FREQUENCY-DEPENDENT CHANGES IN CONTRIBUTION OF SR CA2+ TO CA2+ TRANSIENTS IN FAILING HUMAN MYOCARDIUM ASSESSED WITH RYANODINE

We tested the influence of blocking sarcoplasmic reticulum (SR) functi on with ryanodine (1 mu M) on stimulation rate-dependent changes of in tracellular Ca2+ transients and twitch force in failing human myocardi um. Isometrically contracting, electrically stimulated muscle strips f rom ventricles of 10 end-stage failing human hearts were used, Muscles were loaded with the intracellular Ca2+ indicator aequorin, At stimul ation rates from 0.5-3 Wt, intracellular Ca2+ transients and twitch fo rce were simultaneously recorded before and after ryanodine exposure ( 37 degrees C). Ryanodine significantly reduced twitch force at 1 Hz by 46+/-9% and aequorin light by 57+/-10% in failing human myocardium (P <0.05). The blunted or inverse aequorin light- and force-frequency rel ation became positive after ryanodine: in failing human myocardium, tw itch force and aequorin light before ryanodine did not increase with i ncreasing frequency and force decreased significantly at 3 Hz (P<0.05) . After ryanodine, twitch force (P<0.05) and aequorin light increased with increasing stimulation frequency and were maximum at 2 Hz. The da ta indicate that inhibition of SR function significantly reduces twitc h force and Ca2+ transients in failing human myocardium, but converts the blunted or inverse Ca2+- and force-frequency relation into a posit ive one. We infer that Ca2+ responsible for similar to 50% of twitch f orce is derived from the SR and similar to 50% from sarcolemmal Ca2+ i nflux in failing human myocardium. This sarcolemmal component increase s at higher stimulation frequencies. (C) 1998 Academic Press.