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

Abstract

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. 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. 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+). 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.