Article Text

  1. C. Pott,
  2. X. Ren,
  3. M. C. Jordan,
  4. K. P. Roos,
  5. K. D. Philipson,
  6. J. I. Goldhaber
  1. Cardiovascular Research Laboratories, David Geffen School of Medicine at UCLA, CA


Shortening of the ventricular action potential (AP) is a critical mechanism for the maintenance of Ca2+ homeostasis and contractility in cardiac-specific Na+-Ca2+ exchanger (NCX) knockout (KO) mice. The shortened AP limits Ca2+ influx and increases efficiency of SR Ca2+ release. To investigate the hypothesis that up-regulation of the transient outward current (Ito) shortens the AP in KO myocytes, we recorded Ito in patch-clamped myocytes isolated from NCX KO mice. The pipette solution contained (in mM) 130 KCl, 5.4 NaCl, 1 MgCl2, 10 HEPES, 5 MgATP, 0.1 cAMP, pH 7.2 with KOH. Na+ and Ca2+ currents were blocked by nifedipine (2 μM) and TTX (10 μM) in the external solution, which also contained (in mM) 136 NaCl, 5.4 KCl, 10 HEPES, 1 MgCl2, 0.33 NaH2PO4, 1 CaCl2, 10 glucose, pH 7.4 with NaOH, 26°C. Ito was increased in KO versus WT when cells were depolarized from -80 mV to potentials ranging from -60 to +50 mV (KO: 41 ± 3 pA/pF at +50 mV; n = 13; WT: 20 ± 2 pA/pF at +50 mV; n = 16; p (.01). Ito decay kinetics were also slower in KO. Consistent with increased Ito, electrocardiograms from KO mice exhibited shortened QT intervals (WT: 51 ± 4 ms; n = 8; KO: 38 ± 2 ms; n = 8; p < .05). Expression of the Ito-generating K+ channel subunit Kv4.2 was up-regulated in KO (n = 4; 78 ± 22%; p < .01), whereas no alteration of Kv4.3 and only a slight increase in KChip were detected. We conclude that shortening of the AP in KO myocytes is caused by an increase in Ito due to up-regulation of Kv4.2 protein expression. Since Kv4.2 expression is regulated by Ca2+, we hypothesize that altered Ca2+ handling in NCX KO mice leads to up-regulation of Kv4.2. which. in turn. reduces AP duration and limits Ca2+ influx. This may comprise an important negative feedback mechanism against Ca2+ overload in situations of reduced myocyte Ca2+ extrusion capacity such as during myocardial ischemia.

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