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Changes in villous blood flow in response to indomethacin

Kelly, David Andrew; (1998) Changes in villous blood flow in response to indomethacin. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Introduction: Non-steroidal anti-inflammatory drugs (ie indomethacin) produce gastrointestinal ulceration. Early histology shows villous contraction, buckling of large vessels and distorted endothelium, suggesting that reduced villous blood flow might be involved at an even earlier stage. Blood flow was therefore calculated from measurements of red blood cell velocity and vessel diameters, obtained using in-vivo fluorescence microscopy. Villus histology was preserved at any time point by perfuse-fixation and isolation of villi displaying either stasis or reduced flow. Aims: Firstly, to correlate histological alterations with dynamic blood flow changes, and secondly to assess the effects of the β3-adrenoceptor agonist CL316 243 on blood flow and histology. Results: Neither luminal or iv indomethacin altered villous blood flow or histology. However, combined luminal and iv indomethacin mimicking an oral dose, caused slowing of villous blood flow after 25 mins progressing to blood stasis within 45min. At stasis there was intense endothelial fluorescence, villous shortening, microvascular damage and distortion and epithelial damage limited to a single vessel. At slowing there was only intense endothelial fluorescence and microvascular distortion and damage. Ultrastructural analysis at the point of blood slowing showed endothelial vacuolisation and finger-like projections into the lumen of the villus microvasculature. The ultrastructural changes were more pronounced as blood stasis developed. Activation of β3-adrenoceptors with selective β3-agonists such as CL316, 243 prevented indomethacin-induced reduction of intestinal blood flow and prevented histological changes. CL316, 243 also reversed indomethacin-induced blood stasis and histological damage. Conclusion: Combined systemic and indomethacin causes endothelial damage in villous microvasculature resulting in progressive slowing and stasis in the villus tip, which progresses to full necrosis and ulceration. These events can be prevented and reversed by activation of small intestinal β3-adrenoceptors.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Changes in villous blood flow in response to indomethacin
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Health and environmental sciences
URI: https://discovery.ucl.ac.uk/id/eprint/10105143
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