| Summary: | Objectives
1) To measure conductance and permeability of canine colonic mucosa exposed to increasing concentrations of carprofen.
2) To compare conductance and permeability of canine colonic mucosa exposed to carprofen or 2,4-dinitrophenol (DNP) and tempol blockade.
Design
In vitro randomized block design
Animal
20 mixed breed dogs
Methods
Conductance, mannitol flux, and histology were evaluated in colonic mucosa mounted in Ussing chambers. Mucosa was first exposed to increasing concentrations of carprofen. Mucosa was then exposed to either carprofen (200 μg/ml) or DNP (0.25mM) +/- tempol (1mM) pretreatment. Conductance over time, mannitol fluxes, and frequency of histologic categories were analyzed for treatment effects. Histopathology and electron microscopy were evaluated post experiment.
Results
Mean +/- SEM conductance*time for 400 μg/ml carprofen treated colon was significantly greater than control. Mean +/- SEM conductance*time for carprofen treated colon at 200, 100 and 40 μg/ml were not significantly different from control. Mean +/- SEM conductance*time for 400 μg/ml and 200 μg/ml carprofen treated colon were not significantly different. Period 3 mannitol flux was greater than period 1 for 400 μg/ml and 200 μg/ml carprofen treated colon but not significantly different for 100 μg/ml, 40 μg/ml, and control. Period 3 flux for 400 μg/ml and 200 μg/ml carprofen treated colon were not different but were greater than control. Mean +/- SEM conductance*time for carprofen or DNP treated colon were not significantly different from control regardless of blockade. Period 3 flux for carprofen and DNP treated colon were not different but were greater than control. Period 3 flux for carprofen treated colon with tempol pretreatment was not significantly different than control. Period 3 flux for DNP treated colon with tempol pretreatment was not different than without tempol but was greater than control. Cell sloughing and erosions were observed with high carprofen concentrations. Mitochondrial damage was seen with carprofen treatment compared to DNP treatment or control. Tempol pretreatment effect on mitochondrial morphology was inconsistent.
Conclusion
Carprofen exhibits concentration dependent toxicity to canine colonic mucosa. Carprofen and DNP induce similar mucosal damage evident by changes in electrical conductance, mannitol flux, and histopathology. Carprofen damages enterocyte mitochondria.
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