Аннотация
Ventricular arrhythmias and contractile dysfunction are the main causes
of death in human heart failure (HF). In a rabbit HF model reproducing
these same aspects of human HF, we demonstrate that a 2-fold functional
upregulation of Na$^+$-Ca$^2+$ exchange (NaCaX) unloads sarcoplasmic
reticulum (SR) Ca$^2+$ stores, reducing Ca$^2+$ transients
and contractile function. Whereas beta-adrenergic receptors (beta-ARs)
are progressively downregulated in HF, residual beta-AR responsiveness
at this critical HF stage allows SR Ca$^2+$ load to increase,
causing spontaneous SR Ca$^2+$ release and transient inward current
carried by NaCaX. A given Ca$^2+$ release produces greater arrhythmogenic
inward current in HF (as a result of NaCaX upregulation), and approximately
50\% less Ca$^2+$ release is required to trigger an action potential
in HF. The inward rectifier potassium current (I(K1)) is reduced
by 49\% in HF, and this allows greater depolarization for a given
NaCaX current. Partially blocking I(K1) in control cells with barium
mimics the greater depolarization for a given current injection seen
in HF. Thus, we present data to support a novel paradigm in which
changes in NaCaX and I(K1), and residual beta-AR responsiveness,
conspire to greatly increase the propensity for triggered arrhythmias
in HF. In addition, NaCaX upregulation appears to be a critical link
between contractile dysfunction and arrhythmogenesis.
- 11397771
- a,
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- animal,
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- arrhythmia,
- beta,
- beta-agonists,
- beta-antagonists,
- caffeine,
- calcium,
- cells,
- channels,
- congestive,
- contraction,
- cultured,
- disease
- down-regulation,
- drenergic,
- dysfunction,
- exchanger,
- failure,
- gov't,
- heart
- inwardly
- isoproterenol,
- left,
- membrane
- models,
- myocardial
- p.h.s.,
- patch-clamp
- potassium
- potassium,
- potentials,
- propranolol,
- rabbits,
- receptors,
- rectifying,
- research
- reticulum,
- sarcoplasmic
- sodium,
- sodium-calcium
- support,
- techniques,
- u.s.
- up-regulation,
- ventricular
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