SR calcium handling and calcium after-transients in a rabbit model
of heart failure.
Cardiovasc Res, 58 (1):
99--108 (April 2003)Abstract
OBJECTIVE: After-depolarization associated arrhythmias are frequently
observed in heart failure and associated with spontaneous calcium
release from sarcoplasmic reticulum (SR), calcium after-transients.
We hypothesize that disturbed SR calcium handling underlies calcium
after-transients in heart failure (HF). METHODS: We measured the
stimulation rate dependence (0.2-3 Hz) of diastolic calcium, calcium
transient amplitude and SR calcium content in left ventricular myocytes
isolated from hearts of rabbits with pressure and volume overload-induced
HF and age-matched control animals. Cytosolic calcium was measured
with indo-1. In some experiments, delayed after-depolarizations (DADs)
were monitored with the voltage sensitive dye di-4-Annepps. SR calcium
content was estimated from the response to rapid cooling (RC). After-transients
were elicited in the presence of norepinephrine (100 nmol/l) after
cessation of burst pacing. RESULTS: With increasing stimulation rate
(0.2-3.0 Hz): (1) steady state diastolic Ca(i) increased from 102
to 174 nmol/l in HF and from 44 to 103 nmol/l in control, (2) calcium
transient amplitudes decreased from 310 to 254 nmol/l in HF and increased
from 186 to 429 nmol/l in control, (3) SR calcium content decreased
from 1.25 to 1.09 mmol/l in HF and increased from 1.51 to 2.48 mmol/l
in control, (4) in HF and control, the end diastolic SR membrane
calcium gradient decreased by about 30\%; at any stimulation rate,
the magnitude of gradient in HF was one-third of control, (5) systolic
depletion of SR was 85\% in HF and 60\% in control. In HF, noradrenaline
(100 nmol/l) increased SR calcium content and SR membrane gradient
by 40\% versus about 7\% in control. Calcium after-transients were
observed in 14 out of 18 HF rabbits, and none in eight control animals
and were associated with DADs. Calcium after-transients were associated
with a 35\% decrease in SR calcium content. The frequency of occurrence
of calcium after-transients was related to diastolic calcium. CONCLUSIONS:
in HF, diastolic calcium is increased and both SR calcium content
and SR membrane calcium gradient are decreased in a stimulation rate-dependent
manner. In HF, beta-adrenergic stimulation can partly restore the
SR calcium content and SR membrane gradient at higher stimulation
rates in a meta-stable condition; upon transition to low stimulation
rates, the SR membrane can no longer maintain this high unbalanced
SR calcium load at increased diastolic calcium, the magnitude of
which is causally related to the occurrence of calcium after-transients.
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