bluuebunny/crossref_metadata_2025 huggingface dataset:
CNS actions of calcitonin gene-related peptide on gastric acid secretion in conscious dogs
Authors: Lenz H. J. , Hester S. E. , Saik R. P. , Brown M. R.
Published: December 2017

To determine the mechanisms of action of calcitonin gene-related peptide (CGRP) in inhibiting gastric acid secretion, we studied awake male beagle dogs fitted with a chronic intracerebroventricular cannula and a gastric fistula. Synthetic rat CGRP (10 pmol/kg to 10 nmol/kg) given intracerebroventricularly or intravenously significantly inhibited pentagastrin-stimulated gastric acid secretion. CGRP (1 nmol/kg) given intracerebroventricularly decreased acid secretion stimulated by 2-deoxy-D-glucose but not by histamine. CGRP-(1–14), [Tyr23]CGRP-(23–37), and [acetamidomethyl-Cys2,7]CGRP, the linear peptide molecule devoid of the disulfide bridge, did not affect gastric secretion. Ganglionic blockade with chlorisondamine, a vasopressin antagonist, naloxone, and truncal vagotomy did not abolish the gastric inhibitory action of CGRP given intracerebroventricularly. CGRP administered intracerebroventricularly and intravenously decreased gastric acid secretion, but not plasma gastrin concentrations stimulated by an 8% peptone meal. It is concluded that CGRP given intracerebroventricularly or intravenously inhibits gastric acid secretion in conscious dogs; the intact molecule appears to be necessary for biological activity; and inhibition of gastric acid secretion by CGRP in the dog is not mediated by the autonomic nervous system or vasopressin-, opiate-, or gastrin-dependent pathways.
Distribution of epidermal growth factor binding sites in the adult rat liver
Authors: Chabot J. G. , Walker P. , Pelletier G.
Published: December 2017

The localization of epidermal growth factor (EGF) receptors was studied in the liver by use of light microscope autoradiography performed at different time intervals (2–60 min) after intravenous injection of 125I-EGF into adult rat. The results revealed a substantial binding of EGF to parenchymal cells of the liver. Control experiments indicated that the autoradiographic labeling was due to specific interaction of 125I-EGF with its receptor. A very steep portal-to-central lobular concentration gradient for 125I-EGF uptake was observed. The time course study performed on parenchymal cells of periportal regions of lobules showed that, at the 2-min time interval, most silver grains were found at the periphery of these cells and that the maximal values were reached 7 min after injection. After, the number of grains decreased progressively and their localization in the cytoplasm indicated the internalization of the ligand. The present results demonstrate that EGF injected into the general circulation preferentially binds to hepatocytes located in the periportal area and is rapidly internalized.
Potassium selectivity of frog gastric luminal membrane
Authors: Kasbekar D. K.
Published: December 2017

Transmural potential difference (PD) and resistance (R) changes after luminal or serosal instillation of K+ were determined under various conditions in chambered preparations of frog gastric mucosae. Potassium selectivity of the luminal membrane is indicated by the rapid reversal of the inverted PD of mucosae bathed in NaCl-free, choline sulfate (Ch2SO4)-Ringer on the serosal side and unbuffered hypertonic Ch2SO4 solution on the luminal side on luminal K+ instillation. The delta PD responses are significantly attenuated, however, in histamine-stimulated mucosae bathed in hypotonic or in burimamide-inhibited mucosae bathed in hyper- and hypotonic luminal media, which suggests that the K+ selectivity of the luminal membrane resides largely in the tubular cell apical membrane. Imposing a serosal-to-luminal transmucosal K+ gradient in both histamine-stimulated and omeprazole-inhibited mucosae also reversed the normal orientation of PD but not in those inhibited with burimamide. In the latter, the PD inversion was attenuated but maintained its normal orientation. These data suggest that burimamide, but not omeprazole, acts by blocking luminal membrane K+ conductance. The inverted PD in mucosae bathed in Cl-free media may thus be due partially or fully to K+ diffusion driven by the cell-to-lumen K+ gradient via the luminal K+ conductance pathway. These findings have implications for the controversy surrounding the postulated electrogenicity of the gastric proton pump.
Absorption of glucose polymers from canine jejunum deprived of pancreatic amylase
Authors: Kerzner B. , Sloan H. R. , McClung H. J. , Chidi C. C. , Ailabouni A. H. , Seckel C.
Published: December 2017

We evaluated the absorption of glucose polymers in canine jejunal Thiry-Vella fistulas proven to be free of pancreatic amylase. Medium-length oligomers with degrees of polymerization of 6 through 10 glucose units (DP 6–10) and long-chain material (DPavg23) were isolated from a cornstarch hydrolysate. We perfused 90, 180, and 360 mg/dl solutions of glucose, DP 6–10, and DPavg23 at 0.4, 1.9, and 3.4 ml/min. At all perfusion rates carbohydrate absorption decreased as the chain length of the oligomers increased, and these differences persisted even at the slowest perfusion rate employed. In two additional animals the fistulas were perfused at 3.4 ml/min with the three test carbohydrates at concentrations of 90, 180, 225, 270, 315, 360, 405, and 450 mg/dl. At this flow rate, the assimilative process of DP 6–10 and the long-chain fraction appeared to be saturated at carbohydrate concentrations above 360 mg/dl, whereas the absorption of glucose was linearly related to concentration throughout the range studied. With both groups of polymers, the fluid emerging from the fistula was virtually free of glucose, a finding that suggests that polymer digestion, not glucose absorption, is the rate-limiting step for polymer assimilation.
Effect of duodenal bile acid delivery on fasting intestinal motor activity
Authors: Scott R. B.
Published: December 2017

