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Inhibition of tyrosine kinase inhibitor (ST638) against platelet activating factor induced gastric mucosal injury in rats
158
Antioxidant Therapy: Ischemia/Reperfusion,Burn/Trauma
16.29 CULTURED HEART MUSCLE CELLS - A MODEL FOR THE EVALUATION OF CARDIOPROTECTIVE ANTIOXIDANT COMPOUNDS B. Wagenknecht, M.Hug, G.HUbner* and K. Werdan; Dept. of Medicine I, Klinikum Grosshadern and *Inst. of Pathology, Univ. of Munich, F.R.G. Oxidative stress seems to play an important role in the pathogenesis of impaired cardiac function in various myocardial diseases. To study whether oxygen free radicals (OFR) have direct cardiotoxic effects in cardiomyocytes, we exposed cultured neonatal rat heart muscle cells to an enzymatically OFR-generating system. In v i t r o assays: Xanthine (O.8mM)/xanthine oxidase (50 mU/lO0 mU) generates 0~- ( i n i t i a l rate: 15 vs 26 nmol/min), H202 (conc. after 45 min: 340 vs 440 pM) and OH" in a time- and concentration-dependent way. I , vivo assays: In cultured heart muscle cells OFR cause negative chronotropy (TI/9: 15 min) and arrhythmias, decrease of cel1-~TP (T~/~:20 min) followed by ultrastructural alterat#6hs (swelling of mitochondria, hypercontracture of myofibrils). Eva] u a t i o . of drugs: SOD (lO0 U/ml) abolishes selectively 0~- formation, catalase (CAT; 100 U/ml) prevents H~O~ formation, th~ calcium antagonist felodipine (up to lO M) has no scavenging effects. In cardiomyocytes, CAT prevents the f a l l in cell-ATP and the functional and ultrastructural alterations, whereas SOD is not protective. Conclusion: Cultured heart muscle cells are a suitable experimental model for the evaluation and screening of cardioprotective antioxidant compounds by comparing the in vitro function with cellular effects.
16.31 INFLUENCE
OF SUPEROXIOE DISMUTASE AND ILOPROST ON THE ISCHEMIA INDUCED ARRHYTHMIAS ANO POSTISCHEMICIMYOCAROIAL FUNCTION U. Zelck , F. J~nichen and U. Karnstedt 1 Institute of Pharmacologyland Toxicology, 2 The University of Rostock and Greifswald , GDR The reduction of infarct size by superoxide dismutase (SOD) and/or Iloprost in cases of longer ischemia (60-120 min) must not necessarily be accompanied by an improvement of the postischemic myocardial function )PIMF) in the central parts of the ischemic area. Therefore we measured directly the regional systolic shortening (RSS) in the centre of the temporarily ischemic region of "open chest" rats after 60 min of coronary occlusion (CO). SOD was given as a bolus injection into the carotid artery (CA) during the 5th min both the CO period and the 60 min reperfusion period. The Iloprost infusion into the CA began 5 min after CO and lasted 120 min. The PIMF was significantly improved by the 2x12.000, 2 x 20.000and the 2 x 40.000 U/kg SOD application, whereby human and bovine SOD's showed equieffective effects. Iloprost in doses of 200 ng/kg min was also effective, whereas doses of i00 ng/kg min had no significant effect. The arrhythmia score in the early phase of arrhythmia(first 30 min) was significantly diminished by SOD in doses of 20.000 and 40.000 U/kg. Also here human and bovine SOD's had equieffective effects. Iloprost in doses of I00 or 200 ng/kg min had no antiarrhythmic effects. The application of SOD must be favoured because of its additional antiarrhythmic effects.
INIIIRITIONOF TYROS/ME KINASE INHIBITOR (ST638) AGAINST PLATELET ACITVA~ING FACTOR INDUCED GASTRIC MUCOSAL IN~URY IN RATS H.Ichikawa~ T.Yoshikawa~ Y.Naito,H.Takano, M.Yasud8~ S.Takahash~ and M.Kofido.First Department of Medicine, ~
EFFECTS OF DILTIAZEM AND LOW-DOSEASPIRIN ON LIPIDPEROXIDATION IN PATIENTS WITH CORONARY HEARTDISEASE Xue ZHao,Yuanhui Zhang, and Hunfan9 Fen9 Department of Cardiotooy, Southwestern HospitaL, Chongqino 630030, China The e f f e c t s of therapeutic dose of dittiazem, aspirin 30n9 daily and their combination on sermi tipidperoxides (LPO) Level and Cu-Zn superoxide dismutase (CuZn-SOD) concentration were investi ated in 60 patients with coronary heart disease in a pLacebo-controLLed, randomized protocot. Thirty-two healthy subjects were also investioated as normal contrott oroup.These a0ents were given for 10-14 days. Serum LPO Level in the patients was abnormaLLy elevated, whereas no si nificant difference in serum CuZn-SOD concentration could be found between the healthy subjects and the patients.Both dittiazom and aspirin could markedty decrease serum LPO Level in the patients, with inhibition of 1 5 . 8 ~ and 1 7 . 1 ~ respectively. The inhlbitary e f f e c t of their combination on serum LPO Level increased to 2 4 . 3 ~ . Serum CuZn-SOD concentration was unaffected si@nificantty by any drug.These date indicate that both therapeutic dose of dittiazom and low-dose aspirin may inhibit tipldperoxldatlon in patients with coronary heart dlsease, and the combination of both aents result in the best effect.
