Metabolic changes during post-ischaemic reperfusion.
We attempted to identify the nature and time-course of metabolic changes occurring during ischaemia followed by reperfusion either in coronary artery disease patients undergoing intracoronary thrombolysis or in isolated and perfused rabbit hearts. Arterial and coronary sinus differences for oxygen, lactate, glucose, free fatty acid and creatine kinase were measured in patients undergoing successful intracoronary thrombolysis of left anterior descending occlusion. Early reperfusion (after 160 mins of ischaemia) restored aerobic metabolism and myocardial contractility. In contrast, reperfusion after more prolonged ischaemia (335 mins) did not restore mitochondrial function or contractile activity of the myocytes. Results obtained using isolated and perfused rabbit hearts also confirm that the likelihood of recovery during reperfusion depends on the rapidity of recanalization. Furthermore the data reported indicate that on reperfusion after prolonged ischaemia (90 mins) cell damage occurs, leading to a breakdown of the permeability barrier to ions and to larger molecules such as creatine phosphokinase. As a consequence, reperfusion produces a large increase of intracellular calcium, whilst the intracellular magnesium content is severely reduced. Under these conditions, with the observed loss of magnesium from the cell, mitochondrial calcium transport is highly stimulated and the equilibrium between ATP synthesis and calcium influx is shifted towards calcium influx. This sequence of events leads to mitochondrial calcium overload with subsequent damage of mitochondrial structure and loss of the ability to synthesize ATP. Reperfusion of the isolated rabbit hearts with solutions containing high magnesium and low calcium for 10 mins reduced mitochondrial calcium overload. This, in turn, resulted in maintenance of ATP synthesis and, on return to normal perfusate, in partial recovery of developed pressure and myocardial ATP content. These findings may be of importance in the restoration of blood flow to ischaemic heart muscle during thrombolysis.
Ferrari
R
R
Università degli Studi di Brescia, Cattedra di Cardiologia, Italy.
Ceconi
C
C
Curello
S
S
Cargnoni
A
A
Condorelli
E
E
Belloli
S
S
Albertini
A
A
Visioli
O
O
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D003326:Coronary Circulation; D003327:Coronary Disease / Q000378:metabolism* / Q000503:physiopathology; D005342:Fibrinolysis; D006801:Humans; D066298:In Vitro Techniques; D008274:Magnesium / Q000378:metabolism / Q000494:pharmacology; D009206:Myocardium / Q000378:metabolism; D010725:Phosphocreatine / Q000378:metabolism; D011817:Rabbits
D010725:Phosphocreatine; D000255:Adenosine Triphosphate; D008274:Magnesium; D002118:Calcium