Fasting duodenal bile acid delivery is pulsatile and is cyclically coordinated with the duodenal migrating myoelectric complex (MMC). To determine whether duodenal bile acid delivery influences the duodenal cycle period (CP) of the MMC or the intensity of duodenal motor activity, three dogs were prepared with a duodenal cannula, permitting cannulation of the common bile duct, duodenal infusion, and manometry. CP was measured with the enterohepatic circulation intact and after the common bile duct was cannulated to divert endogenous bile from the duodenum during continuous duodenal infusion (1.6 ml/min) of 0, 2.5, 12.5, or 25 mM sodium taurocholic acid in 154 mM NaCl. During a second protocol with the enterohepatic circulation intact, a control and subsequent CP were measure, and a pulse (1 ml/min for 10 min) of pooled dog bile (112 mM total bile acids) or 0, 20, 80, or 140 mM sodium taurocholic acid in 154 mM NaCl was infused into the duodenum at 40% of the second CP (as estimated from control CP). A motility index was calculated for an interval commencing at 40% of the control CP and at the start of pulse infusion in the succeeding CP. There was no significant difference in CP with the enterohepatic circulation intact compared with that during continuous duodenal infusion of sodium taurocholic acid. There was no significant change in CP or motility index after premature pulse infusion of sodium taurocholic acid or pooled dog bile. Variation in duodenal bile acid delivery did not modulate intensity of duodenal motor activity or cycling of the MMC.
Endogenous prostaglandins in gastric alkaline response in the rat stomach after damage
Authors: Takeuchi K. , Ueki S. , Tanaka H.
Published: December 2017

A role of endogenous prostaglandins in gastric alkaline response (an increase of luminal pH) and functional recovery was investigated in the rat stomach after damage with acidified taurocholate (TC, 20 mM) or aspirin (ASA, 40 mM). Exposure of the stomach to TC or ASA similarly produced a transmucosal potential difference (PD) reduction and enhancement of H+ backdiffusion. The PD was restored gradually with time, and this process was much faster in the case of TC compared with ASA. After exposure to TC, acid secretion ceased and bicarbonate (0.5–1 mu eq/10 min) appeared in the lumen, whereas acid secretion persisted in the stomach exposed to ASA. However, in the presence of cimetidine (8 mg . kg-1 . h-1), these two agents produced a similar degree of luminal alkalinization (approximately 1 mu eq/10 min of HCO3-). Pretreatment with indomethacin (5 mg/kg, sc) significantly inhibited luminal alkalinization and PD recovery seen after exposure to TC. Concurrent administration of 16,16-dimethyl prostaglandin E2 (3 micrograms/kg, sc) antagonized the effects of indomethacin in stomachs exposed to TC and also unmasked luminal alkalinization and expedited the PD recovery in stomachs exposed to ASA. The levels of PGE2 and 6-keto-PGF1 alpha in the corpus mucosa were significantly increased in stomachs exposed to TC, but decreased in those exposed to ASA. These results indicate that luminal alkalinization of the stomach after damage with TC results from both an inhibition of acid secretion caused by endogenous prostaglandins and an increased appearance of HCO-3, and may play a role in functional recovery of the damaged mucosa. Gastric alkalinization seems to be a common phenomenon after exposure to mucosal damaging agents unless they have an inhibitory effect on prostaglandin biosynthesis.
New proglumide-analogue CCK receptor antagonists: very potent and selective for peripheral tissues
Authors: Niederau C. , Niederau M. , Williams J. A. , Grendell J. H.
Published: December 2017

The present study evaluates the ability of two recently synthesized analogues of proglumide, both 4-benzamido-N,N-di-alkyl-glutaramic acid derivatives, to act as cholecystokinin receptor antagonists. Both new antagonists inhibited cholecystokinin-stimulated amylase release and, similarly, binding of 125I-cholecystokinin to isolated rat pancreatic acini. These effects displayed competitive kinetics; both antagonists showed no agonist activity and were specific in that only those secretagogues were inhibited that interact with the cholecystokinin receptor. Both antagonists also inhibited binding of 125I-cholecystokinin to mouse pancreatic membrane particles similarly to results with rat pancreatic acini. With the more potent of the two new antagonists, half-maximal inhibition of action and binding of cholecystokinin was observed with low concentrations of approximately 10(-7) M; compared with proglumide, the new antagonists were as much as 4,000 times more potent. Unlike proglumide, which inhibits binding of cholecystokinin to pancreas and brain tissue similarly, both antagonists inhibited binding of cholecystokinin to the pancreas at much lower concentrations compared with brain. The more potent of the inhibitors was 300 times more potent in inhibiting binding of cholecystokinin to pancreatic tissues compared with brain.
Calcium absorption in rat large intestine in vivo: availability of dietary calcium
Authors: Ammann P. , Rizzoli R. , Fleisch H.
Published: December 2017

Calcium absorption in the large intestine of the rat was investigated in vivo. After a single injection of 45CaCl2 into the cecum, 26.0 +/- 2.5% (mean +/- SE, n = 9) of the 45CaCl2 injected disappeared. This absorption was modulated by 1,25-dihydroxyvitamin D3, increased to 64.0 +/- 4.2% under a low-Ca diet, and increased under low-Pi diet. In contrast, when the difference of nonradioactive Ca in the cecal content and the feces was measured, only 4.1 +/- 4.6% (not significant) was absorbed. Secretion of intravenously injected 45Ca into the lumen was small and not altered by any of the conditions tested. When cecum contents were placed into duodenal tied loops, 14 +/- 6.2% were absorbed in situ when 45Ca was given orally, whereas when 45Ca was directly added to the content 35.6 +/- 4.6% were absorbed (P less than 0.02). These results indicate that the large intestine has an important vitamin D-dependent Ca absorptive system detectable if 45Ca is injected into the cecum. However, it is not effective in vivo because the Ca arriving in the large intestine appears to be no longer in an absorbable form.
Dose-related effects of synthetic human beta-endorphin and naloxone on fed gastrointestinal motility
Authors: Camilleri M. , Malagelada J. R. , Stanghellini V. , Zinsmeister A. R. , Kao P. C. , Li C. H.
Published: December 2017

