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Metabolic aspects of ischaemia
P . M . Grinwald, Department of Physiology, University of Melbourne, Vic 3052. Ca~- overload which occurs in reperfused_ ischaemic tissue is preceded by 9 dlsturbances in Na~ and K+ b a l a n c e Since CaZ+ uptake is strongly influenced b~ " , ex~racellular ~a+ , CaZ + overload may occur by a Na~ -sensitlve process i . e . Na+ /CaZ + exchange. Na- pump activity was determined by analysis + of tissue K- content in , + . . perfused rat heart after elther normal K (5.9 mM) or zero-K perfuslon, applied for 7 min after various periods of hypoxia. Poorly perfused regions of myocardium were excluded from sampling by means of dye added to the perfusate {uring the final 30 sec of perfusion. Errors ~ue to extracellular space variations in K content were found to be n e g l i g i b l e . The Na~ pump perceptibly slowed a f t e r 20 mill hypoxia (P
2BCALCIUM OVERLOAD IN ISCHAEMIC MYOCARDIUM: ROLE OF SODIUM,
29METABOLIC ASPECTS OF ISCHAEMIA. M.G. Clark* and G.S. PattenS. *Department of Biochemistry, University of Tasmania, Hobart, and tCSIRO Division of Human N u t r i t i o n , Adelaide. The metabolic effects of global ischaemia in the isolated perfused rat heart were examined in glycogen-containing and glycogen-depleted states. When cardiac glycogen levels were normal (>70 ~mol/g dry wt) ischaemia resulted in cessation of contracti l i t y a f t e r 3 min, a decrease in ATP from 20 to 14 ~mol/g dry wt, a decrease in the ATP~ADP r a t i o from 4 to 1.5, but no increase in the rate of uptake and metabolism of [5-JH]glucose, which remained at the control (pre-ischaemic) value of 0.65 ~mol/min/ g dry wt for I0 min. Phosphorylase was activated f o r a transient period (1-3 min) before c o n t r a c t i l i t y ceased. Phosphofructokinase was not activated (k m remained 9 unchanged) and ischaemic contracture did not develop even 12 m n a f t e r cessatlon of contractility. I f glycolysis increases under these conditions i t ~~s the result of t increased substrate saturation of phosphofructokinase and not a Ca -mediated m o d i f i c a t i o n of the enzyme. When cardiac glycogen levels were depleted by p r i o r exposure of the heart to epinephrine for 5 min, ischaemia resulted in cessation of c o n t r a c t i l i t y a f t e r 2 min, the development of ischaemic contracture w i t h i n 7 min, and again no a c t i v a t i o n of e i t h e r phosphorylase or phosphofructokinase. Since phosphofructokinase is activated in normally perfused hearts under conditions when L+ i n t r a c e l l u l a r levels of Ca are increased, i t is concluded that ischaemic contracture is not associated with an increase in Caz+.
3 0 T H E EFFECT OF AGENTS THAT ALTER CONTRACTILITY UPON THE BASAL AND ACTIVATION METABOLISM OF THE (TJINEA-PIG HEART. D.S. Loiselle, Department of Physiology, School of Medicine, University of Auckland, Auckland, New Zealand. The isolated, Langendorff-perfused guinea pig heart has been used to study the effect, upon both basal and activation metabolism of agents that alter cardiac contractility. Basal metabolism is defined as the rate of energy expenditure (oxygen constm~otion plus lactate production) of the arrested heart. Activation metabolism is defined as the energy expenditure in excess of the basal component of the empty, beating heart. It is assumed to reflect primarily the energetics of calcit~n cycling. The basal metabolic rate was the same whether arrest was achieved by low Ca or high (15 to 40 raM) K . The metabolzc cost of actlvatzon varzed directly with Ca concentration whereas the basal metabolism was uninfluenced. Basal metabolism was unaltered by isoprenaline despite a 50% increase in the activation component. Caffeine (i0 raM) caused only a modest (15%) increase of activation metabolism, but a large (2.5 - fold) increase in the basal metabolic rate. This could not be attributed to the associated decrease in coronary vascular resistance because adenosine had no effect on basal metabolism despite causing coronary vasodilation. It is concluded that the caffeine effect represents near-maximal stimulation of the sarcoreticular Ca-ptm~ together with an increased rate of futile cross-bridge cycling.
2BCALCIUM OVERLOAD IN ISCHAEMIC MYOCARDIUM: ROLE OF SODIUM,
29METABOLIC ASPECTS OF ISCHAEMIA. M.G. Clark* and G.S. PattenS. *Department of Biochemistry, University of Tasmania, Hobart, and tCSIRO Division of Human N u t r i t i o n , Adelaide. The metabolic effects of global ischaemia in the isolated perfused rat heart were examined in glycogen-containing and glycogen-depleted states. When cardiac glycogen levels were normal (>70 ~mol/g dry wt) ischaemia resulted in cessation of contracti l i t y a f t e r 3 min, a decrease in ATP from 20 to 14 ~mol/g dry wt, a decrease in the ATP~ADP r a t i o from 4 to 1.5, but no increase in the rate of uptake and metabolism of [5-JH]glucose, which remained at the control (pre-ischaemic) value of 0.65 ~mol/min/ g dry wt for I0 min. Phosphorylase was activated f o r a transient period (1-3 min) before c o n t r a c t i l i t y ceased. Phosphofructokinase was not activated (k m remained 9 unchanged) and ischaemic contracture did not develop even 12 m n a f t e r cessatlon of contractility. I f glycolysis increases under these conditions i t ~~s the result of t increased substrate saturation of phosphofructokinase and not a Ca -mediated m o d i f i c a t i o n of the enzyme. When cardiac glycogen levels were depleted by p r i o r exposure of the heart to epinephrine for 5 min, ischaemia resulted in cessation of c o n t r a c t i l i t y a f t e r 2 min, the development of ischaemic contracture w i t h i n 7 min, and again no a c t i v a t i o n of e i t h e r phosphorylase or phosphofructokinase. Since phosphofructokinase is activated in normally perfused hearts under conditions when L+ i n t r a c e l l u l a r levels of Ca are increased, i t is concluded that ischaemic contracture is not associated with an increase in Caz+.
3 0 T H E EFFECT OF AGENTS THAT ALTER CONTRACTILITY UPON THE BASAL AND ACTIVATION METABOLISM OF THE (TJINEA-PIG HEART. D.S. Loiselle, Department of Physiology, School of Medicine, University of Auckland, Auckland, New Zealand. The isolated, Langendorff-perfused guinea pig heart has been used to study the effect, upon both basal and activation metabolism of agents that alter cardiac contractility. Basal metabolism is defined as the rate of energy expenditure (oxygen constm~otion plus lactate production) of the arrested heart. Activation metabolism is defined as the energy expenditure in excess of the basal component of the empty, beating heart. It is assumed to reflect primarily the energetics of calcit~n cycling. The basal metabolic rate was the same whether arrest was achieved by low Ca or high (15 to 40 raM) K . The metabolzc cost of actlvatzon varzed directly with Ca concentration whereas the basal metabolism was uninfluenced. Basal metabolism was unaltered by isoprenaline despite a 50% increase in the activation component. Caffeine (i0 raM) caused only a modest (15%) increase of activation metabolism, but a large (2.5 - fold) increase in the basal metabolic rate. This could not be attributed to the associated decrease in coronary vascular resistance because adenosine had no effect on basal metabolism despite causing coronary vasodilation. It is concluded that the caffeine effect represents near-maximal stimulation of the sarcoreticular Ca-ptm~ together with an increased rate of futile cross-bridge cycling.