Long-term treatment of spontaneously hypertensive rats with losartan and molecular basis of modulating Ito of ventricular myocytes

Abstract

The present study aimed to determine the effect of chronic treatment with losartan on transient outward potassium current (Ito) and the expression levels of potassium voltage-gated channel subfamily D members 2 and 3 (Kv4.2 and 3) and voltage-gated potassium channel-interacting protein 2 (KChIP2) in rats. Spontaneously hypertensive (SH) rats and Wistar-Kyoto (WKY) rats were used in the study. The rats were divided into lo-SH and SH groups and los-WKY and WKY groups, respectively. Ito was recorded and expression levels of Kv4.2, Kv4.3 and KChIP2 were measured by western blot analysis and quantitative polymerase chain reaction. Ito current density was smaller in SH compared with WKY, los-WKY and los-SH groups (P<0.01). Inactivation time constant of myocytes was larger in SH compared with WKY, los-WKY and los-SH groups (P<0.01). The mean levels of mRNA and protein of Kv4.2 and Kv4.3 were significantly lower in the SH compared with WKY, los-WKY and los‑SH groups in vivo and in vitro (P<0.01). The Pearson statistical test showed no correlation between the expression levels of Kv4.2, Kv4.3, KChIP2 and the changes in blood pressure in the losartan treatment group. In conclusion, chronic blockade of angiotensin II type 1 receptors with losartan reversed SH rats' electrical remodeling and shortened action potential duration, which was associated with an increase in Ito density as the expression levels of Kv4.2, Kv4.3 increased and the expression levels of KChIP2 decreased. However, the expression levels of Kv4.2, Kv4.3 and KChIP2 were not correlated with the change in blood pressure in the losartan treatment group. Losartan may decrease the inactivation time by increasing the expression of KChIP2.

Expression of Kv4.2 and Kv4.3 potassium channels in human umbilical veins from normal, diabetic and hypertensive pregnancies

“…Diminished expression of Kv4.2 and Kv4.3 subunits has been reported in cardiac myocytes from spontaneously hypertensive rats alongside with lower A-type currents density 32,33 .…”

Allisartan ameliorates vascular remodeling through regulation of voltage-gated potassium channels in hypertensive rats

“…Inhibition of Kv channels decreases the outflow of K + and increases the inflow of Ca 2+ resulting in membrane depolarization and vasoconstriction. It also inhibits the cell apoptosis cycle, which further causes the contraction, increase and proliferation of smooth muscle cells, and promotes the thickening of smooth muscle layer [ 34 – 36 ]. Of these, Kv7 family was reported to regulate myogenic and vasoconstrictor-induced tone in different blood vessels [ 36 ].…”

Nkx2.5/CARP signaling pathway contributes to the regulation of ion channel remodeling induced by rapid pacing in rat atrial myocytes

“…L-type Ca 2+ current is activated by membrane depolarization and contributes to the formation of the action potential plateau phase (23). As in the ventricular muscle cells, the transient outward K + current (I to ) is the basis of early rapid repolarization of atrial action potential, while Kv4.3 is the major pore-forming subunit of I to channels (24). Atrial rapid pacing, as occurs in atrial fibrillation, may lead to a decrease in the density of functional ion channels (Na + , Ca 2+ and K + ) (25); however, no effect was observed on the intrinsic properties of single ion channels.…”