In humans, plasma beta-endorphin levels rise during application of acute stressful stimuli (vertigo, cold pain, and transcutaneous electrical stimulation) that induce gut motor disturbances. Whereas it is possible that circulating beta-endorphin participates in the mediation of these central effects on gut motility, its role cannot be established solely on the basis of changes in plasma levels. Therefore, we designed the present study to investigate 1) the dose-related effects of intravenous synthetic human beta-endorphin and naloxone on gastrointestinal pressure activity in fed healthy individuals; and 2) the interactions of the opiate agonist and antagonist. Infusion of beta-endorphin increased pyloric phasic pressure activity (P less than 0.001) and induced intestinal bursts of rhythmic activity (P less than 0.05) which interrupted normal fed motility. These effects were dose related, with the pyloric dose-response profile being essentially linear. The effects in the proximal intestine were obtained with doses of beta-endorphin at 250 ng X kg-1 X min-1 or greater. In the antrum, there was an overall reduction in phasic pressure activity (P less than 0.02), which was predominantly an effect of the highest dose of beta-endorphin infused (2,500 ng X kg-1 X min-1). Naloxone by itself had no significant effect on fed upper gut motility. However, naloxone significantly inhibited the effect of the lower doses of beta-endorphin on the pylorus. In addition, naloxone significantly reduced the probability of beta-endorphin, triggering intestinal bursts of rhythmic activity. These data suggest that beta-endorphin may play a humoral role in the stimulation of fed pyloric contraction at physiological levels.(ABSTRACT TRUNCATED AT 250 WORDS)
Plasma cholecystokinin and pancreatic growth during adaptation to dietary protein
Authors: Green Gary M. , Levan Van H. , Liddle Roger A.
Published: December 2017

Page G70: Gary M. Green, Van H. Levan, and Roger A. Liddle. “Plasma cholecystokinin and pancreatic growth during adaptation to dietary protein.” Page G70: sentence beginning on line 7, second column, should read “Therefore we hypothesized that increased dietary protein would raise plasma CCK levels only transiently, the levels returning to normal when pancreatic synthesis and secretion of proteases increased sufficiently to inhibit CCK release”.
Actions of vasoactive intestinal peptide and secretin on chief cells prepared from guinea pig stomach
Authors: Sutliff V. E. , Raufman J. P. , Jensen R. T. , Gardner J. D.
Published: December 2017

Vasoactive intestinal peptide and secretin increased cellular cAMP and pepsinogen secretion in dispersed chief cells from guinea pig gastric mucosa. With each peptide there was a close correlation between the dose-response curve for changes in cellular cAMP and that for changes in pepsinogen secretion. Vasoactive intestinal peptide-(10–28) and secretin-(5–27) had no agonist activity and antagonized the actions of vasoactive intestinal peptide and secretin on cellular cAMP and pepsinogen secretion. Studies of binding of 125I-vasoactive intestinal peptide and of 125I-secretin indicated that gastric chief cells possess four classes of binding sites for vasoactive intestinal peptide and secretin and that occupation of two of these classes of binding sites correlates with the abilities of vasoactive intestinal peptide and secretin to increase cellular cAMP and pepsinogen secretion. What function, if any, is mediated by occupation by the other two classes of binding sites remains to be determined.
Age-related changes in sodium-dependent glucose transport in rat small intestine
Authors: Freeman H. J. , Quamme G. A.
Published: December 2017

Brush-border membrane vesicles were purified from jejunoileal segments of rats ranging from 3 to 156 wk. The kinetics of sodium-dependent glucose cotransport were studied under voltage-clamped, zero trans conditions over a wide range of cis-glucose concentrations (0.005-1.5 mM). Initial glucose uptake in brush-border membrane vesicles isolated from the proximal intestinal segment (50 cm from ligament of Treitz) of rats less than 7-8 wk of age demonstrated a distinct curvilinear Hofstee plot consistent with multiple-transport mechanisms. One system possessed an apparent Vmax of 10.6 +/- 0.5 nmol X mg prot-1 X min-1 and Km of 630 +/- 18 microM. The second system was characterized by Vmax of 0.9 +/- 0.1 nmol X mg prot-1 X min-1 and Km of 12 +/- 1 microM. In contrast, the distal segment (50 cm to end of small intestine) possessed only one sodium-dependent glucose carrier system. The apparent Vmax and Km were 1.11 +/- 0.20 nmol X mg protein-1 X min-1 and 49 +/- 7 microM, respectively. Sodium-activation curves in the presence of 0.3 and 0.03 mM glucose were consistent with more than one sodium ion with both systems. In contrast, rats 12-13 wk old and older possessed both sodium-dependent transport systems in the proximal early and distal small intestine. The high-capacity system is more abundant in the proximal than the distal segment. These data suggest that, under these specific conditions, there are two sodium-dependent glucose carriers in the intestine of young rats: one located in the jejunum characterized by high capacity and low affinity, and the second located throughout the jejunoileum characterized by low capacity and high affinity. Furthermore with age there is a development of the low-affinity system in the distal segments so that both systems are found along the length of the jejunum and ileum. Accordingly, serial and parallel heterogeneity of sodium-dependent glucose transport exists along the small intestine.
Role of sodium ion in transport of folic acid in the small intestine
Authors: Zimmerman J. , Selhub J. , Rosenberg I. H.
Published: December 2017

