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The effect of dietary fish-oil on cardiac function and serum lipids during acute and chronic ischemia in pigs
j Mol Cell Cardiol 18 (Supplement 2) (1986) 64CALCIUM ANTAGONISTS AND REPERFUSION-INDUCED ARRNYTHMIAS IN THE C O N S C I O ~ RAT. K. Kinoshita, D.J.Hearse, N.V.Braimbridge, A.S.Manning. The Heart Research Unit, The Rayne Institute, St Thomas' Hospital, London SEI, U.K. We have assessed the effects of three calcium antagonists (diltiazem, verapamil and nifedipine) on reperfusion-induced arrhythmias in the conscious rat. The LAD was occluded for 5 min followed by 10 min re~erfusion. I the control group (n=15), all animals exhibited ventricular tachycardla (VT) and n fibrillation (VF) during reperfusion and 87% died as a result of these ventricular arrhythmias. Administration (i.v. 10 min prior to LAD occlusion, n=12 in each group) of ~.5 and 2.0mg/kg diltiazem, 0.5 and 5.0mg/kg verapamil and 5.0 and 50ug/k~ nifedipine dramatically reduced the incidence of reperfusion-induced arrhythmlas. This anti-arrhythmic effect of the calcium antagonists resulted in much lower mortality.
control Incidence (%) VT VF Mortality
Diltlazem O.5mg/kg 2.0mg/kg
i00 75 i00 50** 87 42* =p=less than U.Ub,
verapamll 0.5mg/kg 5.0mg/kg
42** 25*** 25** ''p=Iess than
92 58* 25"* U.UI,
Niteaipime 5.0ug/kg 50ug/kg
0"** 75 0"** 33*** 0"** 25** -*-p=less than U.UUI
58* 25*** 8***
Ischemia-induced ST segement elevation was reduced by pretreatment with each calcium antagonist. Although the higher dose of verapamil decreased heart rate, there were no significant changes in heart rate in the other groups. Thus, diltiazem, verapamil and nifedipine exerted similar potent protective effects against reperfusion-induced lethal arrhythmias in the conscious rat.
6 5 F R E E RADICAL QUENCHING AND REPERFUSION-INDUCED ARRHYTHMIAS: DOSE-RESPONSE STUDIES FOR SUPEROXIDE DISMUTASE AND CATALASE IN THE ANAESTBETIZED RAT. E. Riva, D.J. Hearse, A.S. Manning. The Heart Research Unit, The Rayne Institute, St Thomas' Hospital, London SEI, UK. It has been suggested that oxygen-derived free radicals contribute to the genesis of reperfusion-induced arrhythmias which occur following transient periods of myocardial ischemia. In 'in vitro' studies, inhibitors of free radical formation and free radical scavengers have been shown to reduce the incidence of reperfusion-induced ventricular fibrillation. In the present study, the anti-arrh[thmic properties of superoxide dismutase (SOD) and/or catalase were assessed in vivo in the anaesthetized rat with regional ischaemia (7 min of left coronary artery occlusion) and reperfusion (i0 min). SOD (3500, 17500, 35000, 87500 and 350000 IU/kg) or catalase (420, 4200, 42000, 420000 and 1050000 IU/kg) were administered intravenously to rats (n=15 for each dose) 2 min prior to reperfusion. Protection was observed with bell-shaped dose-response profiles for each enzyme. With SOD, the incidence of ventricular fibrillation was reduced from its untreated control value of 73% to 60%, 67%, 33%, 67% and 67% respectively, and mortality was reduced from 47% to 27%, 20%, 7%, 27% and 47% respectively. With catalase, the incidence of ventricular fibrillation was reduced to 53%, 47%, 33%, 56% and 53% and mortality was reduced to 27%, 27%, 13%, 13% and 33% respectively. In further studies, the anti-oxidant enzymes were administered 3 mln prlor to coronary occlusion and comparable protection was observed. When optimal activities of SOD (35000 IU/kg) and catalase (420000 IU/kg) were used in combination prior to ischemia, additive protection was observed; the incidence of ventricular fibrillation fell from 73% to 13% (p= less than 0.01) and mortality fell from 47% to 7% (p= less than 0.02). In conclusion, enzymes which quench oxygen-derived free radicals reduce the incidence of reperfusion-induced arrhythmias in vivo in a dose-dependent manner by a mechanism which is operative during reperfusion.
6 6 T H E EFFECT OF DIETARY FISH-OIL ON CARDIAC FUNCTION AND SERUM LIPIDS DURING ACUTE AND CHRONIC ISCHEMIA IN PIGS. J.M. Hartog, J.M.J. Lamers, C.E. Essed, P.D. Verdouw, Thoraxcenter, Erasmus University Rotterdam, Rotterdam, The Netherlands. Two month feeding with ]0% mackerel-oil (M, n=]2) caused decreases in plasma cholesterol (4]%) level and triglycerides (62%) while a ]0% lard feeding (L, n=]2) had no effect in plasma lipids. The dietary effects on acute ischemic events were studied in open-chest anesthetized pigs (M, n=8 and L, n=8). After 6 successive 5 min coronary artery occlusions interrupted by ]0 min of reperfusion, left ventricular filling pressure was ]]4% (L) and ]28% (M) of the first pre-occlusion value, stroke volume 69% in both L and M and max LVdP/dt 59% in L and 62% in M. Cardiac output was ]0% lower in L, because of a decrease in heart rate (]3%), but due to a more pronounced peripheral vasoconstriction (]32 vs ]]8%) mean arterial pressures were identical (75%). Thus, high fish-oil intake did not cause negative effects on cardiac function during acute ischemic events. In another series, pigs were fed either 10% L (n=8) or 5% L and 5% M .(L+M, n=8) for 4 months. After 2 months a 2 m m constrictor was placed around a coronary artery. Two months later perfusion of the ischemic myocardium was reduced by 43% L and 3]% L+M (p < 0.05), although collateral flow was equal in both groups. The L+M diet (n=]6) caused decreases in plasma cholesterol (19%) and triglyceride (49%) during the 4 month dietary period. Thus, the lipid lowering effects of dietary fish-oll are dose-dependent, but low dosage of fish-oil, probably by antithrombotic actions, attenuated the decrease in myocardial perfusion.
