significantly increased bile acid-induced luminal hydrogen ion loss and DNA efflux. Leukotriene receptor blockade not only blocked this effect, but also significantly decreased the injury from bile acid alone. Thus, both LTC4 and LTD4 exacerbate the superficial gastric mucosal injury caused by physiologic concentrations of bile acids. Leukotriene receptor blockade with SKF-104353 completely blocks these effects and reduces injury from bile acid alone.

Animals↗
PubMed1990

Serum isoenzymes in cancer diagnosis and management.

The 10 isoenzyme markers discussed here represent those that in the author's judgment show promise as effective tumor markers. The relative usefulness of these isoenzymes as tumor markers is summarized in Table 6. Each isoenzyme is evaluated by a rating system, with a scale of 0-5 points in each of seven categories. The hypothetical ideal tumor marker received 5 points in all seven categories for a total score of 35. Unfortunately, less than perfect scores ranging from 9 to 26 were found for the 10 isoenzymes evaluated here. The five best isoenzymes were neuron-specific enolase (26 points), prostatic acid phosphatase (23 points), placental alkaline phosphatase (20 points), thymidine kinase 1 (16 points), and lactate dehydrogenase 1 (16 points). In general, low isoenzyme scores can be attributed to the problems exhibited by all tumor markers: insensitivity to early-stage malignancies and false-positive elevations in nonmalignant diseases. Nevertheless, each of the 10 isoenzymes described here has potential clinical usefulness to support a diagnosis of cancer and/or to assist in the monitoring of therapy.

Biomarkers, Tumor↗
PubMed1990

Adaptive cytoprotection of gastric surface epithelial cells against injury by physiologic concentrations of bile acid.

The purpose of this study was to determine whether adaptive cytoprotection of gastric mucosa could be demonstrated with concentrations of bile acid, which is normally found in the human stomach, and whether cyclooxygenase inhibition, in turn, could blunt the response. Surface epithelial cell exfoliation and ion fluxes were used as end points. A transduodenal gastric cannula was placed, and the pylorus/gastroesophageal junction was ligated in adult male Sprague-Dawley rats that had been anesthetized. In experiment 1 (N = 30), rat stomachs were exposed for 15 minutes to 5 ml of either a neutral test solution (160 mmol/L NaCl, pH 7) or 1 mmol/L acidified taurocholate (ATC) (100 mmol/L HCl, 60 mmol/L NaCl, 1 mmol/L taurocholic acid; pH 1.2). All rats were subsequently exposed for 15 minutes to 5 mmol/L ATC during which time mucosal injury was assessed by measuring net flux of H+, Na+, and K+, volume, and DNA efflux. In experiment 2 (N = 35), all stomachs were pretreated for 15 minutes with 1 mmol/L ATC before mucosal injury with 5 mmol/L ATC (15 minutes). Eighteen rats were pretreated with indomethacin (5 mg/kg) subcutaneously 75 minutes before the experiment was begun, and the same parameters were measured. Pretreatment of rat gastric mucosa with 1 mmol/L ATC significantly attenuated the mucosal injury that was seen with subsequent exposure to 5 mmol/L ATC, resulting in significantly (p less than 0.05) less luminal H+ loss (-16 +/- 4 vs -32 +/- 4 mEq/15 min) and DNA efflux (181 +/- 21 vs 270 +/- 25 micrograms/15 min) than the nonadapted group. Indomethacin pretreatment significantly attenuated the adaptive protective response, resulting in greater loss of H+ (-29 +/- 4 vs -18 +/- 3) and DNA efflux (190 +/- 35 vs 110 +/- 18, both p less than 0.05) after exposure to 5 mmol/L ATC. These studies demonstrate that adaptive cytoprotection of gastric mucosa occurs with physiologic concentrations of an irritant that is normally present in the stomach. Indomethacin blunts this effect, which suggests that adaptive cytoprotection in this setting may be mediated by production of endogenous prostaglandins.

Acids↗