Persistent activation of a swelling-activated cation current in ventricular myocytes from dogs with tachycardia-induced congestive heart failure

The hypothesis that cellular hypertrophy in congestive heart failure (CHF) modulates mechanosensitive (ie, swelling- or stretch-activated) channels was tested. Digital video microscopy and amphotericin-perforated-patch voltage clamp were used to measure cell volume and ion currents in ventricular myocytes isolated from normal dogs and dogs with rapid ventricular pacing-induced CHF. in normal myocytes, osmotic swelling in 0.9x to 0.6x isosmotic solution (296 mOsm/L) was required to elicit an inwardly rectifying swelling-activated cation current (I-Cir,I- swell) that reversed near -60 mV and was inhibited by 10 mu mol/L Gd3+, a mechanosensitive channel blocker. Block of I-Cir,I-swell by Gd3+ simultaneously reduced the volume of normal cells in hyposmotic solutions by up to approximate to 10%, but Gd3+ bad no effect on volume in isosmotic solution. In contrast, I-Cir,I-swell was persistently activated under isosmotic conditions in CHF myocytes, and Gd3+ decreased cell volume by approximate to 8% Osmotic shrinkage in 1.1x to 1.5x isosmotic solution inhibited both I-Cir,I-swell and Gd3+-induced cell shrinkage in CHF cells, whereas osmotic swelling only slightly increased I-Cir,I-swell, The K-0.5 and Hill coefficient for Gd3+ block of I-Cir,I-swell and Gd3+-induced cell shrinkage were estimated as approximate to 2.0 mu mol/L and approximate to 1.9, respectively, for both normal and CHF cells. In both groups, the effects of Gd3+ on current and volume were blocked by replacing bath Na+ and K+ and were linearly related with varying Gd3+ concentration and the degree of cell swelling. CHF thus altered the set point for and caused persistent activation of I-Cir,I-swell. This current may contribute to dysrhythmias, hypertrophy, and altered contractile function in CHF and may be a novel target for therapy.