The effect of sodium on folate transport across the intestinal luminal membrane was analyzed using two techniques: the "influx" chamber and isolated brush-border membrane vesicles. Preincubation of tissue in Na+-free medium did not have a consistent effect on folic acid influx provided that Na+ was present in the test solution. Replacement of Na+ in the test solution by choline+ resulted in a significant reduction of folic acid influx. However, when intestinal sheets that had been equilibrated in Na+-free solution were exposed to test solution containing either Na+, Li+, K+, Rb+, Cs+, Tris+, or guanidinium+ as main cations, folic acid influx was not significantly decreased. Concentration-dependence studies showed that replacement of Na+ by Rb+ did not affect the saturable mechanism of folate transport. Rather, a decrease in nonsaturable folic acid uptake accounted for the slightly reduced influx observed in the presence of Rb+. Experiments with brush-border membrane vesicles revealed that methotrexate uptake was significantly higher in the presence of external Na+ than in the presence of K+, but was not different from uptake in the presence of K+ plus valinomycin. These data suggest that the saturable component of folate transport is not Na+ dependent, and nonsaturable transport of folic acid across the luminal membrane occurs in part through a conductive pathway that involves a negatively charged species of folate and a cation whose membrane permeability affects the rate of folate transport. The importance of Na+ in this process in vivo derives from the fact that Na+ is the most permeant cation available at the absorptive site in the small intestine.
Role of thyroxine on postnatal development of ileal active bile salt transport
Authors: Heubi J. E.
Published: December 2017

The role of thyroid hormone on the postnatal development of ileal active taurocholate transport uptake was measured by an in vitro incubation technique in Sprague-Dawley rats. In 16-day-old rats treated with pharmacological doses of L-thyroxine (50 micrograms X 100 g body wt-1 X day-1 on days 10-13), ileal active transport appeared precociously whose Km was 1.60 +/- 0.48 mM and Vapp (apparent maximal velocity) was 8.09 +/- 1.14 nmol X min-1 X mg dry wt-1, while age-matched shams had only passive diffusion of taurocholate. To determine whether enhanced endogenous secretion of thyroxine was capable of stimulating development of ileal active taurocholate transport, thyrotrophic stimulating hormone (TSH) (0.5 U/100 g body wt twice daily) was given on days 10-13, with uptake measured on day 16. Following TSH treatment, only passive transport for taurocholate was observed in the ileum; uptake rates were consistently higher than those for untreated controls at each study concentration. Thyroidectomy performed at age 14 days with uptake measured at age 21 days did not ablate development of ileal active transport but resulted in a significant reduction (P less than 0.001) in the Vapp (7.39 +/- 1.10 nmol X min-1 X mg dry wt-1) and a significant increase (P less than 0.014) in Km (1.72 +/- 0.53 mM) compared with age-matched controls. Thyroid hormone does not appear to be obligatory for the postnatal development of ileal active taurocholate transport.
Muscarinic receptor subtypes on rat pancreatic acini: secretion and binding studies
Authors: Louie D. S. , Owyang C.
Published: December 2017

Characterization of muscarinic receptor subtypes on rat pancreatic acinar cells was examined by using specific muscarinic receptor antagonists to study amylase secretion and binding of [N-methyl-3H]scopolamine ([3H]NMS). Rat pancreatic acini were dispersed in HEPES-Ringer buffer and incubated with acetylcholine +/- 4-diphenylacetoxy-N-methylpiperadine-methiodide (4-DAMP, a specific M2 muscarinic receptor antagonist) or +/- pirenzepine (a specific M1 muscarinic receptor antagonist). 4-DAMP (10(-9) to 10(-6) M) caused a progressive parallel rightward shift in the acetylcholine dose-response curve without a change in maximal amylase release. Only high concentrations of pirenzepine (10(-6) to 10(-4) M) caused a rightward shift in the dose-response curve to acetylcholine. Schild analysis of the data indicated an inhibitory constant (Ki) of 200 pM for 4-DAMP and 183 nM for pirenzepine. The slope of the Schild regression lines was not different from unity, suggesting competitive inhibition. Binding of 50 pM [3H]NMS was specific, rapid, and saturable. [3H]NMS binding was displaced by increasing concentrations of 4-DAMP or pirenzepine with apparent Ki's of 102 pM and 330 nM, respectively, and similar maximal binding levels of 60 fmol/mg prot. We have demonstrated that 4-DAMP has an approximately 1,000-fold greater potency than pirenzepine to inhibit amylase release and binding, indicating that cholinergic-stimulated amylase release from pancreatic acini is mediated by M2 muscarinic receptors.
Effect of Bt2cGMP on action of cholecystokinin in isolated perfused rat pancreas
Authors: Otsuki M. , Okabayashi Y. , Ohki A. , Nakamura T. , Tani S. , Fujii M. , Oka T. , Sankaran H. , Baba S.
Published: December 2017

We have examined the effects of Bt2cGMP on cholecystokinin stimulation of pancreatic exocrine secretion in the isolated perfused rat pancreas. Bt2cGMP produced a concentration-dependent inhibition of the stimulatory effects of cholecystokinin octapeptide (CCK-8, 100 pM) on both pancreatic juice flow and enzyme secretion. Adding 1 mM Bt2cGMP rapidly and completely abolished CCK-8-stimulated pancreatic juice and enzyme secretion. Adding 500 microM Bt2cGMP for 10 min at the termination of 1 nM of CCK-8 infusion caused an immediate and persistent inhibition of the residual response. In contrast, treatment with C-terminal CCK antiserum I had no influence on the residual response. To account for the ability of Bt2cGMP to function as a competitive antagonist of the action of CCK and the ability of the nucleotide to inhibit the residual stimulation caused by CCK, we feel that Bt2cGMP hindered the binding of CCK not only by reducing the association rate constant for hormone binding but also accelerating the dissociation rate.
Chromatographic and immunochemical studies on postsecretory processing of gastrin in the pig
Authors: Power D. M. , Bunnett N. , Dimaline R.
Published: December 2017

