Persistent Activation of a Swelling-Activated Cation Current in Ventricular Myocytes From Dogs With Tachycardia-Induced Congestive Heart Failure

Abstract

Abstract —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 0.9× to 0.6× isosmotic solution (296 mOsm/L) was required to elicit an inwardly rectifying swelling-activated cation current ( I Cir,swell ) that reversed near –60 mV and was inhibited by 10 μmol/L Gd 3+ , a mechanosensitive channel blocker. Block of I Cir,swell by Gd 3+ simultaneously reduced the volume of normal cells in hyposmotic solutions by up to ≈10%, but Gd 3+ had no effect on volume in isosmotic solution. In contrast, I Cir,swell was persistently activated under isosmotic conditions in CHF myocytes, and Gd 3+ decreased cell volume by ≈8%. Osmotic shrinkage in 1.1× to 1.5× isosmotic solution inhibited both I Cir,swell and Gd 3+ -induced cell shrinkage in CHF cells, whereas osmotic swelling only slightly increased I Cir,swell . The K 0.5 and Hill coefficient for Gd 3+ block of I Cir,swell and Gd 3+ -induced cell shrinkage were estimated as ≈2.0 μmol/L and ≈1.9, respectively, for both normal and CHF cells. In both groups, the effects of Gd 3+ on current and volume were blocked by replacing bath Na + and K + and were linearly related with varying Gd 3+ concentration and the degree of cell swelling. CHF thus altered the set point for and caused persistent activation of I Cir,swell . This current may contribute to dysrhythmias, hypertrophy, and altered contractile function in CHF and may be a novel target for therapy.