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No-formation in bovine endothelial cells and protection of isolated ischemic rat hearts is mediated by local CE-inhibition
J Mol Cell Cardiol 24 (Supplement I) (1992) O-16-6
CARDIOPROTECTION BY NISOLDIPINE: ROLE Roberto Ferrari, Salvatore Cur&a, Claudia Ceconi, Cardiology, University of Brescia, Brescia, Italy.
OF TIMING OF ADMINISTRATION Anna Cqnoni, Evasio Pa&i, Gdoardo
Visioli.
Department
of
Nisoldipine (N), was administered at 10m9 M to isolated and perfused rabbit hearts submitted to 60’ ischaemia (1 ml/tin) followed by 30’ of reperfusion. N was delivered either 30’ before ischaemia, at the onset and after 30’ of iscbaemia and during repefusiononly. Cardiac protection was evaluatedin termsof recovery of the left ventricular pressure developed during reperfosion, release of CPK, mitochondrial function, tissue contents of ATP and CP, calcium homeostasis and the occurrence of oxidative stress, established measuring content and release of reduced and oxidized glutathione (GSH-GSSG). The cytopmtective action of N occurs in absence of negative inotropism and is closely related to the time of administration. Optimal myocardial preservation in achieved when N is given before or at the onset of ischaemia. Prophylactic administrationof N improved the recovery of the developed pressure from 15.9+1.0 to 47.8~1.9 mmHg, (P
O-16-7 NO-FORMATION
IN BOVINE ENDOTHELIAL CELLS AND PROTECTION OF ISOLATED ISCHEMIC BAT HEARTS IS MElDIATED BY LOCAL CEINFIIBITION Wolfgang Linz, Gabriele Wiemer and Bernward A. Schblkens Hoechst AG, D-6230 Frankfurt/Main, Germany We were interested if increased endogenous bradykinin (BK) via local CE-inhibition with ramiprilat (RT) induces nitric oxide (NO)-formation in cultured bovine aortic endothelial cells (BAEC) and furthermore is NO built up by this way protective in isolated rat hearts with postischemic reperfusion arrhythmias. 61n BAEC, CE-inhibition by FT (1x10-’ - 1~10~~ mol/l) or addition of exogenous BK (1~10-~ 1x10- mol/l) stimulated the formation of NO assessed by endothelial cyclic GMP- and prgta!yclinsynthesis. Cychc GMP Synthesis was completely supposed by the NO sy?thase inhibitor N -mtro;Lmol/l). In isolated yorkmg arginine (L-?A 1x10- mo!/l) an! by .tie B.2 anqomst HOE 140 (lgOrat hearts subjected to local lscherma with reperfusron both RT (1x10- mol/l) and BK (1x10- molll) reduced the incidence and duration of ventricular fibrillation. In parallel myocardial function (left ventricular pressure, coron p flow) and metabolism (l$gh energy rich phosphates), were improved. Addition of L-NNA (1x10- molll) or HOE 140 (1x10- mol/l) abolished the protective effects on the isolated ischemic rat heart. Inhibition of CE localized on the luminal side of the vascular endothelium results in increased synthesis of NO and prostacyclin by local accumulation of endothelium-derived BK. In ischemic rat hearts these mechanisms lead to cardioprotection.
0-16-8
R?O?X~IYr EFyT Ofl~I~uI~I~IT;~ 3 S ak.N ih . 6abae.
7 TIAC REIUWSIW IWlRY. Institute oa hof er andJ Stvk
for Heart Res., Slovak Aca& of Sciences: Eratislava', Czech and Slovak iederaiive Republik. The effect of pretreatint by phenothiazines - Chlorpromazine (0%) and Triflouperazine (TFP) on reperfusion injury of ischemic myocardiumwere,studied. Reperfusion after 40 min of ischeraia is known to result in morphological, functional and biochemical changes identical with those induced by enhanced cytosolic Ca2* concentration. Left descendin coronary ligation was performed on 70 dogs divided into four groups. Group I: occlusion (Occ 3 only (60 min, 120 min and 180 min); group II: 15 do s (60 min Occ + 120 min reperfusion, R); group III: 20 dogs (60 min Occ, 15 mg CPR, 120 min Rg; g roup IV: 20 dogs (60 min Occ, 2 mg TFP + 120 min R). CPR or TFP were administered 30 min before, 1 min prior or 30 min after the Oct. The effects of drugs were quantified on tetrazolium stained gross sections and studied from physiological, biochemical and ultrastructural points of view. The effect was dose dependent. The lowest amount of CPR exhibiting sufficient protective effect was 10 mg/kg bw and drugs were effective even if arhninistered 30 min after the Oct. Treatment of animals with phenothiazines considerably improved the ultrastructure of myocytes in area at risk, and allowed for the recover of about 60% of endangered myocytes after reflow restoration. Inhibition of calmdu f in appears to be an important factor in diminishing effect of calcium overload in postischemic reperfusion injury. Other effects such as kmbrane protection and scavenging of free radicals can not be ruled out. S.88
CARDIOPROTECTION BY NISOLDIPINE: ROLE Roberto Ferrari, Salvatore Cur&a, Claudia Ceconi, Cardiology, University of Brescia, Brescia, Italy.