Immunoreactive forms of gastrin in antral mucosal extracts and in gastric venous plasma of the pig were compared using ion-exchange and gel-filtration chromatography and radioimmunoassay using three region-specific antiserums. In antral mucosal extracts, gastrin heptadecapeptide (G-17) accounted for over 90% of the total C-terminal immunoreactivity, but in gastric venous plasma it accounted for only 47% of total C-terminal immunoreactivity. The remaining C-terminal immunoreactivity was accounted for by shorter C-terminal forms. Unsulfated and sulfated G-17 contributed 44.1 and 49.2%, respectively, of C-terminal immunoreactivity in antral mucosa. In contrast, they contributed 14 and 30%, respectively, to total C-terminal immunoreactivity in gastric venous plasma. Incubation of antral extracts with plasma in vitro resulted in a slow loss of intact G-17 (32.3% in 60 min) that could not account for the production of C-terminal fragments in vivo. Moreover, when antral extracts were infused into the gastroepiploic artery, over 90% of the gastrin present in the antral venous outflow corresponded to G-17. These observations suggest that it is unlikely that enzymes involved in the generation of the C-terminal forms are located either in blood or on the luminal side of the endothelial membrane. It is proposed, then, that antral gastrin is converted into shorter C-terminal fragments at or before the time it enters the circulation and that the major storage forms of gastrin in tissue account for less than 50% of the material in the gastric venous outflow.
Regional blood flow in newborn piglets during environmental cold stress
Authors: Mayfield S. R. , Stonestreet B. S. , Brubakk A. M. , Shaul P. W. , Oh W.
Published: December 2017

Regional blood flow, oxygen delivery, and vascular resistance were determined in newborn piglets during a successful homeothermic response to environmental cold stress. Eight 3- to 4-day-old awake piglets were studied in a thermoneutral environment and 30, 45, and 60 min after onset of environmental cold stress. During cold stress, blood flow was significantly increased to skeletal muscle, the thermogenic organ, and decreased to the small intestine (P less than 0.05). Because arterial oxygen content (CaO2) was stable during the study, changes in oxygen delivery (CaO2 X blood flow) paralleled blood flow. Vascular resistance during cold stress was significantly decreased in skeletal muscle and increased in both the adrenals and the small intestine (P less than 0.05). We conclude that, during successful thermogenesis, the redistribution of cardiac output toward the thermogenic organ (skeletal muscle) is associated with a significant decrease in intestinal blood flow and oxygen delivery. This is not a passive process as evidenced by the coincident observation of increased intestinal vascular resistance.
Acylcarnitines: drug absorption-enhancing agents in the gastrointestinal tract
Authors: Fix J. A. , Engle K. , Porter P. A. , Leppert P. S. , Selk S. J. , Gardner C. R. , Alexander J.
Published: December 2017

Acylcarnitines were tested as potential absorption-enhancing agents for drugs that are poorly absorbed from the gastrointestinal tract. Urethan-anesthetized Sprague-Dawley rats and conscious Beagle dogs were used. Palmitoyl-DL-carnitine was the most effective acylcarnitine tested, although significant increases in drug absorption were observed with acylcarnitines containing C12 through C18 fatty acid chains. Palmitoyl-DL-carnitine afforded significant increases in the absorption of cefoxitin, gentamicin, cytarabine, somatostatin analogue, and alpha-methyldopa. The response to palmitoyl-DL-carnitine was concentration dependent and reversible within 60-120 min. Histological examination of the intestinal tissue revealed no apparent change in mucosal structural integrity at doses of palmitoyl-DL-carnitine that resulted in increased drug absorption. The acylcarnitines were effective in increasing drug absorption from the small intestine and the rectal compartment of both rats and dogs. The data also demonstrated effectiveness with aqueous and solid dosage forms (Witepsol H-15 suppositories). The data suggest that acylcarnitines may be effective and safe absorption-enhancing agents for a variety of drugs.
Effect of food intake on intestinal cholesterol synthesis in rats
Authors: Feingold K. R. , Zsigmond G. , Lear S. R. , Moser A. H.
Published: December 2017

The mechanism by which diabetes results in an increase in small intestinal cholesterol synthesis is unknown. Previous studies have demonstrated that limiting food intake prevents the increase in intestinal cholesterol synthesis, and it has therefore been proposed that the stimulation of cholesterol synthesis in the small intestine is secondary to the hyperphagia that is associated with poorly controlled diabetes. To shed further light on the role of hyperphagia we have studied the effect on cholesterol synthesis of a variety of conditions that increase food intake. In third-trimester pregnant animals, lactating animals, obese animals, and in animals infused intragastrically with 16 g glucose/day vs. 8 g glucose/day, we have observed that an increase in food intake is associated with an increase in small intestinal cholesterol synthesis. Furthermore, these findings support the hypothesis that hyperphagia is the chief stimulus for the increase in cholesterol synthesis in the small intestine of diabetic animals. Additional studies have demonstrated that simply increasing the bulk of food ingested by adding Alphacel to the diet does not alter cholesterol synthesis in the small intestine. Lastly, in animals in whom Thiry fistulas were surgically constructed we observed that cholesterol synthesis is increased in the diabetic animals in both the segment of the small intestine in contact with the food stream and the segment of the small intestine that is excluded from contact. This observation suggests that the direct contact of the intestinal mucosa with caloric sources is not the sole trigger for increasing small intestinal cholesterol synthesis in hyperphagic diabetic animals.(ABSTRACT TRUNCATED AT 250 WORDS)
Preferential hepatic uptake of iron from rat asialotransferrin: possible engagement of two receptors
Authors: Rudolph J. R. , Regoeczi E. , Chindemi P. A. , Debanne M. T.
Published: December 2017

