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 (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.