6.30
16.32
Antioxidant Therapy: Ischemia/Reperfusion,Burn/Trauma
16.29 CULTURED HEART MUSCLE CELLS - A MODEL FOR THE EVALUATION OF CARDIOPROTECTIVE ANTIOXIDANT COMPOUNDS B. Wagenknecht, M.Hug, G.HUbner* and K. Werdan; Dept. of Medicine I, Klinikum Grosshadern and *Inst. of Pathology, Univ. of Munich, F.R.G. Oxidative stress seems to play an important role in the pathogenesis of impaired cardiac function in various myocardial diseases. To study whether oxygen free radicals (OFR) have direct cardiotoxic effects in cardiomyocytes, we exposed cultured neonatal rat heart muscle cells to an enzymatically OFR-generating system. In v i t r o assays: Xanthine (O.8mM)/xanthine oxidase (50 mU/lO0 mU) generates 0~- ( i n i t i a l rate: 15 vs 26 nmol/min), H202 (conc. after 45 min: 340 vs 440 pM) and OH" in a time- and concentration-dependent way. I , vivo assays: In cultured heart muscle cells OFR cause negative chronotropy (TI/9: 15 min) and arrhythmias, decrease of cel1-~TP (T~/~:20 min) followed by ultrastructural alterat#6hs (swelling of mitochondria, hypercontracture of myofibrils). Eva] u a t i o . of drugs: SOD (lO0 U/ml) abolishes selectively 0~- formation, catalase (CAT; 100 U/ml) prevents H~O~ formation, th~ calcium antagonist felodipine (up to lO M) has no scavenging effects. In cardiomyocytes, CAT prevents the f a l l in cell-ATP and the functional and ultrastructural alterations, whereas SOD is not protective. Conclusion: Cultured heart muscle cells are a suitable experimental model for the evaluation and screening of cardioprotective antioxidant compounds by comparing the in vitro function with cellular effects.
16.31 INFLUENCE
OF SUPEROXIOE DISMUTASE AND ILOPROST ON THE ISCHEMIA INDUCED ARRHYTHMIAS ANO POSTISCHEMICIMYOCAROIAL FUNCTION U. Zelck , F. J~nichen and U. Karnstedt 1 Institute of Pharmacologyland Toxicology, 2 The University of Rostock and Greifswald , GDR The reduction of infarct size by superoxide dismutase (SOD) and/or Iloprost in cases of longer ischemia (60-120 min) must not necessarily be accompanied by an improvement of the postischemic myocardial function )PIMF) in the central parts of the ischemic area. Therefore we measured directly the regional systolic shortening (RSS) in the centre of the temporarily ischemic region of "open chest" rats after 60 min of coronary occlusion (CO). SOD was given as a bolus injection into the carotid artery (CA) during the 5th min both the CO period and the 60 min reperfusion period. The Iloprost infusion into the CA began 5 min after CO and lasted 120 min. The PIMF was significantly improved by the 2x12.000, 2 x 20.000and the 2 x 40.000 U/kg SOD application, whereby human and bovine SOD's showed equieffective effects. Iloprost in doses of 200 ng/kg min was also effective, whereas doses of i00 ng/kg min had no significant effect. The arrhythmia score in the early phase of arrhythmia(first 30 min) was significantly diminished by SOD in doses of 20.000 and 40.000 U/kg. Also here human and bovine SOD's had equieffective effects. Iloprost in doses of I00 or 200 ng/kg min had no antiarrhythmic effects. The application of SOD must be favoured because of its additional antiarrhythmic effects.
INIIIRITIONOF TYROS/ME KINASE INHIBITOR (ST638) AGAINST PLATELET ACITVA~ING FACTOR INDUCED GASTRIC MUCOSAL IN~URY IN RATS H.Ichikawa~ T.Yoshikawa~ Y.Naito,H.Takano, M.Yasud8~ S.Takahash~ and M.Kofido.First Department of Medicine, ~
EFFECTS OF DILTIAZEM AND LOW-DOSEASPIRIN ON LIPIDPEROXIDATION IN PATIENTS WITH CORONARY HEARTDISEASE Xue ZHao,Yuanhui Zhang, and Hunfan9 Fen9 Department of Cardiotooy, Southwestern HospitaL, Chongqino 630030, China The e f f e c t s of therapeutic dose of dittiazem, aspirin 30n9 daily and their combination on sermi tipidperoxides (LPO) Level and Cu-Zn superoxide dismutase (CuZn-SOD) concentration were investi ated in 60 patients with coronary heart disease in a pLacebo-controLLed, randomized protocot. Thirty-two healthy subjects were also investioated as normal contrott oroup.These a0ents were given for 10-14 days. Serum LPO Level in the patients was abnormaLLy elevated, whereas no si nificant difference in serum CuZn-SOD concentration could be found between the healthy subjects and the patients.Both dittiazom and aspirin could markedty decrease serum LPO Level in the patients, with inhibition of 1 5 . 8 ~ and 1 7 . 1 ~ respectively. The inhlbitary e f f e c t of their combination on serum LPO Level increased to 2 4 . 3 ~ . Serum CuZn-SOD concentration was unaffected si@nificantty by any drug.These date indicate that both therapeutic dose of dittiazom and low-dose aspirin may inhibit tipldperoxldatlon in patients with coronary heart dlsease, and the combination of both aents result in the best effect.
6.30
16.32