J Mol Cell Cardiol 18, 883-884 (1986)

Reply to a Letter by Drs Kent i sh and Al len

In a recent review I summarised experimental evidence in the literature that suggested that the cytoplasmic phosphorylation potential had at least two important roles in the cardiac cell. These included (i) the control of myo- cardial respiration and (ii) regulation of free energy availability upon hydrolysis of ATP. This latter role raised the possibility that con- tractile performance could be compromised either by AGATp having a direct effect on force production at the crossbridge level or an indi- rect effect via alteration of the normal calcium cycle.

In the accompanying letter to the Editor, Drs Kentish and Allen produce elegant evi- dence, in my view quite clear-cut, that is not compatible with the idea that the fall in the thermodynamic affinity for ATP hydrolysis, which they also detect [1, 6], is responsible for the rapid fall in contractility during hypoxia. In particular their experimental results suggest that a rise in intracellular Pi is the primary cause of hypoxic contractile failure. There are now several observations in the lit- erature that show that variations in the level of inorganic phosphate influence crossbridge kinetics [3, 8]. I t is also clear that the effects of Pi are not restricted to actions on the activa- tion and contractile systems since Armiger, Humphrey, West and Knell [2] have s h o w n in the perfused rat heart that normoxic glucose free perfusion with high concentra- tions (30 mM) of Pi markedly depresses con- tractile function for about 10 min after which there is partial recovery (to about 50% of control); most interestingly after 30 min of such perfusions there are essentially normal levels of ATP and glycogen present.

My interest in the idea that a change in AGAT P might control contractility came from some energy studies my colleagues and I were carrying out where cardiac failure was being induced by the chronic administration of anthracycline chemotherapeutic agents. Pre-

liminary biochemical analyses upon the failing hearts (Kotsanas and Gibbs, unpub- lished results) suggest that the decline in con- tractility cannot be related to the small change in AGATp that we have measured: as in some of Dr Allen's experiments the data are more explicable in terms of a depressed calcium cycle.

This rePlY to Drs Kentish and Allen also provides me with an opportunity to briefly update my remarks about the role of the cyto- plasmic phosphorylation potential in respir- atory control. I regret that in my earlier review I overlooked the work of Jacobus and colleagues that focusses attention on the role of [ADP]fr~ e in respiration. There are diver- gent views about the factors controlling res- piration [5, 7]. Recently Starnes, Wilson and Erecinska [9] have shown in the working per- fused rat heart that oxygen consumption can be linearly related to the cytoplasmic phos- phorylation potential in two different sub- strates (glucose or acetate). Now although the slopes of the relationships were similar they were clearly not coincident and I think this reduces the status of the phosphorylation potential to that of being one of several factors that regulate respiration. I am indebted to Professor Howard Morgan for drawing my attention to a good review by Hansford [4] which marshalls impressive evidence that mitochondrial calcium transport may have a central role to play in the control of energy metabolism.

I am delighted that many of the questions that I raised in my review have been so promptly answered.

Col in Gibbs

Reader in Physiology Monash University

Clayton, Victoria 3168 Australia

0022 2828/86/090883 +02 $03.00/0 �9 1986 Academic Press Inc. (London) Limited

884 C. Gibbs

R e f e r e n c e s 1 ALLEN, D. G., MORRIS, P. G., ORCHARD, C. H., PIROLO, J. S. A nuclear magnetic resonance study of metabolism in

the ferret heart during hypoxia and inhibition ofglycolysis. J Pbysio1361,185-204 (1985). 2 ARMIGER, L. C., HUMPHREY, S. M., WEST, E. J. N., KNELL, C. M. The effects of raised phosphate level on the

energy metabolism, contractile function, and fine structure of oxygenated and oxygen-deficient myocardium. Heart and Vessels 2, f~14 (1986).

3 BRANDT, P. W., Cox, R. N., KAWAI, M., ROBINSON, T. Regulation of tension in skinned muscle fibers. Effect of cross-bridge kinetics on apparent Ca 2+ sensitivities.J Gen Physio179, 997 1016 (1982).

4 HANSVORD, R. G. Relation between mitochondrial calcium transport and control of energy metabolism. Rev Physiol Biochem Pharmacol 102, 1-72 (1985).

5 JACOBUS, W. E. Respiratory control and the integration of heart high-energy phosphate metabolism by mitochon- drial creatine kinase. Ann Rev Physio147, 707 726 (1985).

6 KENTISH, J. C. The effects of inorganic phosphate and creatine phosphate on force production in skinned muscles from rat ventricle. J Physio1370, 585-604 (1986).

7 MELA-RmER, L. M., BUKOSKI, R. D. Regulation of mitochondrial activity in cardiac cells. Ann Rev Physiol 47, 645 664 (1985).

8 ROSSMANITH, G. H., HAMILTON, A. M., FISHER, A.J., FARROW, A. J., Hon, J. F. Y. Mechanical consequences of variations in the level of phosphate in rabbit psoas muscle fibres. Proceedings Australian Physiol Pharmacol Soc. 16, 227P (1985).

9 STARNES, J. W., WILSON, D. F., ERECINSKA, M. Substrate dependence of metabolic state and coronary flow in perfused rat heart. AmJ Physio1249, H799-H806 (1985).