| 1. |
- Ewert, Sara, 1974, et al.
(författare)
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Angiotensin II induced contraction of rat and human small intestinal wall musculature in vitro
- 2006
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Ingår i: Acta Physiologica. - : Wiley. - 1748-1708 .- 1748-1716. ; 188:1, s. 33-40
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Angiotensin II (Ang II) is a well-known activator of smooth muscle in the vasculature but has been little explored with regard to intestinal wall muscular activity. This study investigates pharmacological properties of Ang II and expression of its receptors in small-intestinal smooth muscle from rats and humans. METHODS: Isometric recordings were performed in vitro on small intestinal longitudinal muscle strips. Protein expressions of Ang II typ 1 (AT1R) and typ 2 (AT2R) receptors were assessed by Western blot. RESULTS: Ang II elicited concentration-dependent contractions of rat jejunal and ileal muscle preparations. The concentration-response curve (rat ileum, EC(50): 1.5 +/- 0.9 x 10(-8) M) was shifted to the right by the AT1R receptor antagonist losartan (10(-7) M) but was unaffected by the AT2R antagonist PD123319 (10(-7) M) as well as by the adrenolytic guanethidine (3 x 10(-6) M) and the anticholinergic atropine (10(-6) M). Human duodenal, jejunal and ileal longitudinal muscle preparations all contracted concentration-dependently in response to Ang II. The concentration-response curve (human jejunum, EC(50): 1.5 +/- 0.8 x 10(-8) M) was shifted to the right by losartan (10(-7) M) but was unaffected by PD123319 (10(-7) M). Both AT1R and AT2R were detected in all segments of the rat small intestinal wall musculature, whereas only AT1R was readily detectable in the human samples. CONCLUSION: Ang II elicits contractions of small-intestinal longitudinal muscle preparations from the small intestine of rats and man. The pharmacological pattern and protein expression analyses indicate mediation via the AT1R.
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| 2. |
- Ewert, Sara, 1974, et al.
(författare)
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Dynamic expression of the angiotensin II type 2 receptor and duodenal mucosal alkaline secretion in the Sprague-Dawley rat
- 2006
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Ingår i: Experimental Physiology. - : Wiley. - 0958-0670. ; 91:1, s. 191-199
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Tidskriftsartikel (refereegranskat)abstract
- Activation of angiotensin II type 2 receptors (AT2R) has been shown to stimulate duodenal mucosal alkaline secretion (DMAS) in Sprague-Dawley rats (S-D). This finding could not be confirmed in another line of S-D, and the present study investigates whether the level of AT2R expression determines the response to the AT2R agonist CGP42112A. DMAS was measured in anaesthetized rats using in situ pH-stat titration. Real-time PCR and Western blot were used to assess AT1R and AT2R RNA and protein expression, respectively. CGP42112A (0.1 microg kg(-1)min(-1) I.V.) elicited a 45% net increase in DMAS in the previous S-D line studied, whereas no change occurred in the new S-D line. Luminal administration of prostaglandin E2 (10(-5) M) increased DMAS similarly in both S-D lines. AT2R protein expression was significantly higher in tissue from the previous line compared to the new line. Individual AT1R to AT2R ratios (RNA and protein) were significantly higher in the new line compared to the previous S-D line. In the new S-D line intravenous infusion of angiotensin II (Ang II; 10 microg kg(-1) h(-1)) over 120 min significantly lowered the duodenal AT1aR to AT2R RNA ratio. Prolonged Ang II infusion over 240 min increased AT2R protein expression and evoked a 42% stimulatory response in DMAS to CGP42112A. The level of local AT2R expression determines the effect of the AT2R agonist CGP42112A on rat duodenal mucosal alkaline secretion. AT2R expression should be confirmed before interpreting the experimental effects of pharmacological interferences with this receptor.
