Activation of gadolinium-sensitive ion channels in cardiomyocytes in early adaptive stages of volume overload-induced heart failure

OBJECTIVE: The objective of this study was to investigate whether gadolinium (Gd(3+))-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 Ca(2+)(Ca(2+)(i)) was examined using fluorescence imaging and the Ca(2+)-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 microM Gd(3+)-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 Gd(3+)-sensitive current contributed to inward currents at mV< or =-80 and outward currents at >+20 mV. The enhanced Gd(3+)-sensitive current was absent in myocytes from 8- and 10-wk ACF rats. 10 or 100 microM Gd(3+) had no appreciable effect on resting Ca(2+)(i) of myocytes from 5-d ACF or corresponding sham rats. The Gd(3+)-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 Ca(2+). CONCLUSION: A basally-active, Gd(3+)- and GsMTx-4-sensitive SAC current that is non-selective for Na(+) and K(+), but impermeable to Ca(2+) under resting conditions is transiently elevated in LV myocytes from rats in early stages of volume overload-induced HF.