Abstract
OBJECTIVE: In patients with heart disease, the transition from compensatory
hypertrophy to heart failure (HF) is associated with altered calcium
handling. Up-regulated Na(+)/H(+)-exchanger (NHE-1) activity underlies
increased Na(+)(i) and disturbance of cellular calcium handling
in HF. We hypothesize that chronic inhibition of NHE-1 activity prevents
the hypertrophic response, cellular remodeling, and development of
HF. METHODS: Rabbits received a control or cariporide (inhibitor
of NHE-1) diet for 3 months, starting after induction of combined
volume and pressure overload. Age-matched animals served as control.
Development of HF was examined echocardiographically and electrocardiographically
after 3 months. Na(+)(i), Ca(2+)(i), pH(i), and action potentials
were measured in left ventricular midmural myocytes with SBFI, indo-1,
SNARF, and di-4-anepps. Sarcoplasmic reticulum calcium content was
calculated from the response of Ca(2+)(i) to rapid cooling. Calcium
after-transients were elicited by cessation of rapid stimulation
(3 Hz) in the presence of 100 nmol/l noradrenalin. RESULTS: Chronic
treatment of rabbits with the specific Na(+)/H(+)-exchanger activity
inhibitor cariporide greatly attenuated development of hypertrophy
and entirely abolished development of HF; the heart/body weight ratio
increased only little, no change in lung weight occurred, left ventricular
dimensions and fractional shortening changed mildly, ascites was
not present, QT duration did not increase, and sudden death did not
occur. Chronic cariporide treatment also prevented cellular electrical
and ionic remodeling. Myocyte dimensions were unaltered, action potentials
were not prolonged, cytoplasmic sodium and NHE-1 activity did not
increase, cytoplasmic and SR calcium handling remained undisturbed,
and no increase of the incidence of calcium after-transient dependent
delayed after depolarizations (DADs) occurred. CONCLUSION: We conclude
that enhanced activity of NHE-1 underlies cardiac cellular electrical
and ionic remodeling in experimental heart failure, and that chronic
dietary treatment with cariporide attenuates hypertrophy, development
of HF, and cellular remodeling.
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