Endothelial changes precede mucosal ulceration induced by indomethacin: an experimental study in the rat.
BACKGROUND
Indomethacin has been shown to damage the villous microvasculature concomitant with alterations in villous blood flow in the rat.


OBJECTIVE
To test the hypothesis that alterations in blood flow result from ultrastructural damage to microvasculature endothelium.


METHODS
In anaesthetized rats, jejunal villi were exteriorized in a chamber and blood flow in surface capillaries visualized by fluorescence microscopy. Villi were exposed both luminally and systemically to indomethacin (100 microg/mL) for 10 min or until blood slowing or stasis had occurred in superficial capillaries (n=3 per group). Control animals received both a luminal and intravenous vehicle for 45 min (n=3). The small intestines were vascular perfusion-fixed with 1.5% glutaraldehyde and studied by transmission electron microscopy.


RESULTS
All controls appeared to be ultrastructurally normal. A 10 min exposure to indomethacin had no effect upon the epithelium but resulted in mild endothelial vacuolization and the development of small finger-like projections into the lumen of villus surface microvasculature. At the point of blood slowing, villus tip epithelium was again normal but the endothelial vacuolization and finger-like projections became more obvious. The endothelial projections and vacuolization became severe at the point of blood stasis; this also coincided with epithelial degeneration.


CONCLUSIONS
This study shows that villus surface microvasculature is the earliest site of morphological damage after indomethacin exposure.
Kelly
D
D
Royal Free & University College Medical School, Royal Free Campus, London, UK.
Anthony
A
A
Piasecki
C
C
Lewin
J
J
Pounder
R E
RE
Wakefield
A J
AJ
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000633:toxicity*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000473:pathology / Q000648:ultrastructure; D005260:Female; D007213:Indomethacin / Q000633:toxicity*; D008854:Microscopy, Electron; D051381:Rats; D017207:Rats, Sprague-Dawley; D013276:Stomach Ulcer / Q000139:chemically induced*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D007213:Indomethacin