Reversal and protection against indomethacin-induced blood stasis and mucosal damage in the rat jejunum by a beta3-adrenoceptor agonist.
BACKGROUND
In the rat, indomethacin causes jejunal villous shortening, microvascular distortion, and blood stasis prior to ulceration. The beta3-adrenoceptor agonist CL316,243 (CL) prevents both the early histological changes and ulceration.


OBJECTIVE
To test the hypothesis that the beta3-adrenoceptor agonist CL316,243 exerts its protective effect by prevention and/or reversal of blood flow changes in the rat jejunum exposed to indomethacin.


METHODS
In anaesthetized rats, jejunal villous blood flow was measured in surface capillaries using fluorescence microscopy. Stasis of superficial capillary blood flow was induced by combined topical and i.v. indomethacin (100 microg/mL, 2.8 x 10(-4) M). To examine the effect of CL on blood stasis, CL was applied either i.v. (1 mg/kg) or luminally (100 microg/mL, 2.5 x 10(-5)M) at the onset of stasis. Prophylactic protection was assessed by giving i.v. CL simultaneously with indomethacin. Results were compared with controls which received luminal saline applied at blood stasis. The effect of i.v. CL (1 mg/kg) alone, or luminal CL (100 microg/mL) alone on basal villous blood flow was also examined. The small intestines were perfusion-fixed with 10% formol saline, and removed for histology, n = 5 for all groups.


RESULTS
Luminal CL given at stasis reversed indomethacin-induced stasis within 10 min, whereas i.v. CL did not. Pretreatment with i.v. CL prevented the onset of stasis. Basal blood flow was raised slightly only by luminal CL.


CONCLUSIONS
The beta-adrenoceptor agonist CL316,243 can protect against indomethacin-induced blood stasis in rat jejunal villi.
Kelly
D
D
Department of Anatomy and Developmental Biology, Royal Free and University College Medical School, London, UK.
Piasecki
C
C
Anthony
A
A
Dhillon
A P
AP
Pounder
R E
RE
Wakefield
A J
AJ
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D001783:Blood Flow Velocity / Q000187:drug effects; D004149:Dioxoles / Q000494:pharmacology*; D005260:Female; D005753:Gastric Mucosa / Q000098:blood supply*; D006487:Hemostasis; D007213:Indomethacin; D007579:Jejunal Diseases / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D008856:Microscopy, Fluorescence; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow / Q000187:drug effects; D018709:Statistics, Nonparametric
D000318:Adrenergic beta-Agonists; D004149:Dioxoles; C076126:disodium (R,R)-5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)-amino)propyl)-1,3-benzodioxole-2,3-dicarboxylate; D007213:Indomethacin