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

From the Departments of Internal Medicine (H.F.C.) and Physiology (H.F.C., C.M.B.), Medical College of Virginia, Virginia Commonwealth University, Richmond, Va, and the Division of Cardiology (B.S.S.), Veterans Affairs Medical Center, West Roxbury, and Harvard University, Boston, Mass.

Correspondence to Henry F. Clemo, MD, PhD, Department of Physiology, Medical College of Virginia, PO Box 980551, Richmond, VA 23298-0551. E-mail hclemo{at}hsc.vcu.edu

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 0.9x to 0.6x 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 Gd³⁺, a mechanosensitive channel blocker. Block of I_Cir,swell by Gd³⁺ simultaneously reduced the volume of normal cells in hyposmotic solutions by up to 10%, but Gd³⁺ had no effect on volume in isosmotic solution. In contrast, I_Cir,swell was persistently activated under isosmotic conditions in CHF myocytes, and Gd³⁺ decreased cell volume by 8%. Osmotic shrinkage in 1.1x to 1.5x isosmotic solution inhibited both I_Cir,swell and Gd³⁺-induced cell shrinkage in CHF cells, whereas osmotic swelling only slightly increased I_Cir,swell. The K_0.5 and Hill coefficient for Gd³⁺ block of I_Cir,swell and Gd³⁺-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 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,swell. This current may contribute to dysrhythmias, hypertrophy, and altered contractile function in CHF and may be a novel target for therapy.

Key Words: arrhythmia • cardiomyopathy • cardiac edema • cell size • ion channel gating

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