| 1. |
- Webb, Dominic-Luc, et al.
(author)
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The type 2 CCK/gastrin receptor antagonist YF476 acutely prevents NSAID-induced gastric ulceration while increasing iNOS expression
- 2013
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In: Naunyn-Schmiedeberg's Archives of Pharmacology. - : Springer Verlag (Germany). - 0028-1298 .- 1432-1912. ; 386:1, s. 41-49
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Journal article (peer-reviewed)abstract
- YF476 differs from the proton pump inhibitor (PPI) esomeprazole in mode of action by antagonizing the type 2 receptor of cholecystokinin/gastrin (CCK-2R). YF476 protection against diclofenac-induced gastric ulcers was compared to esomeprazole and correlated with plasma levels of hormones related to gastric pH (gastrin, ghrelin, and somatostatin), gastric gene expression of these hormones, their receptors, and inducible nitric oxide synthase (iNOS). YF476 or esomeprazole pretreatments were followed by diclofenac. Four hours later, gastric tissue was excised and analyzed for ulcer index. An intragastrically implanted Bravo capsule measured pH for 5 days during YF476 plus pentagastrin treatment. Changes in gene expression were assayed for gastrin, ghrelin, and somatostatin; their receptors; and iNOS. YF476 acutely (within 4 h) protected against diclofenac-induced gastric ulcers equivalent to esomeprazole. Gastric pH recorded during 5 days in the presence of pentagastrin was 1.83 (+/- 0.06). YF476 raised pH to 3.67 (+/- 0.09) and plasma ghrelin, gastrin, and somatostatin increased. YF476 increased gene expression of somatostatin receptor and gastrin, while ghrelin receptor decreased; transcripts coding ghrelin, somatostatin, and CCK-2R remained unchanged. In the presence of diclofenac, esomeprazole increased expression of all these transcripts and that of iNOS, while YF476 yielded only decreased CCK-2R and increased iNOS transcripts. YF476 is a potential new preventative treatment for patients at risk of nonsteroidal antiinflammatory drug (NSAID)-induced ulceration. Gastric gene expressions of ghrelin, gastrin, and somatostatin and their receptors differ between esomeprazole and YF476. Despite these differences and different modes of action to raise gastric pH, both drugs acutely increase iNOS, suggesting iNOS expression parallels pH.
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| 2. |
- Rudholm, Tobias, et al.
(author)
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Bravo capsule system optimizes intragastric pH monitoring over prolonged time : Effects of ghrelin on gastric acid and hormone secretion in the rat
- 2008
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In: World Journal of Gastroenterology. - : Baishideng Publishing Group Inc.. - 1007-9327 .- 2219-2840. ; 14:40, s. 6180-6187
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Journal article (peer-reviewed)abstract
- Aim: To evaluate measurements of intragastric pH with the Bravo capsule system over a prolonged time. Methods: A Bravo capsule was placed inside the rat gastric body and pH was studied for periods up to five consecutive. days. For comparison, a gastric fistula model was used. Effects of ghrelin and esomeprazole, with or without pentagastrin, on gastric pH were studied. In addition, effects of esomeprazole on plasma ghrelin, gastrin and somatostatin were analyzed. Results: All rats recovered after surgery. The average 24-h pH during free feeding was 2.3 +/- 0.1 (n = 20) with a variation of 18% +/- 6% over 5 d. Ghrelin, 2400 pmol/kg, t.i.d. increased pH from 1.7 +/- 0.1 to 3.1 +/- 0.3 (P < 0.01) as recorded with the Bravo system. After esomeprazole (1 mg/kg, 3 mg/kg and 5 mg/kg) there was a dose-dependent pH increase of maximally 3.4 +/- 0.1, with day-to-day variation over the entire period of 8% +/- 3%. The fistula and pH studies generated similar results. Acid inhibition with esomeprazole increased plasma ghrelin from 10 +/- 2 pmol/L to 65 +/- 26 pmol/L (P < 0.001), and somatostatin from 10 +/- 2 pmol/L to 67 +/- 18 pmol/L (P < 0.001). Conclusion: pH measurements with the Bravo capsule are reliable, and comparable to those of the gastric fistula model. The Bravo system optimizes accurate intragastric pH monitoring over prolonged periods and allows both short- and long-term evaluation of effects of drugs and hormones.
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| 3. |
- Rudholm, Tobias, et al.
