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Abstract

Rats treated with DOCA salts and subjected to abdominal aortic stenosis display left ventricle hypertrophy associated with a decrease in cardiac I(to) current density and prolongation of the action potential duration. We investigated the molecular basis of these electrophysiological defects by analyzing the amount of mRNA corresponding to the genes encoding the a subunits of the left ventricle K+ channel at the steady state. The mRNAs corresponding to the a subunits of the K+ channel (Kv1.2, Kv1.4, Kv1.5, Kv2. 1, Kv4.2 and Kv4.3) were measured by quantitative RT-PCR using a specific Kv internal standard. In control rats, the Kvl.5 gene was only expressed at a low level, whereas the Kv4.2 and Kv4.3 genes were expressed at a high level. Regardless of the etiology of the hypertrophy, the amounts of Kv1.4 and Kv1.5 mRNAwere similar in treated, sham and control rats. The amounts of Kv1.2 and Kv2.1 mRNA were markedly lower in DOCA-salt treated rats (66%) than in sham-DOCA rats, but no effect was observed after stenosis. The very conservative Kv4.2 and Kv4.3 genes were found to be downregulated simultaneously in both type of hypertrophy. However, the steady-state amount of Kv4 mRNA was even lower in rats with DOCA-salt-induced hypertrophy than in those with stenosis-induced ventricular hypertrophy. Therefore, the decrease in I(to) density, consecutively to pressure- and volume-overload, is due to a large decrease in the amount of Kv4.2 and Kv4.3 mRNA. In addition, DOCA-salt treatment alters the amounts of Kv transcripts independently to cardiac hypertrophy, suggesting that the mineralocorticoid may be involved in Kv gene expression.

Candesartan Cilexetil Attenuates Arrhythmogenicity Following Pressure Overload in Rats via the Modulation of Cardiac Electrical and Structural Remodeling and Calcium Handling Dysfunction

“… 8 , 9 , 30 Accordingly, we demonstrated that the I to current density was downregulated in response to pressure overload, which could be prevented by candesartan cilexetil treatment. However, the I ss and I K1 densities as well as the corresponding Kv2.1 and Kir2.1 protein levels were not changed, as reported previously, 34 , 35 excluding their involvement in APD prolongation. Peak I Na is mainly responsible for the upstroke of cardiac action potential.…”

“…In rat LV hypertrophy, Kv4.2 and Kv4.3 mRNA are downregulated with no accompanying change in Kv1.4 mRNA. 34 Our results further confirmed the downregulation of both Kv4.2 and Kv4.3 protein and mRNA levels, with no changes in Kv1.4 or KChIP2 protein in the hypertrophied left ventricle. Chronic candesartan cilexetil treatment preserved the I to density accompanied by normal recovery kinetics in banded rat myocytes, perhaps mainly by restoring the Kv4.2 and Kv4.3 channel expression.…”

T-type Ca2+ signalling regulates aldosterone-induced CREB activation and cell death through PP2A activation in neonatal cardiomyocytes

“…The Ca v 3.1, Ca v 3.2, cyclophylin primers, and quantitative RT–PCR procedures have been described elsewhere. 5,15 Briefly, quantitative RT–PCR was performed with a normalized RNA aliquot (1 µg) and a known amount of cRNA internal control (2.5 × 10 6 molecules). The internal control differed from the target counterpart by only one restriction site.…”

Three cases of corticosteroid therapy triggering ventricular fibrillation in J-wave syndromes

“…Regarding the relation between corticosteroids and potassium channels, deoxycorticosterone acetate salt treatment alters the amount of K v transcripts, suggesting that mineralocorticoids may be involved in K v gene expression [15]. Chronic dexamethasone treatment also decreases the transient outward current ( I to ) density [16], which would be expected to enhance the transmural dispersion of repolarization. In Andersen–Tawil syndrome, a rare disorder of periodic paralysis caused by mutations in the KCNJ2 gene, which encodes the inward rectifier potassium channel Kir 2.1, stress or corticosteroids exacerbate the symptoms [17, 18].…”