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On the mode of cardioprotective action of nitroxyl radicals
J Mol Cell Cardiol 24 (Supplement V) (1992)
October 1,1992 Consequences of Myocardial
Oral presentation III: 10.40 - 12.20 Ischemia and their Treatment
19
TRANSIENT INITIAL REPERFUSION WlTH OXYGENATED CARDIOPLEGIA: CONTRASTING EFFECTS OF SUBSTRATE ADDlTION TO ST THOMAS’ SOLUTIONS 1 AND 2. Deborah M Harvey, Graham E Venn, David J Chambers. Cardiac Surgical Research, The Rayne Institute, StThomas'Hospital,LondonSEl7EH,UK. Theprotectiveeffectsofcardioplegicarrestandhypothermiaonischemicmyocardiummaybenegated by 'reperfusioninjury'.Modifcationoftheinitialreperfusionsolutionmayprovideadditionalprotection.Weusedthe isolatedworkingrath~toinvestigatewhether(i)transientinitialreperfusionwithoxygenated(95%0 +50COz) StThomas'Hospitalcardioplegicsolutions (STl:[mM]Na+, 144;K+,u); M~,16;Caz+,2.4;pmcaine,1:~2:[mMl: Na+, 110; K+, 16; Me, 16; Ca*+,1.2; HCO%',10) after hypothermic (20°C) global ischemia would improve postischemicfunctionalrecoveryand(ii)additionofsubstrates(glucoseorpyruvate)couldfintherinfluenceanyeffect. Afteraerobicperfusionwithbicarbonatebuffer[BB](conbolfunctionmeasured),arrestwithnon-oxygenatedSTl orST2andglobal(2O0C)ischemiafor2or4h,respectively,heartswerereperfused(Langendorff)initiallywith STIandST2for5,10,15or20minbeforeBB(30mintotalLangendorffand30minworkingmode(function measured)reperfusion).STlcausedadme-dependentdecreaseinrecovery:aorticflow(AF)was31f8%,~%, 0%and0%,respectively,comparedto51f6%incontrolhearts(BBalone).ST2hadnoeffect:recovery(AF)was 65f6%in controlheartsversus651t5%,~7%,5~%and5(n7%,respectively.Additionofglucose(llmM)to STlorST2(5minreperfusion)hadnoeffect;recoverywas41+14%and53f7%vs54f7%and5~7%(controls), resDectivelv.Pvruvate15mM)addedtoSTlalsohadnoeffectanddidnot~ucethedele~riouseffect:however. ad;lingpyr;vatktoSTisi~cantly@<0.05)improvedrecovery(AF:68~7%~~4~%incontrol(nosubstratej hearts).Pyruvatemaystimulatepost-ischemicoxidativephosphorylation,therebyreducing'reperfusioninjury'.
79
EFFECTS OF SOD, CATALASE, AND EGB 761 ON REPERFUSION INJURY IN ISOLATED RAT HEARTS M.T. Droy-Lefaix, A. Tosaki*. IPSEN, Paris, France; *Biol. Res. Ctr., Szeged, Hungary. Effects of superoxide dismutase (SOD), catalase (CAT), and EGB 761 (extract of Ginkgo biloba) on rep&&on-induced ventricular fibrillation o/F), ventricular tachycardia (VT), and the formation of oxygen free radicals were studied after 30 min ischemia followed by reperfusion in isolated hearts. Rats received 104, 2~10~ or 5~10~ U/kg of SOD (i.v.), 2.5x104, 5~10~ or 10’ U/kg of CAT (i.v.), 25, 50, 100 or 200 mg/kg of EGB 761 (per OS), respectively, for 10 days (“chronic application”). Neither SOD nor CAT reduced the incidence of VF and VT, but EGB 76 1 dose-dependently reduced the incidence of VF and VT. The combination of SOD (5~10~ U/kg) with CAT (5~10~ U/kg) decreased VF and VT, and a same reduction was observed when SOD (5~10~ U/kg) was given in combination with EGB 761 (50 mg/kg). When SOD (5x10’ U/L) and CAT (5~10~ U/L) were included in the perfusion buffer and coadministered (“acute treatment”), the incidence of VF and VT was significantly reduced. The combination of SOD (5~10~ U/L) with EGB 761 (50 mg/L) also reduced VF and VT. EGB 761 (200 mg/L) or the coadministration of EGB 761(50 mg/L) with SOD (5~10~ U/L) completely abolished the formation of oxygen radicals during reperfusion measured by electron spin resonance spectroscopy. Our results indicate that free radical scavengers may reduce the severity of reperfusion-induced injury.
