Abstract
OBJECTIVE: Cytosolic sodium (Na+i) is increased in heart failure
(HF). We hypothesize that up-regulation of Na+/H+-exchanger (NHE)
in heart failure is causal to the increase of Na+i and underlies
disturbance of cytosolic calcium (Ca2+i) handling. METHODS: Heart
failure was induced in rabbits by combined volume and pressure overload.
Age-matched animals served as control. Na+i, cytosolic calcium
Ca2+i and cytosolic pH (pH(i)) were measured in isolated left ventricular
midmural myocytes with SBFI, indo-1 and SNARF. SR calcium content
was measured as the response of Ca2+i to rapid cooling (RC). Calcium
after-transients were elicited by cessation of rapid stimulation
(3 Hz) in the presence of 100 nmol/l noradrenalin. NHE and Na+/K+-ATPase
activity were inhibited with 10 micromol/l cariporide and 100 micromol/l
ouabain, respectively. RESULTS: At all stimulation rates (0-3 Hz)
Na+i and diastolic Ca2+i were significantly higher in HF than
in control. With increasing frequency Na+i and diastolic Ca2+i
progressively increased in HF and control, and the calcium transient
amplitude (measured as total calcium released from SR) decreased
in HF and increased in control. In HF (at 2 Hz), SR calcium content
was reduced by 40\% and the calcium gradient across the SR membrane
by 60\%. Fractional systolic SR calcium release was 90\% in HF and
60\% in control. In HF the rate of pH(i) recovery following acid
loading was much faster at all pH(i) and NHE dependent sodium influx
was almost twice as high as in control. In HF cariporide (10 micromol/l,
5 min) reduced Na+i and end diastolic Ca2+i to almost control
values, and reversed the relation between calcium transient amplitude
and stimulation rate from negative to positive. It increased SR calcium
content and SR membrane gradient and decreased fractional systolic
SR depletion to 60\%. Cariporide greatly reduced the susceptibility
to develop calcium after-transients. In control animals, cariporide
had only minor effects on all these parameters. Increase of Na+i
with ouabain in control myocytes induced abnormal calcium handling
as found in HF. CONCLUSIONS: In HF up-regulation of NHE activity
is causal to increased Na+i and secondarily to disturbed diastolic,
systolic and SR calcium handling. Specific inhibition of NHE partly
normalized Na+i, end diastolic Ca2+i, and SR calcium handling
and reduced the incidence of calcium after-transients. Chronic treatment
with specific NHE inhibitors may provide a useful future therapeutic
option in treatment of developing hypertrophy and heart failure.
- /&/
- animals;
- antagonists
- antiporter,
- calcium,
- cardiac,
- cells,
- concentration;
- cultured;
- cytosol,
- failure,
- guanidines,
- heart
- hydrogen-ion
- inhibitors/physiology;
- metabolism;
- myocytes,
- pharmacology;
- rabbits;
- reticulum,
- sarcoplasmic
- sodium,
- sodium-hydrogen
- sulfones,
- up-regulation
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