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- Kordasti, Shirin, 1975, et al.
(författare)
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Effects of cholera toxin on the potential difference and motor responses induced by distension in the rat proximal small intestine in vivo
- 2006
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Ingår i: American Journal of Physiology - Gastrointestinal and Liver Physiology. - : American Physiological Society. - 0193-1857 .- 1522-1547. ; 290:5
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Tidskriftsartikel (refereegranskat)abstract
- Cholera toxin (CT) may induce uncontrolled firing in recurrent networks of secretomotor neurons in the submucous plexus. This hypothesis was tested in chloralose-anesthetized rats in vivo. The secretory reflex response to graded intestinal distension was measured with or without prior exposure to luminal CT. The transmural potential difference (PD) was used as a marker for electrogenic chloride secretion. In controls, distension increased PD, and this response was reduced by the neural blocker tetrodotoxin given serosally and the vasoactive intestinal peptide (VIP) receptor antagonist [4Cl-D-Phe(6),Leu(17)]VIP (2 mu g.min(-1).kg(-1) iv) but unaffected by the serotonin 5-HT3 receptor antagonist granisetron, by the nicotinic receptor antagonist hexamethonium, by the muscarinic receptor antagonist atropine, or by the cyclooxygenase inhibitor indomethacin. Basal PD increased significantly with time in CT-exposed segments, an effect blocked by granisetron, by indomethacin, and by [4Cl-D-Phe(6),Leu(17)]VIP but not by hexamethonium or atropine. In contrast, once the increased basal PD produced by CT was established, [4Cl-DPhe(6),Leu(17)] VIP and indomethacin had no significant effect, whereas granisetron and hexamethonium markedly depressed basal PD. CT significantly reduced the increase in PD produced by distension, an effect reversed by granisetron, indomethacin, and atropine. CT also activated a specific motility response to distension, repeated cluster contractions, but only in animals pretreated with granisetron, indomethacin, or atropine. These data are compatible with the hypothesis that CT induces uncontrolled activity in submucous secretory networks. Development of this state depends on 5-HT3 receptors, VIP receptors, and prostaglandin synthesis, whereas its maintenance depends on 5-HT3 and nicotinic receptors but not VIP receptors. The motility effects of CT (probably reflecting myenteric activity) are partially suppressed via a mechanism involving 5-HT3 and muscarinic receptors and prostaglandin synthesis.
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| 2. |
- Kordasti, Shirin, 1975, et al.
(författare)
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Rotavirus infection is not associated with small intestinal fluid secretion in the adult mouse.
- 2006
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Ingår i: Journal of virology. - 0022-538X .- 1098-5514. ; 80:22, s. 11355-61
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Tidskriftsartikel (refereegranskat)abstract
- In contrast to humans, adult but not infant small animals are resistant to rotavirus diarrhea. The pathophysiological mechanism behind this age-restricted diarrhea is currently unresolved, and this question was investigated by studying the secretory state of the small intestines of adult mice infected with rotavirus. Immunohistochemistry and histological examinations revealed that rotavirus (strain EDIM) infects all parts of the small intestines of adult mice, with significant numbers of infected cells in the ilea at 2 and 4 days postinfection. Furthermore, quantitative PCR revealed that 100-fold more viral RNA was produced in the ilea than in the jejuna or duodena of adult mice. In vitro perfusion experiments of the small intestine did not reveal any significant changes in net fluid secretion among mice infected for 3 days or 4 days or in those that were noninfected (37 +/- 9 microl . h(-1) . cm(-1), 22 +/- 13 microl . h(-1) . cm(-1), and 33 +/- 6 microl . h(-1) . cm(-1), respectively) or in transmucosal potential difference (4.0 +/- 0.3 mV versus 3.9 +/- 0.4 mV), a marker for active chloride secretion, between control and rotavirus-infected mice. In vivo experiments also did not show any differences in potential difference between uninfected and infected small intestines. Furthermore, no significant differences in weight between infected and uninfected small intestines were found, nor were any differences in fecal output observed between infected and control mice. Altogether, these data suggest that rotavirus infection is not sufficient to stimulate chloride and water secretion from the small intestines of adult mice.
