Effects of dimethyl sulfoxide, allopurinol, 21-aminosteroid U-74389G, and manganese chloride on low-flow ischemia and reperfusion of the large colon in horses
Authors: Moore Rustin M. , Muir William W. , Bertone Alicia L. , Beard Warren L. , Stromberg Paul C. 
Published: January 2024

SUMMARY
Thirty horses were randomly assigned to 1 of 5 groups. All horses were anesthetized and subjected to ventral midline celiotomy, then the large colon was exteriorized and instrumented. Colonic arterial blood flow was reduced to 20% of baseline (bl) and was maintained for 3 hours. Colonic blood flow was then restored, and the colon was reperfused for an additional 3 hours. One of 5 drug solutions was administered via the jugular vein 30 minutes prior to colonic reperfusion: group 1, 0.9% NaCl; group 2, dimethyl sulfoxide: 1 g/kg of body weight; group 3, allopurinol: 25 mg/kg; group 4, 21-aminosteroid U-74389G: 10 mg/kg; and group 5, manganese chloride (MnCl2): 10 mg/kg. Hemodynamic variables were monitored and recorded at 30-minutes intervals. Systemic arterial, systemic venous (sv), and colonic venous (cv) blood samples were collected for measurement of blood gas tensions, oximetry, lactate concentration, Pcv, and plasma total protein concentration. The eicosanoids, 6-keto prostaglandin Flα, prostaglandin E2 and thromboxane B2, were measured in cv blood, and endotoxin was measured in cv and sv blood. Full-thickness biopsy specimens were harvested from the left ventral colon for histologic evaluation and determination of wet weight-to-dry weight ratios (WW:DW). Data were analyzed, using two-way ANOVA for repeated measures, and statistical significance was set at P < 0.05. Heart rate, mean arterial pressure, and cardiac output increased with MnCl2 infusion; heart rate and cardiac output remained increased throughout the study, but mean arterial pressure returned to bl values within 30 minutes after completion of MnCI2 infusion. Other drug-induced changes were not significant. There were significant increases in mean pulmonary artery and mean right atrial pressures at 2 and 2.5 hours in horses of all groups, but other changes across time or differences among groups were not observed. Mean pulmonary artery pressure remained increased through 6 hours in all groups, but mean right atrial pressure had returned to bl values at 3 hours. Mean colonic arterial pressure was significantly decreased at 30 minutes of ischemia and remained decreased through 6 hours; however, by 3.25 hours it was significantly higher than the value at 3 hours of ischemia. Colonic arterial resistance decreased during ischemia and remained decreased throughout reperfusion in all groups; there were no differences among groups for colonic arterial resistance. Colonic venous Po2, oxygen content, and pH decreased, and Pco2 and lactate concentration increased during ischemia but returned to bl values during reperfusion. Compared with bl values, colonic oxygen extraction ratio was increased from 0.5 to 3 hours. By 15 minutes of reperfusion, colonic oxygen extraction ratio had decreased from the bl value in all groups and either remained decreased or returned to values not different from bl through 6 hours. Colonic venous 6-keto prostaglandin Flα and prostaglandin E2 concentrations increased during ischemia, but returned to bl on reperfusion; there were no changes in thrombox- ane2 concentration among or within groups. Endotoxin was not detected in cv or sv blood after ischemia or reperfusion. There were no differences among or within groups for these variables. Low-flow ischemia and reperfusion (i-r) of the large colon caused mucosal injury, as evidenced by increases in percentage of surface mucosal disruption, percentage depth of mucosal loss, mucosal hemorrhage, mucosal edema, mucosal interstitial-to-crypt ratio, mucosal neutrophil index, submucosal venular neutrophil numbers, and mucosal cellular debris index. There was a trend (P = 0.06) toward greater percentage depth of mucosal loss at 6 hours in horses treated with dimethyl sulfoxide, compared with the vehicle control solution. There were no differences in the remainder of the histologic variables among groups. Full-thickness and mucosal WW:DW increased with colonic I-R, but there were no differences among groups. There was a trend (P = 0.09) toward neutrophil accumulation, as measured by myeloperoxidase activity, in the lungs after colonic I-R, but there were no differences among groups. There was no change in lung WW:DW after colonic I-R. There were no beneficial effects of drugs directed against oxygen-derived free radical-mediated damage on colonic mucosal injury associated with low-flow I-R. Deleterious drug-induced hemodynamic effects were not observed in this study.