Experiment And Clinical Study On Treatment Of Ventricular Arrhythmias With Losartan

Part 1 Influence of Losartan and Enalapril on ion current of left ventricular myocytes in spontaneously hypertensive ratObjective:To identify if Losartan having anti-arrhythmic effects independently or not and to identify what ionic channel Losartan influences on, we use cell electrophysiological technique in order to study influence of Losartan, which was compared with Enalapril, on the sodium current (INa), the L-type calcium current (ICa-L), the transient outward potassium current (Ito). the delayed rectifier K+ current (Ik), and the inward rectifier potassium currents (Ikl) in spontaneous hypertensive rat (SHR).Methods:Thirty-six 18-week-old male SHR weighing 330～360 g were assigned to one of three groups randomly:Losartan group (Los-SH group,10 mgxkg-1×d-1, ig), Enalapril group (Ena-SH group,10 mgxkg-1×d-1, ig) and placebo group (SH group). Twelve 18-week-old male WKY-Kyoto rats weighing 330-360 g served as control (WKY group). After 8 weeks, action potential (AP) and membrane currents, such as INa, ICa-L, Ito, Ik, Ikl, were recorded in left ventricular myocytes using patch-clamp technique.Results:The blood pressure at the age of 26 weeks was higher in SH group than in los-SH group, in Ena-SH group and in WKY group (all p<0.01). The mean cell membrane capacitance were significantly greater in los-SH group, in SH group than in WKY group, in Ena-SH grou after the experiment (all p<0.01). Action potential duration measured at 50% repolarization (APD50) and action potential duration measured at 90% repolarization (APD90) were significantly longer in SH group, Ena-SH group than in WKY group, WKY group (all p<0.01). ICa-L current density was larger in SH group, in Ena-SH group than in WKY group, in los-SH group (all p<0.01). Ito current density was smaller in SH group, in Ena-SH group than in WKY group, in los-SH group (all p<0.01). The Ito amplitude was lower SH group, in Ena-SH group than in WKY group, in los-SH group (all p<0.01). The inactivation time constant of Ito was larger in myocytes isolated from SH group, Ena-SH group than from WKY group, los-SH group (all p<0.01). Ikl current density was smaller in SH group, in Ena-SH group than in WKY group, in los-SH group (all p<0.01).Conclusions:Enalapril and Losartan had the same effect in depressurization, and Enalapril reversed heart hypertrophy in SHR. However, Enalapril had no effect of INa, ICa-L, Ito, Ik, Ikl·Chronic blockade of AT1 receptors with Losartan reversed SH rats electrical remodeling by shortening action potential duration of left ventricular myocytes, decreasing ICa-L current density, increasing Ito,Ikl current density.Part 2 Influence of Losartan and Enalapril on mRNA and protein expression of ion channel on left ventricular myocytes in spontaneously hypertensive ratObjective:We evaluated the effect of chronic treatment with Losartan and Enalapril on mRNA and protein expression of CaL-α1C, Kv4.2. Kv4.3, KChIP2, ERG, KvLQT1, Kir2.1 on left ventricular myocytes in spontaneously hypertensive rat in order to identify molecular basis of modulating ionic current.Methods:We measured the mRNA and protein expression of CaL-α1C, Kv4.2, Kv4.3, KChIP2, ERG, KvLQT1, Kir2.1 on left ventricular myocytes in spontaneously hypertensive rat by RT-PCR and Western blot.Results:The mRNA and protein expression levels of Kv4.2, Kv4.3, Kir 2.1 were significantly lower in myocytes from SH group and Ena-SH group than in myocytes from WKY group and los-SH group (all p<0.01). The mRNA and protein expression levels of KChIP2, CaL-α1C were significantly higher in myocytes from SH group and Ena-SH group than from WKY group and los-SH group (all p<0.01). In Losartan treatment group Pearson correlation coefficients between mRNA and protein expression levels of CaL-α1C, Kv4.2, Kv4.3, KChIP2, Kir2.1 and change in BP was calculated. Those were not correlated with change in BP.Conclusions:Chronic blockade of AT1 receptors with Losartan reverses SH rats electrical remodeling by increasing mRNA and protein expression of Kv4.2, Kv4.3, Kir 2.1 and by decreasing mRNA and protein expression of KChIP2, CaL-α1C. Losartan regulated the expression of Kv4.2, Kv4.3, Kir 2.1 and KChIP2, CaL-α1C transcripts was independent of changes in blood pressure.Part 3 Effects of Losartan and Enalapril on ventricular arrhythmias in patients with hypertension.Objective:To evaluate the effects of Losartan and Enalapril on ventricular arrhythmias in patients with hypertension.Methods:115 subjects aged 55 to 84 years with hypertension and ventricular arrhythmias were randomly assigned to treatment with Losartan or placebo (Enalapril) for 12 months. We compared blood pressure, left ventricular mass index and ventricular arrhythmias in Losartan group with in Enalapril group.Results:At base line, the treatment groups were well matched in terms of age, sex, duration of disease, and blood pressure. By the end of the study, the treatment groups were well matched in terms of combination therapy, and blood pressure had decreased to a similar extent in both groups. Left ventricular mass index is lower in Enalapril group than in Losartan group (p<0.05). However, ventricular arrhythmias is lower in Losartan group than in Enalapril group. Pearson statistical test showed no correlation between reductions of ventricular arrhythmias and reductions of blood pressure or reductions of left ventricular mass index in Losartan treatment group.Conclusions:Initiation of antihypertensive treatment involving Losartan (an angiotensin receptor blocker) in subjects with hypertension appears to lead to better outcomes (reductions of ventricular arrhythmias) than treatment with Enalapril, despite similar reductions of blood pressure.