A New Approach to the Development of Anti-ischemic Drugs. Substances that Counteract the Deleterious Effect of Lysophosphatidylcholine on the Heart.

Abstract

SUMMARYLysophosphatidylcholine (LPC) is an amphiphilic metabolite that can be produced from membrane-phospholipids by activation of phospholipase A2 (PLA2), and it accumulates in the heart during ischemia and reperfusion. It is known that LPC is an arrhythmogenic substance. Recent studies have revealed that LPC produces mechanical and metabolic derangements in perfused working rat hearts, and Ca2+-overload in isolated cardiac myocytes. Thus, LPC possesses an ischemia-like effect on the heart. LPC accumulated in the myocardium activates phospholipase A2, establishing a vicious circle; i.e. LPC itself has an ability to produce another LPC. Therefore, a drug that has an anti-LPC effect would protect or improve ischemia/reperfusion damage. This article will review the effect of LPC in relation to ischemia, and consider a possibility of developing new anti-ischemic drugs on the basis of the anti-LPC action. (Jpn Heart J 1997; 38: 11-25) Key words: Lysophosphatidylcholine, Free fatty acid, Ischemia reperfusion, anti-ischemic drugs SCHEMIA and reperfusion of the heart produce myocardial damage.Although the mechanism of ischemia/reperfusion damage of the heart is not well known, there is a common understanding that Ca2+-overload is the final step in the events induced by ischemia/reperfusion, and that the Ca2+-overload is probably responsible for the ischemia-reperfusion damage. By what mechanism does ischemia/reperfusion induce Ca2+-overload? There are some candidates for the etiology of ischemia/reperfusion-induced Ca2+-overload; one is reduction of the tissue levels of high-energy phosphates including adenosine triphosphateFrom the Department of Pharmacology, Asahikawa Medical College, Asahikawa, Japan, and 1Department of Pharmacology and Toxicology, University of Western Ontario, London , Ontario, Canada.Address for correspondence: Hiroko Hashizume, MD, Department of Pharmacology , Asahikawa Medical College, Nishikagura 4-5, Asahikawa 078, Japan.Received for publication January 12, 1996. Accepted January 19, 1996.11 12 HASHIZUME ET AL Jpn Heart J January 1997(ATP) and the other is production of free radicals. In this mini review we propose that lysophosphatidylcholine (LPC) is also one of the candidates responsible for Ca2+-overload during ischemia and reperfusion, and that substances that counteract the effect of LPC can be new anti-ischemic drugs.

Reduced conduction reserve in the diabetic rat heart: role of iPLA2activation in the response to ischemia

“…Moreover, this increased iPLA 2 activity contributes to the development of ischemiainduced arrhythmias in STZ-induced diabetic hearts. Our results thus lend support to the idea that iPLA 2 should be considered a potential target in developing treatment strategies for diabetic heart disease (20,49).…”

“…The accumulation of AA and LPC causes the end effects on connexins observed in this study (as well as effects on ion channels). The accumulation of these metabolites also exerts "positive feedback," stimulating additional iPLA 2 ␤ activation (5,20). The presence of diabetes before the onset of ischemia is thus expected to result in significant preexisting iPLA 2 ␤ activity at the onset of ischemia, effectively amplifying the iPLA 2 ␤ activation caused by ischemia through the positive feedback mechanism.…”

“…This increase in iPLA 2 activity and LPC content in the diabetic myocardium is comparable with increases observed in the ischemic myocardium. In addition to its effects on ion channels and intercellular coupling, LPC and other products of iPLA 2 activity (free fatty acids) have also been shown to activate iPLA 2 (5,20), establishing a positive feedback loop (referred to as a "vicious circle" in Ref. 20) whereby increased iPLA 2 activity stimulates additional iPLA 2 activity and further LPC and free fatty acid production.…”

“…In addition to its effects on ion channels and intercellular coupling, LPC and other products of iPLA 2 activity (free fatty acids) have also been shown to activate iPLA 2 (5,20), establishing a positive feedback loop (referred to as a "vicious circle" in Ref. 20) whereby increased iPLA 2 activity stimulates additional iPLA 2 activity and further LPC and free fatty acid production. The diabetic myocardium, in addition to already exhibiting an elevated baseline level of iPLA 2 activity and LPC content, may thus also be primed for a more pronounced iPLA 2 response to ischemia.…”

K‐7259: A Cardioprotective Derivative of Dilazep

“…Nevertheless, K-7259 protects brain and heart from hypoxidreoxygenation or ischemidreperfusion damage to a greater extent than dilazep. K-7259 is a promising cytoprotective drug against ischemia/ reperfusion injury in brain and heart (1,23). It is of particular importance to note that K-7259 attenuates the deleterious effects of ischemic poisons (for example, oxygen radicals, lysophosphatidylcholine, and long-chain acyl carnitines) on the heart.…”