Hepatic iron uptake from and degradation of rat asialotransferrin prepared from the least anionic (major) component of rat transferrin were studied in intact rats. In experiments lasting 60-90 min, rat asialotransferrin delivered a three to four times larger fraction of the Fe dose to the liver than rat transferrin. Variations in the concentration of endogenous circulating rat 2Fe-transferrin by up to 300% failed to affect the enhanced hepatic delivery of Fe from rat asialotransferrin. However, pretreating the animals with a large dose of asialomucin, or fully sialylated human transferrin, or a combination of both did affect the delivery. In all cases, rat asialotransferrin delivered Fe to the liver at rates comparable with those seen with rat transferrin. The reason for the efficacy of human transferrin was clarified in competitive binding studies on rat hepatocytes and reticulocytes, which showed that human transferrin possessed an approximately sevenfold higher affinity for rat transferrin receptors than the homologous protein. These findings suggest that the enhanced hepatic uptake of Fe from rat asialotransferrin is mediated by simultaneous binding of the ligand both through its glycan and transferrin receptor affinity site. Pretreatment with asialomucin and human transferrin had no suppressing effect on basal hepatic delivery of iron from rat 2Fe-transferrin. The data suggest that deposition of a significant fraction of Fe in rat liver from rat transferrin is likely to take place by a mechanism not involving transferrin receptors. Desialylation shortened the metabolic half-life of rat transferrin from 33 to 24 h.(ABSTRACT TRUNCATED AT 250 WORDS)
Response of rat jejunum to changes in sodium and volume balance
Authors: Levens N. R.
Published: December 2017

Initial studies determined whether a renal factor facilitates decreased jejunal absorption following volume expansion of the anesthetized rat. Volume expansion (VE) decreased jejunal absorption to the same extent in both normal and nephrectomized animals. Furthermore, VE of a donor animal failed to alter jejunal absorption in a recipient following cross circulation. Thus, a hormonal factor is not implicated in the jejunal response to VE. Additional experiments demonstrated that rats ingesting a high-Na diet exhibited levels of jejunal absorption lower than animals fed a normal-Na diet. High-Na animals were not volume expanded. Plasma aldosterone concentrations and plasma renin activity were reduced in high-Na animals. Bilateral adrenalectomy-nephrectomy inhibited jejunal absorption. However, neither bilateral adrenalectomy nor bilateral nephrectomy alone inhibited jejunal absorption. Furthermore, inhibition of angiotensin formation in adrenalectomized animals failed to alter jejunal absorption. Decreased jejunal absorption in high-Na animals is not due to volume expansion or to inhibition of the renin-angiotensin-aldosterone axis.
Hepatic heme and drug metabolism in rats with chronic mountain sickness
Authors: Bonkovsky H. L. , Lincoln B. , Healey J. F. , Ou L. C. , Sinclair P. R. , Muller-Eberhard U.
Published: December 2017

Rats chronically exposed to hypobaric conditions develop pulmonary hypertension, right heart failure, hemoglobinemia, and in preliminary studies were recently found to have increased hepatic cytochrome P-450 content and activity of heme oxygenase, the rate-limiting enzyme for heme breakdown. To further delineate effects of chronic hypoxic, hypobaric exposure, on hepatic physiology and biochemistry, we have studied heme and drug metabolism in male Sprague-Dawley rats exposed to hypoxic conditions for 4-5 wk. Hypoxia, produced by exposure of rats to room air under hypobaric conditions (approximately 380 Torr), caused marked polycythemia [hematocrit (Hct) 70% vs. control Hct 43%], plasma hemoglobinemia, depletion of plasma haptoglobin, and decreased hemopexin concentrations. It also led to significant (20-30%) increases in concentrations of total hepatic heme and microsomal cytochrome P-450 and increased activities of heme oxygenase. In contrast, activity of 5-aminolevulinate synthase, the rate-limiting enzyme of hepatic heme synthesis, was significantly decreased in hypoxic rats and was not as inducible as in control normoxic rats. Hypoxia did not alter the rest of the heme synthetic pathway, as shown by a normal rate of conversion of 5-aminolevulinate to heme. Hypoxic exposure had no effect on the concentration of hepatic cytochrome-b5 but decreased activity of NADPH-cytochrome c reductase. Rates of metabolism of aminopyrine, benzphetamine, ethoxyresorufin, and warfarin were similar in hepatic microsomes obtained from hypoxic and normoxic rats. Thus the oxygen-requiring processes of hepatic heme and drug metabolism were well maintained despite chronic profound hypoxia sufficient to cause cardiopulmonary complications.
Folate binding and hydrolysis by pig intestinal brush-border membranes
Authors: Reisenauer A. M. , Chandler C. J. , Halsted C. H.
Published: December 2017

