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Extracellular concentration of ascorbic acid and catecholamines in the rat striatum during cerebral ischaemia and reperfusion
J Mol
Cell
Cardiol20
(Supplement
V) (1988)
22
EXTRACELLULAR CONCENTRATION OF ASCORBIC ACID AND CATECHOLAMINES IN THE RAT STRIATUM DURING CEREBRAL ISCHAEMIA AND REPERFUSION. T.P. Obrenovitch, T. Matsumoto, L. Symon. Gough-Cooper Department of Neurological Surgery, Institute of Neurology, London, England. Various data support the concept that, as in other organs, an increased production of free radicals occurs in brain tissue during ischaemia/reperfusion, which could be particularly deleterious to the heavily lipoidal membranes of the central nervous system. One possible source of free radicals in brain tissue could be the oxidation of catecholamines, known to be released during ischaemia. To test this hypothesis, the extracellular levels of ascorbic acid (a free radical scavenger under normal physiologic conditions) and dopamine and its metabolites, were examined in the striatum, a catecholamine-rich structure. Experiments were performed in anesthetized rats subjected to 20-min severe global cerebral ischaemia followed by 80 min reperfusion. Repeated measurements were performed in ViVQ using both voltammetry and dialysis (Dr. G.S. Sarna and Professor G. Curzon, Department of Neurochemistry). Dopamine increased dramatically immediately after the onset of ischaemia, to reach a peak level within the first five minutes (voltammetry), and within the first dialysis sample (20 minutes). It returned as rapidly to its normal level, or slightly below, following reperfusion. Various patterns of changes in ascorbic acid were found during ischaemia, but a marked increase consistantly developed early during reperfusion. These results will be discussed with emphasis on the dual role of ascorbic acid in the central nervous system, e.g. scavenger of free radicals and involvement in neurotransmission.
23
ANTI-ISCHAFZIC ACTION OF N-HYDBOXY AGENT. P.Komarov, A.Morgunov, R.Zhdaoov,
SPIN
LABEL: A NOVEI, AN'j?IOXIDANT Research Institute of Drugs,
M.Bilenko,
the U.S.S.R. We had earlier shown for model systems ( liposomes and liver microsomes ) that N-hydroxy-2,2,6,6,-tetramethylpiperidine (W-OH) derivatives oxidized to nitroxyl membrane lipid peroxidation spin labels in water solutions could markedly inhibit (QO). Injection of highly active sulfur-containing TEXP-OH ( I, IO3 M ) in perfuse medium of isolated and undergoing total ischemia ( 30 min, 37'C ) rat heart ( by the Lsngendorff method ) has shown to improve si@&sntly heart contractile function ( Pmax ) and coronary flow ( CF ) as compared with the control medium ( 36 and 4@, respectively. P 0.01 ). Injection of I ( IO4 M ) into a medium for storage of isolated liver or liver microsomes prevents LPO products accumulation ( MDA ) end destruction of oytoohrome P-450 membrane-bound protein. In vivo injection of I ( 12 mg/kg, i.p. ) increases by a factor of 3 the number of rats survival after sublethal time ( 2.5 hr ) of liver ischaemia. Injection of I ( 60 mg/ , i.p. ) increases by a factor 6 hr isohaemia and reperfusion of 4 the nuinber of rats survival after ischaemic and CF, have improved oonsiderof limbs ), and parameters of the heart function, P es sn?%xidents may turn out to be very ably. Thus, the study of TEMP-OH derivatives, promising
24
for
anti-isohaemio
protection.
EFFECTS OF MILRINONE AND ISOBUTYLMETHYLXANTHINE (IBMX) ON ISCHARMIA INDUCED ARRHYTHMIAS AND PLATELET AGGREGATION IN ANAESTHETISH) RABBITS. M. Holbrook a S.J. Coker. Department of Pharmacology and Therapeutics, University of Liverpool, U.K. The phosphodiesterase (PDE) inhibitors IBMX and milrinone (1OOng kg-l + 1Opg kg-l min-l i.v.) were administered to anaesthetised rabbits. After 10 min the left circumflex coronary artery was occluded for 20 min then reperfused for 10 min and platelet aggregation measured ex viva. n VF Mortality A8T AHR ABP Platelet Aggregation (b m.ir~-~) (mmHq> Collagen % ISO/ADP (mV) Control 6 83% 50% 0.19 + 0.08 -5 + 3 -1 + 4 83% 12 + 5 IBMX 7 14%** 14%* 0.23 -+ 0.07 10 f 3* -5 + 4 43% -12 -+ 8* Milrinone 8 75% 75% 0.42 + O.lO* 32 -+ 6** -12 f 2* 25%* -30 2 11** With both drugs, isoprenaline inhibited ADP induced agqreqation (% ISO/ADP) whereas a small increase-in response was seen in controls. --The number of animals IBMX whose platelets responded to collagen was also reduced by the PDE inhibitors. reduced VF and mortality during ischaemia. Milrinone, however, increased ST-segment These results suggest that the antifibrillatory elevation and VF was always fatal. effect of IBMX is independent of reduced platelet responsiveness. The adverse effects of milrinone may be related to the greater reflex tachycardia observed with . this drug.
