Circulation, Vol 82, 1266-1278, Copyright © 1990 by American Heart Association
JK Gwathmey and RJ Hajjar
A novel approach was developed allowing the measurement of steady-state
force and intracellular calcium concentration ([Ca2+]i) in tetanized human
ventricular trabeculae carneae without pharmacological intervention. We
compared and contrasted three methods of assessing calcium sensitivity of
the myofilaments: 1) force-[Ca2+] relations in skinned fiber preparations,
2) peak twitch force-peak [Ca2+]i relations, and 3) steady-state
force-[Ca2+]i relations in intact muscles. Steady-state contractile
activation was achieved rapidly by tetanizing intact human trabeculae,
loaded with aequorin, a Ca2(+)- sensitive bioluminescent protein, at a
stimulation frequency of 15-20 Hz. Steady-state force and [Ca2+]i were
measured during tetani, and the force versus [Ca2+]i relation was obtained
by varying the extracellular calcium concentration ([Ca2+]o). Force-[Ca2+]i
relations obtained from control and myopathic hearts were fitted to the
Hill equation: %Force = [Ca2+]inh/([Ca2+]inh50% + [Ca2+]inh), where nh is
the Hill coefficient, and [Ca2+]50% is the [Ca2+] required for 50%
activation. The curves of tetani had Hill coefficients of 5.21 +/- 0.20 (n
= 6) and 5.61 +/- 0.60 (n = 10) and [Ca2+]50% of 0.56 +/- 0.05 microM (n =
6) and 0.54 +/- 0.09 microM (n = 10) in control and myopathic muscles,
respectively. We also constructed peak force-peak [Ca2+]i relations using
isometric twitches from the same muscles. These curves were shifted toward
higher [Ca2+]i compared with the steady-state force-[Ca2+]i curve derived
from tetani. Ryanodine (1 microM), which increased the time course of the
Ca2+ and force transients, shifted the peak force-peak [Ca2+]i relation to
the left, without affecting the steady-state force-[Ca2+]i relation.
Exposure to 10 mM caffeine shifted the steady-state force-[Ca2+]i relation
to the left, whereas exposure to 3 microM isoproterenol shifted this
relation to the right. Experiments using skinned fiber preparations were
performed in parallel with experiments on intact muscles from the same
hearts. The force-pCa (-log[Ca2+]) relations in saponin-skinned trabeculae
from control and myopathic tissue were superimposable. Ryanodine (1 microM)
had no effect on the force-pCa relation in skinned fibers. Maximal tension
was evoked by the posttetanic twitch, which was larger than the tetanus.
This potentiation was abolished in the presence of ryanodine, a
sarcoplasmic reticulum inhibitor. We propose that the changes in the
steady-state force-[Ca2+]i relations are correlated with alterations in the
sensitivity of the myofilaments to Ca2+, whereas changes in the peak
force-peak [Ca2+]i relations represent temporal changes in the twitch
transient.(ABSTRACT TRUNCATED AT 400 WORDS)
ARTICLES
Relation between steady-state force and intracellular [Ca2+] in intact human myocardium. Index of myofibrillar responsiveness to Ca2+
Department of Cellular and Molecular Physiology, Harvard Medical School, Boston, MA.
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