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| 3. |
- Kordasti, Shirin, 1975, et al.
(författare)
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Serotonin and vasoactive intestinal peptide antagonists attenuate rotavirus diarrhoea.
- 2004
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Ingår i: Gut. - : BMJ. - 0017-5749 .- 1468-3288. ; 53:7, s. 952-7
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND AIMS: The mechanisms underlying intestinal secretion in rotavirus diarrhoea remain to be established. We previously reported that rotavirus evokes intestinal fluid and electrolyte secretion by activation of the enteric nervous system. We now report that antagonists for the 5-hydroxytryptamine 3 receptor (5-HT(3)) and vasoactive intestinal peptide (VIP) receptor, but not antagonists for 5-hydroxytryptamine 4 receptor or the muscarinic receptor, attenuate rotavirus induced diarrhoea. METHODS: Neurotransmitter antagonists were administered to wild-type or neurokinin 1 receptor knockout mice infected with homologous (EDIM) or heterologous (RRV) rotavirus. RESULTS: While RRV infected mice had diarrhoea for 3.3 (0.2) days (95% confidence interval (CI) 3.04-3.56), the 5-HT(3) receptor antagonist (granisetron) and the VIP receptor antagonist (4Cl-D-Phe(6),Leu(17))-VIP both reduced the total number of days of RRV induced diarrhoea to 2.1 (0.3) (95% CI 1.31-2.9) (p<0.01). EDIM infected mice treated with granisetron had a significantly shorter duration of diarrhoea (5.6 (0.4) days) compared with untreated mice (8.0 (0.4) days; p<0.01). Experiments with neurokinin 1 receptor antagonists suggest that this receptor may possibly be involved in the secretory response to rotavirus. On the other hand, rotavirus diarrhoea was not attenuated in the neurokinin 1 receptor knockout mice. CONCLUSIONS: Our results suggest that the neurotransmitters serotonin and VIP are involved in rotavirus diarrhoea; observations that could imply new principles for treatment of this disease with significant global impact.
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| 4. |
- Kordasti, Shirin, 1975
(författare)
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The enteric nervous sytem and infectious diarrhoea. An experimental study in mouse and rat
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Aim: To evaluate the role of the enteric nervous system in one of the most common types of infectious diarrhoea worldwide, rotavirus infection, and to further clarify the mechanisms behind neurally mediated intestinal secretion. Methods: The experiments were performed on neonatal and adult mice and adult rats. Experimental setups: In vitro: 1. Ussing chamber. 2. Perfusion chamber. In vivo: 1. Recording of secretion, measured as potential difference. 2. Assessment of clinical diarrhoea in an animal model. Results: Rotavirus evokes intestinal fluid and electrolyte secretion by activation of the enteric nervous system. Different drugs blocking nerve activity (tetrodotoxin, lidocaine and hexamethonium) were used to attenuate rotavirus-induced fluid and electrolyte secretion in vitro. Rotavirus diarrhoea was also reduced by neurotransmitter receptor antagonists against vasoactive intestinal peptide and serotonin-3 receptors. Both in vivo and in vitro data suggest that adult mice despite rotavirus replication do not get symptoms in terms of intestinal fluid secretion. Cholera secretion was partially inhibited by blockade of serotonin-3 receptors. Blockade of prostaglandin synthesis and vasoactive intestinal peptide receptors had an effect only if given together with the toxin, while blockade of nicotinic receptors had an effect only on manifest secretion. Cholera toxin simultaneously activated an inhibitory secretomotor mechanism via prostaglandins, serotonin-3 and muscarine receptors. Cholera toxin also induced a specific motor pattern, clusters, provided that the animals were pretreated with a blocker of prostaglandin synthesis, serotonin-3 or the muscarine receptor. Conclusions: This study confirms the importance of nervous mechanisms in secretory diarrhoea by demonstrating an important role in rotavirus disease. Cholera toxin seems to activate both excitatory and inhibitory systems simultaneously. Both the formation of clusters and the different effects of the drugs on developing and manifest secretion are compatible with uncontrolled firing in myenteric and submucous neuron networks. Blockade of uncontrolled network firing may be a new potential target in diarrhoeal disease.
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