Effects of U-74389G, a novel 21-aminosteroid, on small intestinal ischemia and reperfusion injury in horses

Nicholas J. Vatistas From the Comparative Gastroenterology Laboratory, Department of Surgical and Radiological Sciences (Vatistas, Snyder, Hildebrand, Harmon, Woliner), Veterinary Medical Teaching Hospital (Nieto, Henry, Enos), and Department of Anatomy (Magliano), School of Veterinary Medicine, Department of Pediatrics (Barry), School of Medicine, and Department of Statistics (Drake), University of California, Davis, CA 95616, and The Upjohn Co, Kalamazoo, Ml 49001 (Brown).

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Jack R. Snyder From the Comparative Gastroenterology Laboratory, Department of Surgical and Radiological Sciences (Vatistas, Snyder, Hildebrand, Harmon, Woliner), Veterinary Medical Teaching Hospital (Nieto, Henry, Enos), and Department of Anatomy (Magliano), School of Veterinary Medicine, Department of Pediatrics (Barry), School of Medicine, and Department of Statistics (Drake), University of California, Davis, CA 95616, and The Upjohn Co, Kalamazoo, Ml 49001 (Brown).

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Susan V. Hildebrand From the Comparative Gastroenterology Laboratory, Department of Surgical and Radiological Sciences (Vatistas, Snyder, Hildebrand, Harmon, Woliner), Veterinary Medical Teaching Hospital (Nieto, Henry, Enos), and Department of Anatomy (Magliano), School of Veterinary Medicine, Department of Pediatrics (Barry), School of Medicine, and Department of Statistics (Drake), University of California, Davis, CA 95616, and The Upjohn Co, Kalamazoo, Ml 49001 (Brown).

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Faye A. Harmon From the Comparative Gastroenterology Laboratory, Department of Surgical and Radiological Sciences (Vatistas, Snyder, Hildebrand, Harmon, Woliner), Veterinary Medical Teaching Hospital (Nieto, Henry, Enos), and Department of Anatomy (Magliano), School of Veterinary Medicine, Department of Pediatrics (Barry), School of Medicine, and Department of Statistics (Drake), University of California, Davis, CA 95616, and The Upjohn Co, Kalamazoo, Ml 49001 (Brown).

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Michael J. Woliner From the Comparative Gastroenterology Laboratory, Department of Surgical and Radiological Sciences (Vatistas, Snyder, Hildebrand, Harmon, Woliner), Veterinary Medical Teaching Hospital (Nieto, Henry, Enos), and Department of Anatomy (Magliano), School of Veterinary Medicine, Department of Pediatrics (Barry), School of Medicine, and Department of Statistics (Drake), University of California, Davis, CA 95616, and The Upjohn Co, Kalamazoo, Ml 49001 (Brown).

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Sean J. Barry From the Comparative Gastroenterology Laboratory, Department of Surgical and Radiological Sciences (Vatistas, Snyder, Hildebrand, Harmon, Woliner), Veterinary Medical Teaching Hospital (Nieto, Henry, Enos), and Department of Anatomy (Magliano), School of Veterinary Medicine, Department of Pediatrics (Barry), School of Medicine, and Department of Statistics (Drake), University of California, Davis, CA 95616, and The Upjohn Co, Kalamazoo, Ml 49001 (Brown).

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J. Nieto From the Comparative Gastroenterology Laboratory, Department of Surgical and Radiological Sciences (Vatistas, Snyder, Hildebrand, Harmon, Woliner), Veterinary Medical Teaching Hospital (Nieto, Henry, Enos), and Department of Anatomy (Magliano), School of Veterinary Medicine, Department of Pediatrics (Barry), School of Medicine, and Department of Statistics (Drake), University of California, Davis, CA 95616, and The Upjohn Co, Kalamazoo, Ml 49001 (Brown).

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Pegeen Henry From the Comparative Gastroenterology Laboratory, Department of Surgical and Radiological Sciences (Vatistas, Snyder, Hildebrand, Harmon, Woliner), Veterinary Medical Teaching Hospital (Nieto, Henry, Enos), and Department of Anatomy (Magliano), School of Veterinary Medicine, Department of Pediatrics (Barry), School of Medicine, and Department of Statistics (Drake), University of California, Davis, CA 95616, and The Upjohn Co, Kalamazoo, Ml 49001 (Brown).

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L. Reed Enos From the Comparative Gastroenterology Laboratory, Department of Surgical and Radiological Sciences (Vatistas, Snyder, Hildebrand, Harmon, Woliner), Veterinary Medical Teaching Hospital (Nieto, Henry, Enos), and Department of Anatomy (Magliano), School of Veterinary Medicine, Department of Pediatrics (Barry), School of Medicine, and Department of Statistics (Drake), University of California, Davis, CA 95616, and The Upjohn Co, Kalamazoo, Ml 49001 (Brown).

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David Magliano From the Comparative Gastroenterology Laboratory, Department of Surgical and Radiological Sciences (Vatistas, Snyder, Hildebrand, Harmon, Woliner), Veterinary Medical Teaching Hospital (Nieto, Henry, Enos), and Department of Anatomy (Magliano), School of Veterinary Medicine, Department of Pediatrics (Barry), School of Medicine, and Department of Statistics (Drake), University of California, Davis, CA 95616, and The Upjohn Co, Kalamazoo, Ml 49001 (Brown).