(author)
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Release of regulatory gut peptides somatostatin, neurotensin and vasoactive intestinal peptide by acid and hyperosmolal solutions in the intestine in conscious rats
- 2009
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In: Regulatory Peptides. - : Elsevier BV. - 0167-0115 .- 1873-1686. ; 152:1-3, s. 8-12
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Journal article (peer-reviewed)abstract
- The impact of exposure of the intestinal mucosa to acid and hyperosmolal solutions on the release of the inhibitory gut peptides somatostatin (SOM), neurotensin (NT) and vasoactive intestinal peptide (VIP) was studied in conscious rats during pentagastrin-stimulated gastric acid secretion. The animals were equipped with a chronic gastric fistula to measure acid secretion and a jejunal Thiry-Vella loop for intestinal challenge with saline, hydrochloric acid (HCl, 200 mmol L-1) or hyperosmolal polyethylene glycol (PEG, 1200 mOsm kg(-1)). Gut peptide concentrations were measured in intestinal perfusates, and in plasma samples collected during stimulated acid secretion, and at the end of experiments with luminal challenge of the loops. After pentagastrin-stimulation acid secretion was dose-dependently inhibited by intravenous administration of the gastrin receptor antagonist gastrazole, as well as ranitidine and esomeprazole by maximally 73 +/- 10%; 95 +/- 3%; 90 10%, respectively. Acid perfusion of the Thiry-Vella loop caused a prominent release of SOM both to the lumen (from 7.2 +/- 5.0 to 1279 +/- 580 pmol L-1) and to the circulation (from 18 +/- 5.2 to 51 +/- 9.0 pmol L-1) simultaneously with an inhibition of gastric acid secretion. The release of NTand VIP was not affected to the same extent. PEG perfusion of the loop caused a release of SOM as well as NT and VIP, but less. Simultaneously acid secretion was slightly decreased. In conclusion, intestinal perfusion with acid or hyperosmolal solutions mainly releases SOM, which seems to exert a major inhibitory action in the gut, as shown by inhibition of acid secretion. The other peptides NT and VIP also participate in this action but to a much lesser degree. The operative pathways of these gut peptides hence involve both endocrine (SOM) and paracrine actions (SOM, NT, VIP) in order to exert inhibitory functions on the stomach. The inhibitory action of gastrazole, was in a similar range as that of SOM implying that physiological acid-induced inhibition of gastric acid may primarily be exerted through inhibition of gastrin endocrine secretion.
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| 4. |
- Stridh, Sara, et al.
(author)
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Renal interstitial hyaluronan : functional aspects during normal and pathological conditions
- 2012
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In: American Journal of Physiology. Regulatory Integrative and Comparative Physiology. - : American Physiological Society. - 0363-6119 .- 1522-1490. ; 302:11, s. R1235-R1249
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Research review (peer-reviewed)abstract
- The glycosaminoglycan (GAG) hyaluronan (HA) is recognized as an important structural component of the extracellular matrix, but it also interacts with cells during embryonic development, wound healing, inflammation, and cancer; i.e., important features in normal and pathological conditions. The specific physico-chemical properties of HA enable a unique hydration capacity, and in the last decade it was revealed that in the interstitium of the renal medulla, where the HA content is very high, it changes rapidly depending on the body hydration status while the HA content of the cortex remains unchanged at very low amounts. The kidney, which regulates fluid balance, uses HA dynamically for the regulation of whole body fluid homeostasis. Renomedullary HA elevation occurs in response to hydration and during dehydration the opposite occurs. The HA-induced alterations in the physicochemical characteristics of the interstitial space affects fluid flux; i.e., reabsorption. Antidiuretic hormone, nitric oxide, angiotensin II, and prostaglandins are classical hormones/compounds involved in renal fluid handling and are important regulators of HA turnover during variations in hydration status. One major producer of HA in the kidney is the renomedullary interstitial cell, which displays receptors and/or synthesis enzymes for the hormones mentioned above. During several kidney disease states, such as ischemia-reperfusion injury, tubulointerstitial inflammation, renal transplant rejection, diabetes, and kidney stone formation, HA is upregulated, which contributes to an abnormal phenotype. In these situations, cytokines and other growth factors are important stimulators. The immunosuppressant agent cyclosporine A is nephrotoxic and induces HA accumulation, which could be involved in graft rejection and edema formation. The use of hyaluronidase to reduce pathologically overexpressed levels of tissue HA is a potential therapeutic tool since diuretics are less efficient in removing water bound to HA in the interstitium. Although the majority of data describing the role of HA originate from animal and cell studies, the available data from humans demonstrate that an upregulation of HA also occurs in diabetic kidneys, in transplant-rejected kidneys, and during acute tubular necrosis. This review summarizes the current knowledge regarding interstitial HA in the role of regulating kidney function during normal and pathological conditions. It encompasses mechanistic insights into the back-ground of the heterogeneous intrarenal distribution of HA; i.e., late nephrogenesis, its regulation during variations in hydration status, and its involvement during several pathological conditions. Changes in hyaluronan synthases, hyaluronidases, and binding receptor expression are discussed in parallel.