80
ON THE
MODE
OF
CARDIOPROTECTIVE
ACTION
OF
NITROXYL
TICALB
I.E. Blasig, K. Schoenheit, R.F. Haszloff, A. Tosaki . Res. Inst. Mol. Pharmacol., O-1136 Berlin, Germany, Biol. Res. Centre, H-6701 Szeged, Hungary. Nitroxyl radicals have been suggested to reduce reperfusion-induced rhythm disturbances of the heart. The mode of cardioprotective action of these radicals is still unknown. Therefore, the effect of pentamethylimidazoline nitroxyl radical (PMIO') and its nitrone derivative pentamethylimidazoline oxide (PMIO) was investigated in isolated perfused working rat hearts underwent 30 min total global ischemia and reperfusion. During reperfusion, PMIO' (2000 PM) reduced incidence of duration of ventricular tachycardia and imventricular fibrillation, proved coronary flow, aortic flow, left ventricular (LV) developed LV contractility compared to the untreated control (pcO.05, pressure, n=12). PM10 showed cardioprotective effects already in lower concentrations (500 MM, ~~0.01, n=12). Comparing the efficacy of the studied, it is concluded that the protective action is compounds rather related to the nitrone structure than to the nitroxyl radical, indicating a limited pharmacological relevance of nitroxyl compounds. S.16
October 1,1992 Consequences of Myocardial
Oral presentation III: 10.40 - 12.20 Ischemia and their Treatment
19
TRANSIENT INITIAL REPERFUSION WlTH OXYGENATED CARDIOPLEGIA: CONTRASTING EFFECTS OF SUBSTRATE ADDlTION TO ST THOMAS’ SOLUTIONS 1 AND 2. Deborah M Harvey, Graham E Venn, David J Chambers. Cardiac Surgical Research, The Rayne Institute, StThomas'Hospital,LondonSEl7EH,UK. Theprotectiveeffectsofcardioplegicarrestandhypothermiaonischemicmyocardiummaybenegated by 'reperfusioninjury'.Modifcationoftheinitialreperfusionsolutionmayprovideadditionalprotection.Weusedthe isolatedworkingrath~toinvestigatewhether(i)transientinitialreperfusionwithoxygenated(95%0 +50COz) StThomas'Hospitalcardioplegicsolutions (STl:[mM]Na+, 144;K+,u); M~,16;Caz+,2.4;pmcaine,1:~2:[mMl: Na+, 110; K+, 16; Me, 16; Ca*+,1.2; HCO%',10) after hypothermic (20°C) global ischemia would improve postischemicfunctionalrecoveryand(ii)additionofsubstrates(glucoseorpyruvate)couldfintherinfluenceanyeffect. Afteraerobicperfusionwithbicarbonatebuffer[BB](conbolfunctionmeasured),arrestwithnon-oxygenatedSTl orST2andglobal(2O0C)ischemiafor2or4h,respectively,heartswerereperfused(Langendorff)initiallywith STIandST2for5,10,15or20minbeforeBB(30mintotalLangendorffand30minworkingmode(function measured)reperfusion).STlcausedadme-dependentdecreaseinrecovery:aorticflow(AF)was31f8%,~%, 0%and0%,respectively,comparedto51f6%incontrolhearts(BBalone).ST2hadnoeffect:recovery(AF)was 65f6%in controlheartsversus651t5%,~7%,5~%and5(n7%,respectively.Additionofglucose(llmM)to STlorST2(5minreperfusion)hadnoeffect;recoverywas41+14%and53f7%vs54f7%and5~7%(controls), resDectivelv.Pvruvate15mM)addedtoSTlalsohadnoeffectanddidnot~ucethedele~riouseffect:however. ad;lingpyr;vatktoSTisi~cantly@<0.05)improvedrecovery(AF:68~7%~~4~%incontrol(nosubstratej hearts).Pyruvatemaystimulatepost-ischemicoxidativephosphorylation,therebyreducing'reperfusioninjury'.