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| 3. |
- Ewert, Sara, 1974
(författare)
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On angiotensin II receptor type 2 receptors in the small intestine
- 2003
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The endocrine renin-angiotensin system (RAS) is important in the regulation of extracellular fluid volume and systemic blood pressure in strenuous conditions such as hypovolemia. Also present locally in peripheral tissues, all components of RAS are expressed and have been shown to modulate development, cell growth and inflammation. Since the two main receptor subtypes to angiotensin II (AngII) commonly exert counteracting influences their relative expression determines RAS function. The present ... merthesis focuses on AngII influences on mucosal and smooth-muscle function in the small intestine and in particular the angiotensin II type 2 receptor (AT2R) and its postulated post-receptor mediators bradykinin and nitric oxide (NO).To confirm AT1R and AT2R gene transcript and protein expressions, PCR and Western blot were used respectively. Mucosal function in vivo was represented by duodenal mucosal alkaline secretion in adult Sprague-Dawley rats assessed by pH-stat titration, and by mucosal nitric oxide release in jejunum of young landrace pigs assessed by tonometry and chemiluminescense. Smooth-muscle contractility (isometric tension in an organ bath system) was studied in longitudinal preparations of rat and human small-intestine tissue.The receptor-expression analyses demonstrated presence of AT1R and AT2R along the small intestine in rats, pigs and humans. AT2R was not detected in human smooth-muscle preparations. The selective AT2R-agonist CGP42112A at the dose 0.1 microg kg-1 min-1 i.v. stimulated rat duodenal alkaline secretion, a response which was sensitive to the selective bradykinin type 2 receptor antagonist HOE140, indicating mediation by bradykinin receptor type 2 (BK2). Immunohistochemisrtry showed that BK2 receptors were located to duodenal crypt epithelium. The level of AT2R expression varied together with duodenal alkaline secretory responses to CGP42112A. The AT2R-agonist also stimulated NO release from porcine jejunal mucosa, an action which was sensitive to the selective AT2R-antagonist PD123319. In small-intestine smooth-muscle preparations contractile action by AngII was mediated by AT1R in rats and humans. In rat ileum blockade of AT2R, using PD123319, ameliorated AngII-induced contractions indicating a AT2R-mediated relaxatory action. This was not observed in human preparations which also lacked AT2R expression.To summarise, the results demonstate that AT2R influences mucosal and smooth-muscle function in normal small-intestine. The functional significance on an integrated level remains to be elucidated in further detail. It is known that AT1R induces depression of mucosaprotective functions in strenouos circulatory conditions. A function of the AT2R-induced increase in mucosal buffering capacity could be to counteract risk of autodigestive injury. NO contributes to maintenance of mucosal barrier functions. The AT2R-stimulated NO release could be a previously unknown link between RAS and barrier properties of the gastrointestinal mucosa. The emerging view on AT2R-upregulation as 'tissue-preserving' gives new opportunities for treatment in pathological conditions such as inflammation, tumorogenesis and ischemia/reperfusion.
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| 4. |
- Ewert, Sara, 1974, et al.
(författare)
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The bradykinin BK2 receptor mediates angiotensin II receptor type 2 stimulated rat duodenal mucosal alkaline secretion.
- 2003
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Ingår i: BMC physiology. - 1472-6793. ; 3
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: This study investigates bradykinin and nitric oxide as potential mediators of AT2-receptor-stimulated duodenal mucosal alkaline secretion. Duodenal mucosal alkaline secretion was measured in methohexital- and alpha-chloralose-anaesthetised rats by means of in situ pH-stat titration. Immunohistochemistry and Western blot were used to identify the BK2 receptors. RESULTS: The AT2 receptor agonist CGP42112A (0.1 microg kg(-1) min(-1)) administered intravenously increased the duodenal mucosal alkaline secretion by approximately 50 %. This increase was sensitive to the selective BK2 receptor blocker HOE140 (100 ng/kg i.v.), but not to luminal administration of the NOS blocker L-NAME (0.3 mM). Mean arterial pressure did not differ between groups during the procedures. Immunohistochemistry showed a distinct staining of the crypt epithelium and a moderate staining of basal cytoplasm in villus enterocytes. CONCLUSION: The results suggest that the AT2-receptor-stimulated alkaline secretion is mediated via BK2 receptors located in the duodenal cryptal mucosal epithelium.
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| 5. |
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| 6. |
- Laesser, Mats, 1969, et al.
(författare)
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Candesartan improves survival following severe hypovolemia in pigs; a role for the angiotensin II type 2 receptor?