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| 5. |
- Stridh, Sara, 1983-, et al.
(author)
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Inhibition of hyaluronan synthesis in rats reduces renal ability to excrete fluid and electrolytes during acute hydration
- 2013
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In: Upsala Journal of Medical Sciences. - : Informa Healthcare / Upsala Medical Society. - 0300-9734 .- 2000-1967. ; 118:4, s. 217-221
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Journal article (peer-reviewed)abstract
- Background. Hyaluronan (HA) is the dominant glycosaminoglycan in the renomedullary interstitium. Renomedullary HA has been implicated in tubular fluid handling due to its water-attracting properties and the changes occurring in parallel to acute variations in the body hydration status. less thanbrgreater than less thanbrgreater thanMethods. HA production was inhibited by 4-methylumbelliferone (4-MU in drinking water for 5 days, 1.45 +/- 0.07 g/day/kg body weight) in rats prior to hydration. less thanbrgreater than less thanbrgreater thanResults. Following hypotonic hydration for 135 min in control animals, diuresis and osmotic excretion increased while sodium excretion and glomerular filtration rate (GFR) remained unchanged. The medullary and cortical HA contents were 7.85 +/- 1.29 ng/mg protein and 0.08 +/- 0.01 ng/mg protein, respectively. Medullary HA content after 4-MU was 38% of that in controls (2.98 +/- 0.95 ng/g protein, p andlt; 0.05), while the low cortical levels were unaffected. Baseline urine flow was not different from that in controls. The diuretic response to hydration was, however, only 51% of that in controls (157 +/- 36 versus 306 +/- 54 mu l/g kidney weight/135 min, p andlt; 0.05) and the osmolar excretion only 47% of that in controls (174 +/- 47 versus 374 +/- 41 mu Osm/g kidney weight/135 min, p andlt; 0.05). Sodium excretion, GFR, and arterial blood pressure were similar to that in control rats and unaltered during hydration. less thanbrgreater than less thanbrgreater thanConclusions. Reduction of renomedullary interstitial HA using 4-MU reduces the ability of the kidney to respond appropriately upon acute hydration. The results strengthen the concept of renomedullary HA as a modulator of tubular fluid handling by changing the physicochemical properties of the interstitial space.
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| 6. |
- Stridh, Sara, 1983-, et al.
(author)
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Inhibition of mTOR activity in diabetes mellitus reduces proteinuria but not renal accumulation of hyaluronan
- 2015
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In: Upsala Journal of Medical Sciences. - : Uppsala Medical Society. - 0300-9734 .- 2000-1967. ; 120:4, s. 233-240
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Journal article (peer-reviewed)abstract
- OBJECTIVES: Accumulation of extracellular matrix (ECM) components is an early sign of diabetic nephropathy. Also the glycosaminoglycan hyaluronan (HA) is elevated in the renal interstitium during experimental diabetes. The mammalian target of rapamycin (mTOR) pathway participates in the signaling of hyperglycemia-induced ECM accumulation in the kidney, but this has not yet been investigated for HA. We hypothesized that interstitial HA accumulation during diabetes may involve mTOR activation.METHODS: Diabetic rats (6 weeks post-streptozotocin (STZ)) were treated with rapamycin to inhibit mTOR or vehicle for 2 additional weeks. Kidney function (glomerular filtration rate, renal blood flow, urine output) and regional renal HA content were thereafter analyzed. The ability of the animals to respond to desmopressin was also tested.RESULTS: Diabetic animals displayed hyperglycemia, proteinuria, hyperfiltration, renal hypertrophy, increased diuresis with reduced urine osmolality, and reduced weight gain. Cortical and outer medullary HA was elevated in diabetic rats. Urine hyaluronidase activity was almost doubled in diabetic rats compared with controls. The ability to respond to desmopressin was absent in diabetic rats. Renal blood flow and arterial blood pressure were unaffected by the diabetic state. In diabetic rats treated with rapamycin the proteinuria was reduced by 32%, while all other parameters were unaffected.CONCLUSION: Regional renal accumulation of the ECM component HA is not sensitive to mTOR inhibition by rapamycin, while proteinuria is reduced in established STZ-induced diabetes. Whether the diabetes-induced renal accumulation of HA occurs through different pathways than other ECM components, or is irreversible after being established, remains to be shown.
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