DECREASED EXPRESSION OF KV4.2 AND NOVEL KV4.3 K-RNAS IN VENTRICLES OFRENOVASCULAR HYPERTENSIVE RATS( CHANNEL SUBUNIT MESSENGER)

Hypertension-induced cardiac hypertrophy is associated with alteration s 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 renovasc ular hypertensive rats. While generating a rat Kv4.3 probe, we discove red a previously unreported 19-amino acid insertion in the C-terminal intracellular region of the channel subunit. RNase protection assays i ndicated that this novel isoform is predominant in rat lung and heart. Effects of renovascular hypertension were then determined by using re nal artery clipping models: two-kidney, one clip (2K-1C) rats, a model of high-renin hypertension with a normal plasma volume, and one-kidne y, 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 Kv 1.2, Kv1.4, Kv1.5, Kv2.1, or KvLQT1 mRNAs were detected. Similar downr egulation of Kv4.2 and Kv4.3 mRNAs was detected in 1K-1C rats. Chronic administration of captopril, an angiotensin-converting enzyme inhibit or, blocked the development of hypertension and the suppression of Kv4 subfamily channel mRNA expression in 2K-1C rats. Furthermore, captopr il administration to sham-operated rats significantly increased Kv4.2 mRNA. These results indicate that renovascular hypertension causes spe cific reductions in Kv4 subfamily channel mRNA expression and that thi s effect is likely to be mediated primarily by an increase in cardiac afterload.