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Scott A. Brown From the Comparative Gastroenterology Laboratory, Department of Surgical and Radiological Sciences (Vatistas, Snyder, Hildebrand, Harmon, Woliner), Veterinary Medical Teaching Hospital (Nieto, Henry, Enos), and Department of Anatomy (Magliano), School of Veterinary Medicine, Department of Pediatrics (Barry), School of Medicine, and Department of Statistics (Drake), University of California, Davis, CA 95616, and The Upjohn Co, Kalamazoo, Ml 49001 (Brown).

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Christiana Drake From the Comparative Gastroenterology Laboratory, Department of Surgical and Radiological Sciences (Vatistas, Snyder, Hildebrand, Harmon, Woliner), Veterinary Medical Teaching Hospital (Nieto, Henry, Enos), and Department of Anatomy (Magliano), School of Veterinary Medicine, Department of Pediatrics (Barry), School of Medicine, and Department of Statistics (Drake), University of California, Davis, CA 95616, and The Upjohn Co, Kalamazoo, Ml 49001 (Brown).

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Abstract

Objective

To determine the effects of the 21-amino-steroid, U-74389G, on reperfusion of the equine jejunum, using total (TVO) and partial (PVO) vascular occlusion during the ischemic period.

Design

TVO: 16 healthy horses were randomly allotted to 3 groups—4 horses received the vehicle alone, 6 horses received a low dosage (3 mg/kg of body weight), and 6 horses a high dosage (10 mg/kg) of U-74389G. PVO: 10 healthy horses were randomly allotted to 2 groups—5 horses received the vehicle alone, and 5 horses received the low dosage (3 mg/kg) of U-74389G.

Procedure

TVO was induced for 1 hour followed by 2 hours of reperfusion. During PVO, blood flow was reduced to 20% of baseline for 2 hours, followed by 2 hours of reperfusion.

For both models, either the vehicle alone or the drug was given 15 minutes prior to reperfusion. Samples were obtained before, during, and after ischemia for determination of myeloperoxidase (MPO) activity, malondealdehyde (MDA) concentration, concentration of conjugated dienes (PVO experiment only), and morphometric analysis.

Results

TVO: tissue concentration of MDA and MPO activity were not altered in any group by ischemia or reperfusion. During ischemia, mucosal volume and surface area were reduced. After reperfusion, no further reduction occurred. After initial decrease in submucosal volume during ischemia, there was a significant increase after reperfusion in the vehicle-only group (P < 0.05). PVO: there were no alterations in the concentration of either MDA or conjugated dienes. There was a significant increase in the activity of MPO during ischemia and reperfusion (P< 0.05). These effects were similar for the vehicle-only and drug groups. During ischemia, there was a significant decrease in mucosal surface area and volume (P< 0.05), that was continued during reperfusion for the vehicle-only group (P< 0.05). Submucosal volume increased during reperfusion (P< 0.05). Serosal volume was increased during ischemia and reperfusion.

Conclusions and Clinical Relevance

Reduced blood flow during ischemia (PVO group) caused continued loss in mucosal volume and surface area during reperfusion. At the dosage given, the 21-aminosteroid, U-74389G, was not effective in preventing continued reduction in mucosal volume and surface area after restoration of blood supply in the horses subjected to reduced blood flow. (Am J Vet Res 1996; 57:762–770)

Abstract

Objective

To determine the effects of the 21-amino-steroid, U-74389G, on reperfusion of the equine jejunum, using total (TVO) and partial (PVO) vascular occlusion during the ischemic period.

Design

TVO: 16 healthy horses were randomly allotted to 3 groups—4 horses received the vehicle alone, 6 horses received a low dosage (3 mg/kg of body weight), and 6 horses a high dosage (10 mg/kg) of U-74389G. PVO: 10 healthy horses were randomly allotted to 2 groups—5 horses received the vehicle alone, and 5 horses received the low dosage (3 mg/kg) of U-74389G.

Procedure

TVO was induced for 1 hour followed by 2 hours of reperfusion. During PVO, blood flow was reduced to 20% of baseline for 2 hours, followed by 2 hours of reperfusion.

For both models, either the vehicle alone or the drug was given 15 minutes prior to reperfusion. Samples were obtained before, during, and after ischemia for determination of myeloperoxidase (MPO) activity, malondealdehyde (MDA) concentration, concentration of conjugated dienes (PVO experiment only), and morphometric analysis.

Results

TVO: tissue concentration of MDA and MPO activity were not altered in any group by ischemia or reperfusion. During ischemia, mucosal volume and surface area were reduced. After reperfusion, no further reduction occurred. After initial decrease in submucosal volume during ischemia, there was a significant increase after reperfusion in the vehicle-only group (P < 0.05). PVO: there were no alterations in the concentration of either MDA or conjugated dienes. There was a significant increase in the activity of MPO during ischemia and reperfusion (P< 0.05). These effects were similar for the vehicle-only and drug groups. During ischemia, there was a significant decrease in mucosal surface area and volume (P< 0.05), that was continued during reperfusion for the vehicle-only group (P< 0.05). Submucosal volume increased during reperfusion (P< 0.05). Serosal volume was increased during ischemia and reperfusion.

Conclusions and Clinical Relevance

Reduced blood flow during ischemia (PVO group) caused continued loss in mucosal volume and surface area during reperfusion. At the dosage given, the 21-aminosteroid, U-74389G, was not effective in preventing continued reduction in mucosal volume and surface area after restoration of blood supply in the horses subjected to reduced blood flow. (Am J Vet Res 1996; 57:762–770)

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