The intestinal absorption of dietary polyglutamyl folate involves hydrolysis, binding, and transport at the brush-border surface of the enterocyte. We studied the binding of [3H]folic acid ([3H]PteGlu) and the hydrolysis of [14C]pteroyltriglutamate ([14C]PteGlu3) by use of brush-border vesicles prepared from pig jejunal mucosa. [3H] PteGlu associated with the vesicles was not affected by increasing the osmolarity of the incubation solution, verifying that the experiments describe binding and not transport of PteGlu. The binding of [3H]PteGlu was saturable (Kd = 0.08 microM) and pH dependent with maximal binding at pH 5.2. Binding was competitively inhibited by PteGlu3 (Ki = 0.25 microM) and 5-methyltetrahydrofolate (Ki = 0.8 microM) but was not affected by components of the PteGlu molecule. ZnCl2, MgCl2, and MnCl2 enhanced the binding capacity but not the affinity of the binding component for PteGlu. We distinguished the processes of folate binding and hydrolysis by demonstrating differences in metal ion requirements and susceptibilities to various inhibitors. In addition, the binding component and the hydrolytic enzyme had distinct affinities for PteGlu (Ki = 45 microM for PteGlu3 hydrolysis). These data demonstrate pH-dependent, specific, and saturable binding of PteGlu to the intestinal brush-border membrane and suggest that the binding component is separate from the hydrolytic enzyme.
Stimulation of pancreatic acinar cell growth by CCK, epidermal growth factor, and insulin in vitro
Authors: Logsdon C. D.
Published: December 2017

Effects of regulatory molecules on growth of mouse pancreatic acinar cells in culture were examined. The cholecystokinin (CCK) analogue caerulein and cholecystokinin octapeptide (CCK-8) each led to threefold increases in incorporation of [3H]thymidine into DNA. Gastrin, which interacts weakly with the CCK receptor, stimulated DNA synthesis, but only at much higher concentrations. In contrast, other secretagogues that utilize Ca2+ as an intracellular messenger, including carbachol, bombesin, substance P, and the ionophore A23187, did not induce trophic responses. Factors that affect intracellular cAMP concentration, such as secretin, somatostatin, VIP, DBcAMP, and forskolin, did not increase DNA synthesis in cultured pancreatic cells. Insulin and epidermal growth factor induced two- and threefold increases in [3H] thymidine incorporation into DNA, respectively. The effects of insulin were mediated via insulin-like growth factor I receptors. Steroid hormones had little effect on pancreatic acinar cell DNA synthesis. The stimulatory effects of CCK, insulin, and EGF were additive. The combination of caerulein, EGF, and insulin in a hormonally defined medium led to a tenfold increase in the incorporation of [3H]thymidine into DNA. These data indicate that CCK, EGF, and insulin directly increase DNA synthesis in pancreatic acinar cells.
Effects of phorbol esters on sodium and chloride transport in rat colon
Authors: Donowitz M. , Cheng H. Y. , Sharp G. W.
Published: December 2017

To determine the role of protein kinase C in the regulation of active electrolyte transport in rat descending colon, the effects of phorbol dibutyrate (PDB) were studied using the Ussing chamber/voltage-clamp technique. PDB added to the serosal surface increased the short-circuit current in a concentration dependent manner with a EC50 of 3 X 10(-8) M and a maximal effect at 10(-7) M PDB. The effect was not seen with the inactive alpha-phorbol analogue but was reproduced with 1-oleoyl-2-acetylglycerol, a more permeable analogue of diacylglycerol. PDB caused a decrease in mucosal-to-serosal and net fluxes of Na and Cl and an increase in serosal-to-mucosal Cl flux, indicating inhibition of Na and Cl absorption and stimulation of Cl secretion. The PDB-induced increase in Cl secretion was virtually abolished by both indomethacin and ibuprofen, indicating a dependence on arachidonic acid metabolism via the cyclooxygenase pathway. The Cl secretion was inhibited by verapamil and Ca2+-free bathing solution on the serosal surface but not by dantrolene, suggesting the importance of extracellular Ca2+ but not intracellular stored Ca2+ in the PDB-induced secretion. The Cl secretory effect was also inhibited by tetrodotoxin and atropine, suggesting involvement of cholinergic nerves. In contrast, the PDB-induced decrease in Na and Cl absorption was not dependent on metabolites of the cyclooxygenase pathway, not dependent on extracellular Ca2+, and not blocked by tetrodotoxin. It appears likely that protein kinase C is involved in the regulation of rat colonic active Na and Cl absorption and electrogenic Cl secretion but that the pathways involved are different in the two transport systems.
Associations between transports of alanine and cations across cell membrane in rat hepatocytes
Authors: Kristensen L. O.
Published: December 2017

Alanine transport across the liver cell membrane is a regulated key process in the amino acid metabolism of the body. The majority of alanine influx in hepatocytes is Na+ dependent and is stimulated by intracellular negativity. The molar ratio between cotransported Na+ and alanine is 1:1. Alanine efflux is stimulated by intracellular Na+, whereas the role of the membrane potential is unclear. The transmembrane Na+ electrochemical gradient seems to be the exclusive driving force for cellular alanine accumulation. At a physiological Na+ gradient, intracellular alanine can exceed the extracellular concentration about 20-fold, but metabolism will exert a conspicuous sink effect. Na+-coupled uptake of alanine appears to be a challenge that triggers a sequence of regulatory events: increased cellular Na+ leads to an increase in active Na+-K+-pumping and thus in K+ influx; influx of alanine and cations tends to increase the cellular content of osmotically active substances implying a tendency to water uptake; cell swelling, even when modest, induces an increase in the permeability of a conductive pathway for K+ leading to net efflux of K+ (with accompanying anions) and cellular hyperpolarization. Net efflux of K+ prevents excessive cell volume increase during amino acid accumulation, whereas hyperpolarization tends to support the driving force for alanine influx (and anion efflux). The pathway for K+ efflux needs further characterization, but it may involve single-file diffusion with Ca2+ as an activator. This model suggests that cell volume regulatory processes mainly serve to compensate for changes in intracellular content of ions and metabolites during activation of specialized cellular processes.
Increased rate of de novo purine synthesis and its mechanism in regenerating rat liver
Authors: Itakura M. , Maeda N. , Tsuchiya M. , Yamashita K.
Published: December 2017

