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An Altered Repolarizing Potassium Current in Rat Cardiac Myocytes after Subtotal Nephrectomy

PAUL DONOHOE^*, BRUCE M. HENDRY^*, OMAL V. WALGAMA, FEDERICA BERTASO^*, DEBORAH J. HOPSTER, MICHAEL J. SHATTOCK and ANDREW F. JAMES^*

^* Department of Renal Medicine, Guy's King's and St. Thomas' School of Medicine, King's College London, United Kingdom.
Department of Pathology, Guy's King's and St. Thomas' School of Medicine, King's College London, United Kingdom.
Rayne Institute, St. Thomas' Hospital, Guy's King's and St. Thomas' School of Biomedical Sciences, King's College London, United Kingdom.

Correspondence to Dr. Andrew F. James, Department of Renal Medicine, GKT School of Medicine, King's College London, Bessemer Road, London SE5 9PJ, United Kingdom. Phone: +44 (0)20 7928 9292, ext. 3372; Fax: +44 (0)20 7928 0658; E-mail: andrew.f.james{at}kcl.ac.uk

Abstract. Renal failure in humans is associated with electrocardiographic changes including altered QT interval dispersion, which suggests that cardiac myocyte repolarization is abnormal and which appears to correlate with cardiac prognosis. In this study, cardiac myocyte repolarizing currents have been studied in isolated cells from rats 8 wk after subtotal nephrectomy (SNx), using sham-operated animals as controls. In addition, monophasic cardiac action potentials were recorded from the epicardial surface of the left ventricle (LV) apex, LV base, and the right ventricle of isolated perfused hearts paced at 320/min. SNx was associated with cardiac hypertrophy and histologic evidence of myocardial fibrosis, but SNx rats were not hypertensive. Repolarizing K⁺ currents were measured using whole-cell patch-clamp, and 4-aminopyridine (4-AP)-sensitive transient outward (I_to) and 4-AP-insensitive sustained outward (I_so) components were quantified. After SNx, I_to was increased by two to threefold at voltages from -30 to +60 mV and showed increased heterogeneity. For example, at 0 mV voltage clamp pulse, the median I_to was increased from 3.23 pA/pF in control myocytes (interquartile range 3.20 pA/pF, n = 24) to 5.86 pA/pF in SNx myocytes (interquartile range 7.32 pA/pF, n = 21, P < 0.005). The kinetics of inactivation of I_to were altered after SNx with slowing both of the onset and the recovery from inactivation. The mean time constant of inactivation at +30 mV after SNx was 14.2 ± 1.6 ms (n = 20) compared with control values of 9.8 ± 0.6 ms (n = 23, P < 0.05). Neither I_so nor inward rectifier K⁺ currents were altered after SNx. The action potential duration (APD₅₀) at the left ventricular base was approximately 20% shorter (P < 0.02) in hearts from SNx rats compared with controls. 4-AP (2 mM) prolonged the APD₅₀ in all regions in hearts from both SNx and control rats and abolished the APD₅₀ shortening in SNx. These results indicate that abnormalities of the cardiac transient outward K⁺ current contribute to alterations in the cardiac action potential in renal failure and warrant further investigation because they may contribute to altered repolarization and arrythmogenesis.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673