© 1997 American Heart Association, Inc.
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Decreased Expression of Kv4.2 and Novel Kv4.3 K+ Channel Subunit mRNAs in Ventricles of Renovascular Hypertensive Rats
From the Department of Pharmacology (K.T., D.L., K.M.H., E.S.L.) and the Center for Clinical Pharmacology (P.L., E.K.J.), University of Pittsburgh (Pa).
Correspondence to Edwin S. Levitan, E1351 Biomedical Science Tower, Department of Pharmacology, University of Pittsburgh, Pittsburgh, PA 15261. E-mail levitan{at}server.pharm.pitt.edu
Abstract Hypertension-induced cardiac hypertrophy is associated with alterations in ventricular action potentials. To understand molecular mechanisms underlying this electrical abnormality, expression of cardiac voltage-gated K+ channel subunit genes was examined in ventricles of renovascular hypertensive rats. While generating a rat Kv4.3 probe, we discovered a previously unreported 19–amino acid insertion in the C-terminal intracellular region of the channel subunit. RNase protection assays indicated that this novel isoform is predominant in rat lung and heart. Effects of renovascular hypertension were then determined by using renal artery clipping models: two-kidney, one clip (2K-1C) rats, a model of high-renin hypertension with a normal plasma volume, and one-kidney, one clip (1K-1C) rats, a model of normal renin with a raised plasma volume. Expression of Kv4.2 and Kv4.3 mRNAs was diminished by >50% in ventricles of 2K-1C rats; however, no changes in the expression of Kv1.2, Kv1.4, Kv1.5, Kv2.1, or KvLQT1 mRNAs were detected. Similar downregulation of Kv4.2 and Kv4.3 mRNAs was detected in 1K-1C rats. Chronic administration of captopril, an angiotensin-converting enzyme inhibitor, blocked the development of hypertension and the suppression of Kv4 subfamily channel mRNA expression in 2K-1C rats. Furthermore, captopril administration to sham-operated rats significantly increased Kv4.2 mRNA. These results indicate that renovascular hypertension causes specific reductions in Kv4 subfamily channel mRNA expression and that this effect is likely to be mediated primarily by an increase in cardiac afterload.
Key Words: K+ channel • alternative splicing • transient outward current • renovascular hypertension • ventricular hypertrophy
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