In regenerating rat liver at 12 h after a 70% hepatectomy, [14C]glycine incorporation to hepatic acid-soluble purines increased by 2.4-fold with a 26% increase of the mean rapidly miscible glycine pool size and its comparable turnover rate. Amidophosphoribosyltransferase (EC 2.4.2.14, ATase) activity increased 1.8-fold at 18 h and 5-phosphoribosyl-1-pyrophosphate (PRPP) concentration increased 3.0-fold at 12 h after surgery. Decreases in ATP and GTP concentrations of 13 and 15%, respectively, in regenerating rat liver at 12 h after surgery were counterbalanced by increased AMP and GMP concentrations of 13 and 44%, respectively, with comparable inhibitory potentials on ATase. These results suggest than an increased rate of de novo purine synthesis in regenerating rat liver is mediated by the increased ATase activity and PRPP concentrations.
Stimulation of growth of a colon cancer cell line by gastrin
Authors: Kusyk C. J. , McNiel N. O. , Johnson L. R.
Published: December 2017

A relation between duodenal myoelectric and motor activity and alkaline secretion has been investigated in conscious dogs under basal conditions and following vagal excitation with and without pretreatment with atropine or indomethacin. It was found that duodenal alkaline secretion shows typical periodicity in phase with the myoelectric or motor activity of the duodenum, reaching a peak during phase III and a nadir during phase I of the migrating motor complex (MMC). Sham feeding interrupted the motor and secretory MMC cycle and caused a prolonged increase in duodenal myoelectric or motor activity as well as a sudden and marked rise in duodenal alkaline secretion accompanied by a significant elevation in plasma gastrin and pancreatic polypeptide. Atropine and indomethacin abolished the motor and secretory duodenal cycles and reduced basal alkaline secretion significantly. Atropine abolished, whereas indomethacin increased duodenal myoelectric or motor activity during basal conditions and after vagal stimulation. Neither atropine nor indomethacin abolished sham feeding-induced duodenal alkaline secretion. We conclude that duodenal alkaline secretion fluctuates cyclically in phase with duodenal motility, vagal excitation results in a potent stimulation of duodenal motor and secretory activity, and the mechanism of vagally induced duodenal alkaline secretion is only partly cholinergic and does not involve endogenous generation of prostaglandins.
Receptors involved in helodermin action on rat pancreatic acini
Authors: Dehaye J. P. , Winand J. , Damien C. , Gomez F. , Poloczek P. , Robberecht P. , Vandermeers A. , Vandermeers-Piret M. C. , Stievenart M. , Christophe J.
Published: December 2017

Helodermin is a new peptide isolated from the venom of Heloderma suspectum. Its effects on rat pancreatic acini were compared with those of secretin and vasoactive intestinal peptide (VIP). Four classes of receptors with decreasing affinity for secretin (S1, S2, S3, and S4) were first delineated. Occupancy of S1 and S2 by secretin was responsible for a biphasic adenosine 3',5'-cyclic monophosphate (cAMP) response. S3 was VIP preferring so that the VIP-induced increase in cAMP could be inhibited by VIP-(10 --28). S2 and S3 allowed cAMP elevation, protein phosphorylation, weak secretory effects, and potentiation of cholecystokinin octapeptide (CCK-8) when occupied by secretin and VIP, respectively. A more efficient exocytosis was observed with secretin interacting with low-affinity receptors S4. Helodermin increased cAMP levels 14-fold, this increase being inhibited by VIP-(10–28). Low concentrations of helodermin stimulated amylase secretion twofold and potentiated secretion by CCK-8. High concentrations of helodermin stimulated secretion another 2.6-fold. Helodermin bound to the four secretin receptors with a weak selectivity. At low concentration, helodermin stimulated cAMP elevation, protein phosphorylation, amylase release, and potentiation of CCK-8 through S3, whereas at high concentration it stimulated secretion via S4.
Taurocholate transport and Na+-K+-ATPase activity in fetal and neonatal rat liver plasma membrane vesicles
Authors: Suchy F. J. , Bucuvalas J. C. , Goodrich A. L. , Moyer M. S. , Blitzer B. L.
Published: December 2017

The ontogenesis of Na+-K+-ATPase activity and Na+-taurocholate cotransport was studied in basolateral plasma membrane vesicles from fetal and neonatal rat liver. Membrane vesicles from each age group were 30-fold enriched in the basolateral marker enzyme Na+-K+-ATPase, 4- to 7-fold enriched in the bile canalicular membrane marker enzymes alkaline phosphatase and Mg2+ ATPase, and not significantly enriched in activities of marker enzymes for intracellular organelles. Na+-K+-ATPase activity was significantly lower in basolateral membranes from late fetal (day 21–22) and neonatal (day 1) rat liver. Kinetic analysis of Na+-K+-ATPase activity at various concentrations of ATP revealed that the maximum velocity of enzyme reaction (Vmax) for Na+-K+-ATPase was 70 and 90% of adult activity in the fetus and the neonate, respectively. The ATP Km was significantly lower in the neonate than the adult, suggesting a higher affinity of the neonatal enzyme for ATP. In contrast to the early maturation of Na+-K+-ATPase, transport of taurocholate was markedly lower in both fetal and neonatal vesicles compared with the adult. Taurocholate uptake on day 19 of gestation did not differ in the presence of a Na+ or K+ gradient, and uphill transport, as indicated by an overshoot, did not occur. On day 20 taurocholate uptake was stimulated by a Na+ compared with a K+ gradient, and accumulation of isotope above equilibrium was demonstrated. Na+-dependent transport of taurocholate by late fetal (day 22) and neonatal vesicles was saturable but the Vmax at each age was significantly lower and the apparent Km higher in developing compared with adult membrane vesicles.(ABSTRACT TRUNCATED AT 250 WORDS)