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) function with ryanodine (1 microM) on stimulation rate-dependent changes of intracellular Ca2+ transients and twitch force in failing human myocardium. Isometrically contracting, electrically stimulated muscle strips from ventricles of 10 end-stage failing human hearts were used. Muscles were loaded with the intracellular Ca2+ indicator aequorin. At stimulation rates from 0.5-3 Hz, intracellular Ca2+ transients and twitch force 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 relation became positive after ryanodine: in failing human myocardium, twitch force and aequorin light before ryanodine did not increase with increasing 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 data indicate that inhibition of SR function significantly reduces twitch force and Ca2+ transients in failing human myocardium, but converts the blunted or inverse Ca(2+)- and force-frequency relation into a positive one. We infer that Ca2+ responsible for approximately 50% of twitch force is derived from the SR and approximately 50% from sarcolemmal Ca2+ influx in failing human myocardium. This sarcolemmal component increases at higher stimulation frequencies.
Medizinische Klinik III, Universität Freiburg, Germany.
K
K
Schlotthauer
J
J
Schattmann
D M
DM
Bers
L S
LS
Maier
U
U
Schütt
K
K
Minami
H
H
Just
G
G
Hasenfuss
B
B
Pieske
D002118:Calcium / Q000378:metabolism*; D005260:Female; D006333:Heart Failure / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009200:Myocardial Contraction / Q000187:drug effects*; D012433:Ryanodine / Q000494:pharmacology*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*
D012433:Ryanodine; D002118:Calcium