MET‐88: SR Ca 2+ ‐Uptake Stimulator for Treating Chronic Heart Failure

Dysfunction of the sarcoplastic reticulum (SR) and a decrease in SR Ca 2+ ATPase protein levels have been reported in patients with myocardial infarction (MI) and congestive heart failure (CHF) (6,7,18). Contraction and relaxation of cardiac myocytes result from the sequential activation and inactivation of the contractile elements by the alternating rise and fall of the cytosolic Ca 2+ concentration. The SR plays a crucial role in the regulation of cytosolic Ca 2+ cycling. Ca uptake by the cardiac SR occurs through SR Ca-ATPase, the activity of which seems to be maintained by adenosine triphosphate (ATP) produced through glycolysis (11,24). Therefore, compounds that have the ability to regulate the activity of SR Ca -ATPase would seem to be beneficial for the therapy of chronic heart failure. MET-88 [3-(2,2,2-trimethylhydrazinum) propionate] was synthesized by the Institute of Organic Synthesis (Riga, Latvia) as an inhibitor of g-butyrobetaine hydroxylase, the enzyme that catalyzes the synthesis of carnitine from g-butyrobetaine in the liver (23). MET-88 lowers the intercellular level of free carnitine and thus suppresses fatty acid oxidation and facilitates glycolysis (23). MET-88 has the ability to regulate the activity of SR Ca 2+ uptake in rats with heart failure following myocardial infarction. It also has a beneficial effect on cardiac function in rats with experimental MI and in conscious dogs with CHF produced by pulmonary artery constriction and tricuspid valve avulsion. MET-88 has cardioprotective effects on energy metabolism in the ischemic canine heart (16) and on the contractile function and energy metabolism of isolated perfused rat hearts in the hypoxic condition (2). MET-88, unlike a vasodilator or a positive inotropic agent, ameliorates cardiac dysfunction by modulating myocardial energy metabolism. Thus,