Preconditioning and metabolic anti-ischaemic agents

Lionel H. Opie*

Hatter Institute for Cardiology Research, University of Cape Town Faculty of Health Sciences, Cape Town, South Africa

* Corresponding author. Lionel H. Opie, MD, Ph.D., Director, Hatter Institute for Cardiology Research, Univ. of Cape Town Medical School, Observatory, 7925, South Africa. Tel.: +27-21-406-6358; fax: +27-21-447-8789
E-mail address: opie{at}capeheart.uct.ac.za

Received 25 July 2003; accepted 28 July 2003

Abstract

Preconditioning a powerful protective mechanism, is the response to transient ischemia and reperfusion. However, the best way to achieve total protection is to avoid ischemia altogether. Therefore prevention of ischemia and protection by preconditioning are differently mediated so that anti-ischemic agents may not precondition, whereas paradoxically pro-ischemic agents may precondition. Metabolically active agents such as glucose-insulin-potassium, trimetazidine and ranolazine that protect from ischemia, increase glucose metabolism relative to that of fatty acids. By promoting glycolysis they tend to close the ATP-dependent potassium channels that help to mediate preconditioning. By lessening the oxygen-wasting effects of fatty acids, they are mitochondrial protective and oxygen-sparing. These qualities should help in the therapy of myocardial ischemia and also heart failure.

Key Words: Preconditioning • Anti-ischaemic agents • Metabolic protection

1. Introduction

Because cardiologists know that preconditioning (PC) is a very powerful protective mechanism against repeat lethal ischaemia, they may assume that any agent that preconditions is ‘good’, and any agent that does not is ‘bad’. Thus ‘if a drug although acting anti-ischaemically, were to negate this mechanism, it would be a hollow triumph’.1The purpose of this editorial is to argue against this reasoning, intuitively correct but requiring significant modification. Basically, PC results when brief ischaemia is applied to the heart, followed by reperfusion. This is the trigger to PC whereby a major subsequent ischaemic insult can then be better withstood. Optimal PC may require repetitive episodes of brief ischaemia each followed by reperfusion. These sequences immediately give us two important messages. The first (and best) way to protect from ischaemia is to avoid it, while another way is to let ischaemia develop albeit briefly, thereby achieving subsequent protection. However, this ischaemia-induced PC protection is never quite as good as avoiding ischaemia altogether, in that experimental infarct size can be reduced by PC from a control value of about 50% down to only 10 to 20%, but not to zero.2

2. Pro-ischaemic agents that precondition

With this background in mind, an interesting contrast is between the effects of some metabolic anti-ischaemic agents, including trimetazidine (TMZ) and ranolazine, with some pro-ischaemic agents that precondition. Today we know that PC is an immensely complex process involving multiple signalling systems that are still not fully understood.2As active protein kinase C (PKC) is part of the signalling path that is common to many agents that induce PC,3it would be logical that pro-ischaemic agonist agents such as noradrenaline,4angiotensin-II,5and endothelin6that activate PKC as part of their physiological function should also be able to induce PC. These agents transmit their inward message from their surface receptor by G proteins to activate phospholipase C to produce two products that between them increase cell calcium and activate PKC. The associated signalling events are complex but include activation of the K-ATP channels, both on the sarcolemma and on the mitochondria. Thus these three agents can all be expected to exaggerate or even to provoke myocardial ischaemia by their effect in raising cell calcium, but can also invoke protective PC.

Protein kinase A (PKA) also participates in the PC process, in that preconditioning induced by ß-adrenergic stimulation by isoproterenol7or noradrenaline8can be blocked by alprenolol or propranolol. Thus agents known to be antianginal, namely the ß-blockers, can also block PC. This observation should warn us that it is false logic to expect anti-ischaemic agents to mimic a process that is initiated by ischaemia. And, of course, this is no reason not to use ß-blockers as antianginals. How do these basic arguments apply to metabolic anti-ischaemic agents?

3. Glycolytic ATP protects against ischaemia

That the human heart is more than a mechanical pump but has an active metabolism was first shown by Richard Bing in 1954.9Glucose–insulin–potassium (GIK) treatment, introduced by Sodi-Pallares in 1962,10was the first metabolic-based anti-ischaemic therapy to catch the eye of cardiologists. Although now still under test in mega-trials, current data favour its protective use.11In 1970, the proposed mechanism of protection of glucose–insulin switched from promoting potassium entry into ischaemic cells, to the protective role of ATP derived from glucose metabolism, that is glycolytic ATP.12,13The concept introduced was that glycolysis was able to provide ATP that protected the cell membrane, which brings us back to PC.

