154 Antioxidant Therapy: Ischemia/Reperfusion, Bum/Trauma

16.13 INHIBITION OF POSTISCHEMIC REPERFUSION INJURY OF DOG BRAIN BY A SITE DIRECTED SOD DERIVATIVE Masayasu Indue, Yoshimasa Takeda, Hidenori Hashimoto, Futami Kosaka, and Junzo Sasaki Department of Biochemistry, Kumamoto University Medical School and Departments of Anesthesiogy & Anatomy, Okayama University Medical School JAPAN

Oxygen t o x i c i t y is one of the major cause for t issue in jury induced by postischemic reperfu- sion. When the common carot id and vertebral ar- ter ies were occluded for 18 min, a l l dogs died within 7 days due to severe neuronal death. Im- mediat ry a f t e r reper fus ion of the ischemic b ra in , i n t r a c r a n i a l pressure and blood f low markedly increased (react ive hyperperfusion). After 30 min, in t racran ia l pressure decreased with concomitant decrease in blood flow. The blood flow reached a steady state level which was s i gn i f i can t l y lower than in normal animals. We synthesized a SOD der ivat ive (SM-SOD) that c i rculates bound to albumin with a hal f l i f e of 6 h and accumulates in tissues whose extracel - l u la r pH is decreased. Intravenous administra- t ion of SM-SOD (4.5 mg/Kg ) s i gn i f i can t l y in- h ib i ted the increase in reperfusion-induced in- crease in in t racran ia l pressure and normalized the steady-state levels of the blood flow. His- to log ica l analysis revealed that HB-SOD sig- n i f i c a n t l y inh ib i ted the reperfusion-induced in- crease in vascular permeabi l i ty and brain edema. Al l animals injected with SM-SOD survived at least for several months a f ter experiments. SM- SOD permits studies on the mechanism of free- radical in jury of the reperfused brain in vivo.

PROTECTIVE EFFECT OF VITAMINS ON 16.14 INTRACELLULAR ATP DEGRADATION OF RAT HEART TISSUE AFFECTED BY GLOBAL ISCHEMIA _ 31p AND 19F NMR SPECTROSCOPIC STUDY - Masahiko Kotegawa, Takachika Shoji, Nobuya Haramaki, and Ryohei Ogura Department of Medical Biochemistry, Kurume University School of Medicine, Kurume, Japan 830

To clarify the protective mechanism of vitamins against ischemic damage of rat myocardium, NMR spectroscopic examina- tions were carried out. The isolated rat hearts were placed in the NMR in- strument and were perfused by the Lan- gendorff technique, followed by 30 min of global ischemia and 30 min of reper- fusion. From NMR analysis, intercellu- lar ATP and phosphocreatine were found to be degraded remarkably during ische- mia. In the hearts obtained from rats which had received vitamin E (CoQ10), interperitoneally for 7 consecutive days, the vitamin treatment was not able to prevent the degradation of ATP during ischemia, however the ATP content re- turned to the normal level rapidly dur- ing reperfusion following ischemia. In addition, damage to the mitochondrial respiration system due to ischemic stress was prevented. Further detailed effects of fat-soluble and water-soluble antioxidative vitamins on the oxygen cell toxicity during ishemia / reperfu- sion process will be discussed.

16.15 XANTHINE OXIDASE ACTIVITIES AND HYPOXANTHINE CONCENTRATIONS IN SERA OF PATIENTS RECEIVING TPA FOLLOWING ACUTE MYOCARDIAL INFARCTION

Dean P. Loven, Steven C. Kazmierczak, Edna D. Hodges, and Sabra A. Murphy Departments of Radiation Oncology and Clinical Pathology and Diagnostic Medicine, East Carolina University School of Medicine, Greenville, NC 27858

Tissue plasminogen ac t iva tor (TPA) is rout ine ly administered to pat ients presenting in the early stages of acute myocardial infarct ion. The therapeutic action of TPA in relieving obstruction may protect against reperfusion injury. The "washout" phenomenon of TPA has been clearly demonstrated by monitoring the time course of serum creatine kinase (CK) isoenzyme a c t i v i t i e s . We have observed great ly increased hypoxanthine concentrations in sera of patients receiving TPA compared to patients with AMI who do not receive this treatment. This suggests that TPA treatment and subsequent early reperfusion may result in substantial decreases in the tissue concentration of hypoxanthine which might otherwise be metabolized by xanthine oxidase, result ing in the generation of superoxide. Therefore, TPA may protect against reperfusion injury.

ISCHEMIA/REPERFUSION RAT LIVER DAMAGE - 16.16 PREVENTION BY ANTI-OXIDATIVE/ANTI-INFLAMMATORY COMBINATION THERAPY Dusan Marinkovic, Wilma M. Frederiks, Adri Maas Departments of Surgery, Cell Biology & Histology and J. van Gool Institute, Academic Medical Centre, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands

Administration of a combination of dimethyl sulfoxide (DMSO), chlorpromazine hydrochloride (CPZ) and vitamin E (vit. E) was found to result in a significant decrease in liver damage, induced by 60 min. of ischemia followed by reperfusion in fasted rats. Administration of only one of these drugs or a combination of two of these drugs had nor or just a slight effect upon liver injury in this model. Administration of these drugs did not result in liver protection when administered to fed rats; in these animals 60 min. of ischemia resulted in double the amount of necrosis in relation with the same period of ischemia induced in fasted rats. The protective effect of the applied combination therapy on the liver in this model may be due to synergistic anti-oxidative effect and to the ability of these drugs to act mutually as electron and hydrogen ion transport chain with a thereby greater capacity for free radical repair.