Open-system kinetics of myocardial phosphoenergetics during coronary underperfusion

Abstract

A novel hypothesis is proposed and tested describing open-system kinetics for myocardial phosphoenergetics. The hypothesis is that during severe coronary underperfusion there is precise matching of the rates of ATP synthesis and hydrolysis, but despite the precise balance of ATP rates, there is a decrease in the concentration of ATP and an increase in the concentration of phosphocreatine (PCr) caused by the hydrolysis of AMP to adenosine. Isolated rabbit hearts were perfused using a crystalloid medium, and coronary flow was reduced by 95% from baseline for 45 min followed by reperfusion. Phosphorus nuclear magnetic resonance spectroscopy showed a rapid decrease in PCr concentration to 25% of baseline at the onset of underperfusion followed by a gradual increase in PCr to 42% of baseline, while ATP decreased continuously to 65% of baseline. The kinetics of PCr and ATP could only be described by the precise matching of the rates of ATP synthesis and ATP hydrolysis and an open adenylate system that included the decrease in cytosolic AMP concentration via the production and efflux of adenosine. To confirm the hypothesis of open-system kinetics, two independent predictions were tested in separate experiments: 1) total coronary venous purine efflux (adenosine+inosine+hypoxanthine) during underperfusion was equal to the decrease in ATP concentration, and 2) there was no increase in PCr during moderate coronary underperfusion (80% flow reduction). In conclusion, the open nature of the myocardial adenylate system causes mass action effects that exert novel control over PCr and ATP concentrations during coronary underperfusion. The open-system kinetics cause ATP to decrease and PCr to increase, even though there is precise matching of the rates of ATP synthesis and hydrolysis. Finally, the hydrolysis of AMP to adenosine may benefit tissue survival during ischemia by improving the free energy of ATP hydrolysis, thereby delaying or preventing calcium overload.

Myocardial hibernation: a delicate balance

“…Decreased ATP content over time was also observed during continued myocardial ischemia in isolated rat (129), rabbit (94), and piglet (38) hearts and in anesthetized pig (3,122,136) and dog (168) models of short-term hibernation. In contrast to the steady decline in ATP content and like the attenuation of lactate production over time, the myocardial creatine phosphate content was significantly decreased immediately after the onset of ischemia but gradually recovered over time toward control values (Fig.…”

Hibernating myocardium

“…A decrease in ATP content over time was observed during continued myocardial ischaemia in isolated rabbit25 and piglet26 hearts, and in anaesthetised pigs13 14 27 and dogs 28. In contrast to the steady decline in ATP content, but in agreement with the attenuation of lactate production over time, myocardial creatine phosphate content was decreased immediately after the onset of ischaemia but gradually recovered over time towards control values,27 whereas regional myocardial blood flow and contractile function were persistently reduced 13…”

Cardiovascular Effects of Exercise Training

“…Adenosine serves as a myocardial oxygen sensor because it is generated at an accelerated rate when oxygen supply-to-demand relationship falls. 165 3. Carbon dioxide production, which in turn leads to tissue acidosis, is known to increase coronary flow.…”