Abstract
OBJECTIVE: Diastolic calcium is increased in myocytes from failing
hearts despite up-regulation of the principal calcium extruding mechanism
the Na+/Ca2+-exchanger (NCX). We hypothesize that increased diastolic
calcium (Ca2+i) is secondary to increased cytosolic sodium (Na+i)
and decreased driving force of NCX (DeltaG(exch)). METHODS: The stimulation
rate dependence of simultaneously measured cytosolic sodium (Na+i),
calcium transients (Ca2+i) and action potentials were determined
with SBFI, indo-1 and the perforated patch technique in midmural
left ventricular myocytes isolated from rabbits with pressure and
volume overload induced heart failure (HF) and in age matched controls.
Dynamic changes of DeltaG(exch) were calculated. RESULTS: With increasing
stimulation frequency, 0.2-3 Hz (all data HF versus control): Na+i
increased (6.4 to 10.8 versus 3.8 to 6.4 mmol/l), diastolic Ca2+i
increased (142 to 219 versus 47 to 98 nmol/l), calcium transient
amplitude decreased in HF (300 to 250 nmol/l) but increased in control
(201 to 479 nmol/l), action potential duration (APD90) decreased
(380 to 260 versus 325 to 205 ms) and time averaged DeltaG(exch)
decreased (6.8 to 2.8 versus 8.7 to 6.4 kJ/mol. With increasing stimulation
rate the forward mode time integral of DeltaG(exch) decreased in
HF by about 30\%, the reversed mode time integral increased about
ninefold and the duration of reversed mode operation more than sixfold
relative to control. CONCLUSIONS: Na+i is increased in HF and the
driving force of NCX is decreased. NCX exerts thermodynamic control
over diastolic calcium. Disturbed diastolic calcium handling in HF
is due to decreased forward mode DeltaG(exch) secondary to increased
Na+i and prolongation of the action potential. Enhanced reversed
mode DeltaG(exch) may account for increased contribution of NCX to
e-c coupling in HF.
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