OF TIMING OF ADMINISTRATION Anna Cqnoni, Evasio Pa&i, Gdoardo
Visioli.
Department
of
Nisoldipine (N), was administered at 10m9 M to isolated and perfused rabbit hearts submitted to 60’ ischaemia (1 ml/tin) followed by 30’ of reperfusion. N was delivered either 30’ before ischaemia, at the onset and after 30’ of iscbaemia and during repefusiononly. Cardiac protection was evaluatedin termsof recovery of the left ventricular pressure developed during reperfosion, release of CPK, mitochondrial function, tissue contents of ATP and CP, calcium homeostasis and the occurrence of oxidative stress, established measuring content and release of reduced and oxidized glutathione (GSH-GSSG). The cytopmtective action of N occurs in absence of negative inotropism and is closely related to the time of administration. Optimal myocardial preservation in achieved when N is given before or at the onset of ischaemia. Prophylactic administrationof N improved the recovery of the developed pressure from 15.9+1.0 to 47.8~1.9 mmHg, (P
O-16-7 NO-FORMATION
IN BOVINE ENDOTHELIAL CELLS AND PROTECTION OF ISOLATED ISCHEMIC BAT HEARTS IS MElDIATED BY LOCAL CEINFIIBITION Wolfgang Linz, Gabriele Wiemer and Bernward A. Schblkens Hoechst AG, D-6230 Frankfurt/Main, Germany We were interested if increased endogenous bradykinin (BK) via local CE-inhibition with ramiprilat (RT) induces nitric oxide (NO)-formation in cultured bovine aortic endothelial cells (BAEC) and furthermore is NO built up by this way protective in isolated rat hearts with postischemic reperfusion arrhythmias. 61n BAEC, CE-inhibition by FT (1x10-’ - 1~10~~ mol/l) or addition of exogenous BK (1~10-~ 1x10- mol/l) stimulated the formation of NO assessed by endothelial cyclic GMP- and prgta!yclinsynthesis. Cychc GMP Synthesis was completely supposed by the NO sy?thase inhibitor N -mtro;Lmol/l). In isolated yorkmg arginine (L-?A 1x10- mo!/l) an! by .tie B.2 anqomst HOE 140 (lgOrat hearts subjected to local lscherma with reperfusron both RT (1x10- mol/l) and BK (1x10- molll) reduced the incidence and duration of ventricular fibrillation. In parallel myocardial function (left ventricular pressure, coron p flow) and metabolism (l$gh energy rich phosphates), were improved. Addition of L-NNA (1x10- molll) or HOE 140 (1x10- mol/l) abolished the protective effects on the isolated ischemic rat heart. Inhibition of CE localized on the luminal side of the vascular endothelium results in increased synthesis of NO and prostacyclin by local accumulation of endothelium-derived BK. In ischemic rat hearts these mechanisms lead to cardioprotection.
0-16-8
R?O?X~IYr EFyT Ofl~I~uI~I~IT;~ 3 S ak.N ih . 6abae.
7 TIAC REIUWSIW IWlRY. Institute oa hof er andJ Stvk
for Heart Res., Slovak Aca& of Sciences: Eratislava', Czech and Slovak iederaiive Republik. The effect of pretreatint by phenothiazines - Chlorpromazine (0%) and Triflouperazine (TFP) on reperfusion injury of ischemic myocardiumwere,studied. Reperfusion after 40 min of ischeraia is known to result in morphological, functional and biochemical changes identical with those induced by enhanced cytosolic Ca2* concentration. Left descendin coronary ligation was performed on 70 dogs divided into four groups. Group I: occlusion (Occ 3 only (60 min, 120 min and 180 min); group II: 15 do s (60 min Occ + 120 min reperfusion, R); group III: 20 dogs (60 min Occ, 15 mg CPR, 120 min Rg; g roup IV: 20 dogs (60 min Occ, 2 mg TFP + 120 min R). CPR or TFP were administered 30 min before, 1 min prior or 30 min after the Oct. The effects of drugs were quantified on tetrazolium stained gross sections and studied from physiological, biochemical and ultrastructural points of view. The effect was dose dependent. The lowest amount of CPR exhibiting sufficient protective effect was 10 mg/kg bw and drugs were effective even if arhninistered 30 min after the Oct. Treatment of animals with phenothiazines considerably improved the ultrastructure of myocytes in area at risk, and allowed for the recover of about 60% of endangered myocytes after reflow restoration. Inhibition of calmdu f in appears to be an important factor in diminishing effect of calcium overload in postischemic reperfusion injury. Other effects such as kmbrane protection and scavenging of free radicals can not be ruled out. S.88