control Incidence (%) VT VF Mortality
Diltlazem O.5mg/kg 2.0mg/kg
i00 75 i00 50** 87 42* =p=less than U.Ub,
verapamll 0.5mg/kg 5.0mg/kg
42** 25*** 25** ''p=Iess than
92 58* 25"* U.UI,
Niteaipime 5.0ug/kg 50ug/kg
0"** 75 0"** 33*** 0"** 25** -*-p=less than U.UUI
58* 25*** 8***
Ischemia-induced ST segement elevation was reduced by pretreatment with each calcium antagonist. Although the higher dose of verapamil decreased heart rate, there were no significant changes in heart rate in the other groups. Thus, diltiazem, verapamil and nifedipine exerted similar potent protective effects against reperfusion-induced lethal arrhythmias in the conscious rat.
6 5 F R E E RADICAL QUENCHING AND REPERFUSION-INDUCED ARRHYTHMIAS: DOSE-RESPONSE STUDIES FOR SUPEROXIDE DISMUTASE AND CATALASE IN THE ANAESTBETIZED RAT. E. Riva, D.J. Hearse, A.S. Manning. The Heart Research Unit, The Rayne Institute, St Thomas' Hospital, London SEI, UK. It has been suggested that oxygen-derived free radicals contribute to the genesis of reperfusion-induced arrhythmias which occur following transient periods of myocardial ischemia. In 'in vitro' studies, inhibitors of free radical formation and free radical scavengers have been shown to reduce the incidence of reperfusion-induced ventricular fibrillation. In the present study, the anti-arrh[thmic properties of superoxide dismutase (SOD) and/or catalase were assessed in vivo in the anaesthetized rat with regional ischaemia (7 min of left coronary artery occlusion) and reperfusion (i0 min). SOD (3500, 17500, 35000, 87500 and 350000 IU/kg) or catalase (420, 4200, 42000, 420000 and 1050000 IU/kg) were administered intravenously to rats (n=15 for each dose) 2 min prior to reperfusion. Protection was observed with bell-shaped dose-response profiles for each enzyme. With SOD, the incidence of ventricular fibrillation was reduced from its untreated control value of 73% to 60%, 67%, 33%, 67% and 67% respectively, and mortality was reduced from 47% to 27%, 20%, 7%, 27% and 47% respectively. With catalase, the incidence of ventricular fibrillation was reduced to 53%, 47%, 33%, 56% and 53% and mortality was reduced to 27%, 27%, 13%, 13% and 33% respectively. In further studies, the anti-oxidant enzymes were administered 3 mln prlor to coronary occlusion and comparable protection was observed. When optimal activities of SOD (35000 IU/kg) and catalase (420000 IU/kg) were used in combination prior to ischemia, additive protection was observed; the incidence of ventricular fibrillation fell from 73% to 13% (p= less than 0.01) and mortality fell from 47% to 7% (p= less than 0.02). In conclusion, enzymes which quench oxygen-derived free radicals reduce the incidence of reperfusion-induced arrhythmias in vivo in a dose-dependent manner by a mechanism which is operative during reperfusion.
6 6 T H E EFFECT OF DIETARY FISH-OIL ON CARDIAC FUNCTION AND SERUM LIPIDS DURING ACUTE AND CHRONIC ISCHEMIA IN PIGS. J.M. Hartog, J.M.J. Lamers, C.E. Essed, P.D. Verdouw, Thoraxcenter, Erasmus University Rotterdam, Rotterdam, The Netherlands. Two month feeding with ]0% mackerel-oil (M, n=]2) caused decreases in plasma cholesterol (4]%) level and triglycerides (62%) while a ]0% lard feeding (L, n=]2) had no effect in plasma lipids. The dietary effects on acute ischemic events were studied in open-chest anesthetized pigs (M, n=8 and L, n=8). After 6 successive 5 min coronary artery occlusions interrupted by ]0 min of reperfusion, left ventricular filling pressure was ]]4% (L) and ]28% (M) of the first pre-occlusion value, stroke volume 69% in both L and M and max LVdP/dt 59% in L and 62% in M. Cardiac output was ]0% lower in L, because of a decrease in heart rate (]3%), but due to a more pronounced peripheral vasoconstriction (]32 vs ]]8%) mean arterial pressures were identical (75%). Thus, high fish-oil intake did not cause negative effects on cardiac function during acute ischemic events. In another series, pigs were fed either 10% L (n=8) or 5% L and 5% M .(L+M, n=8) for 4 months. After 2 months a 2 m m constrictor was placed around a coronary artery. Two months later perfusion of the ischemic myocardium was reduced by 43% L and 3]% L+M (p < 0.05), although collateral flow was equal in both groups. The L+M diet (n=]6) caused decreases in plasma cholesterol (19%) and triglyceride (49%) during the 4 month dietary period. Thus, the lipid lowering effects of dietary fish-oll are dose-dependent, but low dosage of fish-oil, probably by antithrombotic actions, attenuated the decrease in myocardial perfusion.