Abstract
BACKGROUND AND PURPOSE: Increased activity of the Na+/H+ -exchanger
(NHE-1) in heart failure underlies raised Na+i causing disturbances
of calcium handling. Inhibition of NHE-1, initiated at the onset
of pressure/volume overload, prevents development of hypertrophy,
heart failure and remodelling. We hypothesized that chronic inhibition
of NHE-1, initiated at a later stage, would induce regression of
hypertrophy, heart failure, and ionic and electrophysiological remodelling.
EXPERIMENTAL APPROACH: Development of heart failure in rabbits was
monitored electrocardiographically and echocardiographically, after
one or three months. Cardiac myocytes were also isolated. One group
of animals were treated with cariporide (inhibitor of NHE-1) in the
diet after one month. Cytoplasmic calcium, sodium and action potentials
were measured with fluorescent markers and sarcoplasmic reticulum
calcium content by rapid cooling. Calcium after-transients were elicited
after rapid pacing. Sodium channel current (INa) was measured using
patch-clamp techniques. KEY RESULTS: Hypertrophy and heart failure
developed after one month and progressed during the next two months.
After one month, dietary treatment with cariporide was initiated.
Two months of treatment reduced hypertrophy and heart failure, duration
of action potential QT-interval and QRS, and restored sodium and
calcium handling and the incidence of calcium after-transients. In
cardiac myocytes, parameters of INa were not changed by cariporide.
CONCLUSION AND IMPLICATIONS: In rabbit hearts with hypertrophy and
signs of heart failure one month after induction of pressure/volume
overload, two months of dietary treatment with the NHE-1 inhibitor
cariporide caused regression of hypertrophy, heart failure and ionic
and electrophysiological remodelling.
- /&/
- action
- agents,
- animals;
- antagonists
- anti-arrhythmia
- antiporter,
- calcium
- calcium,
- cardiomegaly,
- cardiomyopathy,
- channels,
- dilated,
- drug
- effects/metabolism;
- effects;
- electrophysiology;
- enzyme
- guanidines,
- inhibitors,
- inhibitors;
- ion
- male;
- metabolism;
- pharmacology
- pharmacology;
- potentials,
- rabbits;
- reticulum,
- sarcoplasmic
- signaling,
- sodium
- sodium,
- sodium-hydrogen
- sulfones,
- therapy/pathology/physiopathology;
Users
Please
log in to take part in the discussion (add own reviews or comments).