Phospholipid N-methylation-dependent alterations of cardiac contractile function by L-methionine

Isolated rat, rabbit and guinea pig hearts exhibited an initial negative inotropic (20-30%) effect followed by a positive inotropic response (60-80%) upon perfusion with 300 microM L-methionine. In contrast, frog hearts did not show any delayed positive inotropic effect, whereas initial negative inotropic effect (25%) of L-methionine was seen. In subsequent studies using rat hearts, methionine was found to induce a dose-dependent increase in contractile force which correlated linearly (r = 0.93) with incorporation of methyl groups into tissue N-methylated phospholipids. The presence of adenosine, L-homocysteine thiolactone and erythro-9-(2-hydroxy-3-nonyl) adenine mixture in the perfusion medium inhibited the contractile effects of L-methionine as well as the incorporation of 3H-methyl groups by about 75%. Cycloleucine, an inhibitor of S-adenosylmethionine synthase, and methyl acetimidate, a blocker of the phosphatidylethanolamine polar groups, inhibited phospholipid N-methylation and prevented the contractile changes due to L-methionine. The initial negative inotropic effect of methionine was attenuated by lowering the concentration of Na+, whereas the delayed positive inotropic effect was dependent on the concentration of Ca++ in the perfusion medium. Ryanodine, a blocker of the sarcoplasmic reticular Ca++ release, prevented the positive inotropic effect of methionine whereas verapamil, a well known Ca++ antagonist, blocked the initial depressant effect and reduced the delayed positive inotropic response. Marked alterations in the sarcolemmal and sarcoplasmic reticular calcium transport activities were seen upon perfusing the hearts with methionine.(ABSTRACT TRUNCATED AT 250 WORDS)