S.26
Cell
Cardiol20
(Supplement
V) (1988)
22
EXTRACELLULAR CONCENTRATION OF ASCORBIC ACID AND CATECHOLAMINES IN THE RAT STRIATUM DURING CEREBRAL ISCHAEMIA AND REPERFUSION. T.P. Obrenovitch, T. Matsumoto, L. Symon. Gough-Cooper Department of Neurological Surgery, Institute of Neurology, London, England. Various data support the concept that, as in other organs, an increased production of free radicals occurs in brain tissue during ischaemia/reperfusion, which could be particularly deleterious to the heavily lipoidal membranes of the central nervous system. One possible source of free radicals in brain tissue could be the oxidation of catecholamines, known to be released during ischaemia. To test this hypothesis, the extracellular levels of ascorbic acid (a free radical scavenger under normal physiologic conditions) and dopamine and its metabolites, were examined in the striatum, a catecholamine-rich structure. Experiments were performed in anesthetized rats subjected to 20-min severe global cerebral ischaemia followed by 80 min reperfusion. Repeated measurements were performed in ViVQ using both voltammetry and dialysis (Dr. G.S. Sarna and Professor G. Curzon, Department of Neurochemistry). Dopamine increased dramatically immediately after the onset of ischaemia, to reach a peak level within the first five minutes (voltammetry), and within the first dialysis sample (20 minutes). It returned as rapidly to its normal level, or slightly below, following reperfusion. Various patterns of changes in ascorbic acid were found during ischaemia, but a marked increase consistantly developed early during reperfusion. These results will be discussed with emphasis on the dual role of ascorbic acid in the central nervous system, e.g. scavenger of free radicals and involvement in neurotransmission.
23
ANTI-ISCHAFZIC ACTION OF N-HYDBOXY AGENT. P.Komarov, A.Morgunov, R.Zhdaoov,
SPIN
LABEL: A NOVEI, AN'j?IOXIDANT Research Institute of Drugs,
M.Bilenko,
the U.S.S.R. We had earlier shown for model systems ( liposomes and liver microsomes ) that N-hydroxy-2,2,6,6,-tetramethylpiperidine (W-OH) derivatives oxidized to nitroxyl membrane lipid peroxidation spin labels in water solutions could markedly inhibit (QO). Injection of highly active sulfur-containing TEXP-OH ( I, IO3 M ) in perfuse medium of isolated and undergoing total ischemia ( 30 min, 37'C ) rat heart ( by the Lsngendorff method ) has shown to improve si@&sntly heart contractile function ( Pmax ) and coronary flow ( CF ) as compared with the control medium ( 36 and 4@, respectively. P 0.01 ). Injection of I ( IO4 M ) into a medium for storage of isolated liver or liver microsomes prevents LPO products accumulation ( MDA ) end destruction of oytoohrome P-450 membrane-bound protein. In vivo injection of I ( 12 mg/kg, i.p. ) increases by a factor of 3 the number of rats survival after sublethal time ( 2.5 hr ) of liver ischaemia. Injection of I ( 60 mg/ , i.p. ) increases by a factor 6 hr isohaemia and reperfusion of 4 the nuinber of rats survival after ischaemic and CF, have improved oonsiderof limbs ), and parameters of the heart function, P es sn?%xidents may turn out to be very ably. Thus, the study of TEMP-OH derivatives, promising
24
for
anti-isohaemio
protection.
EFFECTS OF MILRINONE AND ISOBUTYLMETHYLXANTHINE (IBMX) ON ISCHARMIA INDUCED ARRHYTHMIAS AND PLATELET AGGREGATION IN ANAESTHETISH) RABBITS. M. Holbrook a S.J. Coker. Department of Pharmacology and Therapeutics, University of Liverpool, U.K. The phosphodiesterase (PDE) inhibitors IBMX and milrinone (1OOng kg-l + 1Opg kg-l min-l i.v.) were administered to anaesthetised rabbits. After 10 min the left circumflex coronary artery was occluded for 20 min then reperfused for 10 min and platelet aggregation measured ex viva. n VF Mortality A8T AHR ABP Platelet Aggregation (b m.ir~-~) (mmHq> Collagen % ISO/ADP (mV) Control 6 83% 50% 0.19 + 0.08 -5 + 3 -1 + 4 83% 12 + 5 IBMX 7 14%** 14%* 0.23 -+ 0.07 10 f 3* -5 + 4 43% -12 -+ 8* Milrinone 8 75% 75% 0.42 + O.lO* 32 -+ 6** -12 f 2* 25%* -30 2 11** With both drugs, isoprenaline inhibited ADP induced agqreqation (% ISO/ADP) whereas a small increase-in response was seen in controls. --The number of animals IBMX whose platelets responded to collagen was also reduced by the PDE inhibitors. reduced VF and mortality during ischaemia. Milrinone, however, increased ST-segment These results suggest that the antifibrillatory elevation and VF was always fatal. effect of IBMX is independent of reduced platelet responsiveness. The adverse effects of milrinone may be related to the greater reflex tachycardia observed with . this drug.
S.26