79
EFFECTS OF SOD, CATALASE, AND EGB 761 ON REPERFUSION INJURY IN ISOLATED RAT HEARTS M.T. Droy-Lefaix, A. Tosaki*. IPSEN, Paris, France; *Biol. Res. Ctr., Szeged, Hungary. Effects of superoxide dismutase (SOD), catalase (CAT), and EGB 761 (extract of Ginkgo biloba) on rep&&on-induced ventricular fibrillation o/F), ventricular tachycardia (VT), and the formation of oxygen free radicals were studied after 30 min ischemia followed by reperfusion in isolated hearts. Rats received 104, 2~10~ or 5~10~ U/kg of SOD (i.v.), 2.5x104, 5~10~ or 10’ U/kg of CAT (i.v.), 25, 50, 100 or 200 mg/kg of EGB 761 (per OS), respectively, for 10 days (“chronic application”). Neither SOD nor CAT reduced the incidence of VF and VT, but EGB 76 1 dose-dependently reduced the incidence of VF and VT. The combination of SOD (5~10~ U/kg) with CAT (5~10~ U/kg) decreased VF and VT, and a same reduction was observed when SOD (5~10~ U/kg) was given in combination with EGB 761 (50 mg/kg). When SOD (5x10’ U/L) and CAT (5~10~ U/L) were included in the perfusion buffer and coadministered (“acute treatment”), the incidence of VF and VT was significantly reduced. The combination of SOD (5~10~ U/L) with EGB 761 (50 mg/L) also reduced VF and VT. EGB 761 (200 mg/L) or the coadministration of EGB 761(50 mg/L) with SOD (5~10~ U/L) completely abolished the formation of oxygen radicals during reperfusion measured by electron spin resonance spectroscopy. Our results indicate that free radical scavengers may reduce the severity of reperfusion-induced injury.
80
ON THE
MODE
OF
CARDIOPROTECTIVE
ACTION
OF
NITROXYL
TICALB
I.E. Blasig, K. Schoenheit, R.F. Haszloff, A. Tosaki . Res. Inst. Mol. Pharmacol., O-1136 Berlin, Germany, Biol. Res. Centre, H-6701 Szeged, Hungary. Nitroxyl radicals have been suggested to reduce reperfusion-induced rhythm disturbances of the heart. The mode of cardioprotective action of these radicals is still unknown. Therefore, the effect of pentamethylimidazoline nitroxyl radical (PMIO') and its nitrone derivative pentamethylimidazoline oxide (PMIO) was investigated in isolated perfused working rat hearts underwent 30 min total global ischemia and reperfusion. During reperfusion, PMIO' (2000 PM) reduced incidence of duration of ventricular tachycardia and imventricular fibrillation, proved coronary flow, aortic flow, left ventricular (LV) developed LV contractility compared to the untreated control (pcO.05, pressure, n=12). PM10 showed cardioprotective effects already in lower concentrations (500 MM, ~~0.01, n=12). Comparing the efficacy of the studied, it is concluded that the protective action is compounds rather related to the nitrone structure than to the nitroxyl radical, indicating a limited pharmacological relevance of nitroxyl compounds. S.16