Opening of the K-ATP-channels of the sarcolemmal and mitochondrial membranes is universally thought to be involved in the PC. Although recent emphasis has been on the role of the mitochondrial K-ATP channel,2both sarcolemmal and mitochondrial channels are probably involved.14–16Only the sarcolemmal channel has been cloned and its properties are better defined. This channel is under metabolic control being strongly inhibited by ATP, including that produced by glycolysis.17ATP-inhibition is relieved by breakdown products of ATP, such as ADP, AMP and adenosine. Hence it follows that lack of ATP as in ischaemia should open this channel and help to achieve PC. This sequence also explains why metabolic inhibitors such as cyanide are able to precondition.18Also according to this reasoning, PC induced by deprivation of glucose could be explained at least in part by lessening the production of protective membrane-related glycolytic ATP, thereby helping to close the sarcolemma ATP channel.19Conversely, provision of glucose, known to protect against ischaemia by production of glycolytic ATP, cannot give PC. With this background, we can now turn our attention to the role of metabolically active anti-anginal agents such as trimetazidine and ranolazine.

4. Metabolic antianginal agents

The perfect antianginal agent would totally obviate ischaemia, and therefore be totally incapable of giving PC. This is an important concept, because TMZ is a proven antianginal that does not PC, in line with this basic logic. PC being a response to a deleterious process, namely ischaemia, brings in its wake a number of changes that ordinarily would be conceived as being ‘adverse’ such as uncoupling of oxidative phosphorylation.20Conversely, TMZ protects mitochondria against ischaemia, and could be called a ‘mitochondrial coupling agent’ (Fig. 1), as shown in liver mitochondria.21In this way TMZ can act against the PC-inducing effects of ischaemia itself and mitochondrial uncoupling agents such as dinitrophenol.22This concept fits with the basic data that TMZ inhibits fatty acid oxidation23because high concentrations of fatty acids have adverse uncoupling effects on mitochondria.24Speculatively, it could be these adverse mitochondrial effects that explain why in the ischaemic myocardium fatty acids ‘steal’ the residual oxygen from glucose25as well as the massive loss of myocardial mechanical efficiency in heart failure. Such uncoupling could deplete subsarcolemmal ATP, thereby opening the sarcolemmal K-ATP channels.26



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Fig. 1 Proposed dual consequences of mitochondrial uncoupling. On left, ischaemia via uncoupling is hypothesized to promote preconditioning. On right, fatty acids also acting via uncoupling are proposed to waste oxygen and to increase ischaemia. Therefore metabolically active anti-ischaemic agents that oppose uncoupling could limit both ischaemia and preconditioning. Note that if these agents were completely to abolish ischaemia (top left) then no ischaemic preconditioning could occur. TMZ=trimetazidine; RZ=ranolazine.

 
5. Insulin has multiple anti-ischaemic mechanisms

Insulin is a special case, acting both metabolically to increase glucose uptake and to promote glycogen stores, and also on protective signal systems. Insulin also inhibits mitochondrial fatty acid oxidation, acting via AMP-activated-protein kinase27and hence on malonyl CoA. The latter is a key inhibitor of the entry of fatty acid metabolites into the mitochondria as shown by Lopaschuk and his group.28Insulin can protect even in the absence of provision of external glucose29–31potentially improving mitochondrial energy production by promotion of glycolysis and decreased fatty acid metabolism. Insulin is unique in having the capacity to protect not only during ischaemia29,31but also when given before ischaemiaor only at reperfusion, with a mechanism involving activation of phosphatidylinositol (PI) 3-kinase.32Part of this protective action may be explained by theeffect of insulin acting via PI-3-kinase on the prosurvival mitochondrial pathways.33

6. Metabolic protection underused

How do these proposals, focussing on mitochondrial effects, help us to understand the mechanism of action of the metabolically active antianginal agents, TMZ and ranolazine? There is no conflict between the apparently disparate effects of TMZ on angina (benefits), hibernation (benefits) and on preconditioning (lessens mitochondrial damage, blocks PC). These disparate effects could all follow from the same beneficial effect of TMZ on mitochondrial metabolism. While these comments largely relate to TMZ, it is more than likely that similar principles would apply to ranolazine, another metabolic antianginal agent similarly reducing fatty acid oxidation, which is currently being evaluated for approval for clinical use in the United States. In general, these agents and other metabolic procedures such as GIK are still underused, although they have a totally different mode of action from conventional haemodynamically active agents such as ß-blockers and calcium antagonists. ‘Mitochondrial coupling’ could explain the antianginal effects of TMZ and ranolazine, and also their benefits in experimental heart failure.34Further clinical studies that may extend the clinical indications to heart failure, are clearly warranted.

Acknowledgments

Professor Derek Yellon, Director, the Hatter Institute, University College, London, is thanked for critical review.

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