Copyright © 2006, European Society of Cardiology
Activation of gadolinium-sensitive ion channels in cardiomyocytes in early adaptive stages of volume overload-induced heart failure
aDepartment of Physiology and Biophysics, University of Alabama at Birmingham (UAB), 868 McCallum Basic Health Sciences Building, 1918 University Boulevard, Birmingham AL, 35294, United States
bDepartment of Medicine, Division of Cardiovascular Disease, UAB, United States
cBirmingham Veterans Affairs Medical Center, Birmingham, Alabama, United States
* Corresponding author. Tel.: +1 205 934 1785; fax: +1 205 975 7679. Email address: carmel{at}physiology.uab.edu
Objective: The objective of this study was to investigate whether gadolinium (Gd3+)-sensitive stretch-activated ion channels (SAC) are basally active in left ventricular (LV) myocytes in early stages of heart failure (HF) induced by volume overload.
Methods: The aortocaval fistula (ACF) model was employed to induce HF due to volume overload in rat. At specific time-points, LV myocytes were acutely isolated using a modified Langendorff apparatus. Whole-cell currents were measured using the patch-clamp technique and intracellular Ca2+(Ca2+i) was examined using fluorescence imaging and the Ca2+-sensitive dye Fura-2.
Results: Current–voltage data were obtained from sham and ACF myocytes at 5-d and 2-, 6-, 8- and 10-wk post surgery. Compared to data from matching sham rats, a 10 µM Gd3+-sensitive current at –100 mV comprised a larger fraction of total current in myocytes from 5-d, 2-wk, and 6-wk ACF rats. In general, the Gd3+-sensitive current contributed to inward currents at mV
–80 and outward currents at >+20 mV. The enhanced Gd3+-sensitive current was absent in myocytes from 8- and 10-wk ACF rats. 10 or 100 µM Gd3+ had no appreciable effect on resting Ca2+i of myocytes from 5-d ACF or corresponding sham rats. The Gd3+-sensitive current in 5-d ACF myocytes was i) sensitive to the cation-selective SAC inhibitor, GsMTx-4, ii) non-selective for Na+/K+, and iii) impermeable to Ca2+.
Conclusion: A basally-active, Gd3+- and GsMTx-4-sensitive SAC current that is non-selective for Na+ and K+, but impermeable to Ca2+ under resting conditions is transiently elevated in LV myocytes from rats in early stages of volume overload-induced HF.
KEYWORDS Calcium (cellular); Heart failure; Ion channels; Stretch; Membrane currents
1 Current address: Department of Pharmacology, Louisiana State University Health Sciences Center, New Orleans, LA 70803, United States.
Time for primary review 17 days
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