Molecular basis for losartan regulating transient outward potassium current / 中华老年医学杂志

ABSTRACT

Objective To investigate the molecular basis for anti-ventricular arrhythmic effects by losartan through measuring alteration in mRNA and protein levels of key K+ α channel-and-β subunits (Kv4.2,Kv4.3 and KChIP2) in ventricular myocytes in spontaneously hypertensive rats (SHRs).Methods SHRs were randomly assigned to losartan[10mg·kg-1·d-1,n=12] or placebo (n= 12) with age-and weight-matched WKY rats (n = 12) as control.After 8 weeks of treatment,cardiomyocytes were isolated by enzymolysis.Action potential of cardiomyocytes Ito was recorded,mRNA and protein levels of Kv4.2,Kv4.3 and KChIP2 were assessed by reverse transcriptase polymerase chain reaction and Western blot.Results The action potential duration (APD) measured at 50% and 90% repolarization was shorter in losartan group [(16.82 ± 3.79) ms and (68.49±13.25) ms] than in SHR control group [(24.56±4.59) ms and (73.26±15.47) ms,all P<0.01].Losartan increased Ito current density associated with significant increases in the mean levels of mRNA and protein of Kv4.2 and Ky4.3,and with significant decreases in the mean levels of mRNA and protein of KChIP2 compared with those in placebo SHR (all P<0.01).Conclusions Chronic blockade of AT1 receptors with losartan reverses cardiomyocytes electrical remodeling in SHR,resulting in the shortening of APD,which is associated with increasing Ito density by increasing mRNA and protein expression of Kv4.2,Kv4.3 and by decreasing mRNA and protein expression of KChIP2.