Premium
Mice overexpressing the cardiac sodium‐calcium exchanger: defects in excitation–contraction coupling
Author(s) -
Reuter Hannes,
Han Tieyan,
Motter Christi,
Philipson Kenneth D.,
Goldhaber Joshua I.
Publication year - 2004
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.2003.055046
Subject(s) - medicine , chemistry , myocyte , endocrinology , contraction (grammar) , biophysics , ryanodine receptor , sodium calcium exchanger , calcium , depolarization , biology
Homozygous overexpression of the cardiac Na + –Ca 2+ exchanger causes cardiac hypertrophy and increases susceptibility to heart failure in response to stress. We studied the functional effects of homozygous overexpression of the exchanger at the cellular level in isolated mouse ventricular myocytes. Compared with patch‐clamped myocytes from wild‐type animals, non‐failing myocytes from homozygous transgenic mice exhibited increased cell capacitance (from 208 ± 16 pF to 260 ± 15 pF, P < 0.05 ). Intracellular Ca 2+ oscillations were readily elicited in homozygous transgenic animals during depolarizations to +80 mV, consistent with rapid Ca 2+ overload caused by reverse Na + –Ca 2+ exchange. After normalization to cell capacitance, transgenic myocytes had significant increases in Na + –Ca 2+ exchange activity (318%) and peak L ‐type Ca 2+ current (8.2 ± 0.7 pA pF −1 at 0 mV test potential) compared to wild‐type (5.8 ± 0.9 pA pF −1 at 0 mV, P < 0.02 ). The peak Ca 2+ current amplitude and its rate of inactivation could be modulated by rapid reversible block of the exchanger. Thus, we describe an unexpected direct influence of Na + –Ca 2+ exchange activity on the L ‐type Ca 2+ channel. Despite intact sarcoplasmic reticular Ca 2+ content and larger peak L ‐type Ca 2+ currents, homozygous transgenic animals exhibited smaller Ca 2+ transients (Δ[Ca 2+ ] i = 466 ± 48 n m in transgenics versus 892 ± 104 n m in wild‐type, P < 0.0005) and substantially reduced gain of excitation–contraction coupling. These alterations in excitation–contraction coupling may underlie the tendency for these animals to develop heart failure following haemodynamic stress.