- 2005
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Ingår i: Intensive care medicine. - : Springer Science and Business Media LLC. - 0342-4642 .- 1432-1238. ; 31:8, s. 1109-15
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To investigate the involvement of intestinal angiotensin II type 2 receptors in the outcome of acute severe hypovolemia as well as systemic and regional mesenteric hemodynamics and intestinal mucosal functions in anesthetized pigs. DESIGN AND SETTING: Prospective, interventional animal study in a university research laboratory. SUBJECTS: 53 landrace pigs, 28-35 kg. INTERVENTIONS: 30+30% or 20+20% hemorrhage of estimated total blood volume followed by retransfusion performed in untreated controls, in animals treated with the angiotensin II type 1 receptor blocker candesartan or with a combination of candesartan and the angiotensin II type 2 receptor blocker PD123319. MEASUREMENTS AND RESULTS: Following 30+30% hemorrhage the candesartan-treated animals attained a significantly higher survival rate than controls and animals treated with PD123319 in combination with candesartan. Less pronounced hemorrhage (20+20%) resulted in no mortality and functional variables were assessed. A significantly higher output of jejunal intraluminal nitric oxide occurred during hypovolemia in the candesartan treated group than in controls and animals that received PD123319 in combination with candesartan. Jejunal transmucosal potential difference was significantly better preserved after retransfusion in candesartan-treated animals than in controls. Expression of angiotensin II type 2 receptors in intestinal tissue was significantly higher in animals surviving the 30+30% hemorrhage than in nonsurvivors. CONCLUSIONS: Lethal circulatory failure is possibly influenced by use of angiotensin receptor ligands, and activation of intestinal angiotensin II type 2 receptors may play a significant role in improving the outcome of severe hypovolemia.
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| 7. |
- Laesser, Mats, 1969, et al.
(författare)
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The angiotensin II receptor blocker candesartan improves survival and mesenteric perfusion in an acute porcine endotoxin model.
- 2004
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Ingår i: Acta anaesthesiologica Scandinavica. - 0001-5172. ; 48:2, s. 198-204
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Blockade of the angiotensin II type 1 (AT1) receptor has been demonstrated to ameliorate splanchnic hypoperfusion in acute experimental circulatory failure. This study focused on hemodynamic changes and survival in pigs treated with AT1 blockade prior to or during acute endotoxinemia. METHODS: Escherichia coli lipopolysaccharide endotoxin was infused in anesthetized and mechanically ventilated pigs. Systemic, renal, mesenteric and jejunal mucosal perfusion as well as systemic oxygen and acid-base balance were monitored. The selective AT1 receptor blocker candesartan was administered prior to as well as during endotoxinemia. Control animals received the saline vehicle. RESULTS: Pre-treatment with candesartan resulted in higher survival rate (83%, 10 out of 12 animals) compared with 50% (6 of 12) in control animals and 27% (3 of 11) in animals treated during endotoxinemia. Pre-treatment with candesartan resulted in higher cardiac output, mixed venous oxygen saturation, arterial standard base-excess, portal venous blood flow during endotoxin infusion compared with controls and animals treated during endotoxinemia. No adverse effects were found on neither systemic nor renal circulation. CONCLUSION: The favorable results of AT1 receptor blockade prior to endotoxinemia are lost when blockade is established during endotoxinemia demonstrating the importance of the renin-angiotensin system and its dynamic involvement in acute endotoxinemic shock.
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| 8. |
- Spak, Emma, 1977, et al.
(författare)
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Angiotensin II receptor expression following intestinal transplantation in mice.
- 2006
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Ingår i: The Journal of surgical research. - : Elsevier BV. - 0022-4804. ; 135:1, s. 144-9
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: To further improve the success rate of intestinal transplantation there is a need to find early appearing indicators of rejection. The specific aim of this study was to compare Angiotensin (Ang) II type 1 receptor and Ang II type 2 receptor expression in relation to histological signs of rejection. METHODS: Mice of the C57BL6 strain with syngeneic intestinal grafts were compared to mice subjected to allogeneic intestinal transplantation with BalbC strain as donors. Local expression of Ang II type 1 and 2 receptor was evaluated using rt-PCR and Western blot and compared to histological picture in grafts and native intestine. RESULTS: The Ang II type 2 receptor protein expression was markedly up-regulated in the allogeneically transplanted graft from day 1 postoperatively. Histological signs of rejection were not seen until day 6. CONCLUSION: Intestinal allograft transplantation in mice is associated with a marked up-regulation of the Ang II type 2 receptor. However, the detailed role of the renin-angiotensin system in the immune rejection following intestinal transplantation remains to be clarified.
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| 9. |
- Wählby, Carolina, 1974-, et al.
(författare)
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Finding cells, finding molecules, finding patterns
- 2006
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Ingår i: Advances in Data Mining. ; , s. 15-24
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Konferensbidrag (refereegranskat)abstract
- Many modern molecular labeling techniques result in bright point signals. Signals from molecules that are detected directly inside a cell can be captured by fluorescence microscopy. Signals representing different types of molecules may be randomly distributed in the cells or show systematic patterns indicating that the corresponding molecules have specific, non-random localizations and functions in the cell. Assessing this information requires high speed robust image segmentation followed by signal detection, and finally pattern analysis. We present and discuss this type of methods and show an example of how the distribution of different variants of mitochondrial DNA can be analyzed.
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