Mice overexpressing the cardiac sodium-calcium exchanger: defects in excitation-contraction coupling.
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 (Delta[Ca(2+)](i)= 466 +/- 48 nm in transgenics versus 892 +/- 104 nm 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.
Reuter
Hannes
H
Department of Physiology, Division of Cardiology, David Geffen School of Medicine at UCLA, 47-123 CHS, 10833 LeConte Avenue, Los Angeles, CA 90095-1679, USA.
Han
Tieyan
T
Motter
Christi
C
Philipson
Kenneth D
KD
Goldhaber
Joshua I
JI
D000818:Animals; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000378:metabolism; D004553:Electric Conductivity; D015870:Gene Expression; D006352:Heart Ventricles; D006720:Homozygote; D007425:Intracellular Membranes / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000378:metabolism*; D009994:Osmolar Concentration; D018408:Patch-Clamp Techniques; D019831:Sodium-Calcium Exchanger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism* / Q000502:physiology
D020746:Calcium Channels, L-Type; D019831:Sodium-Calcium Exchanger; D002110:Caffeine; D002118:Calcium