Transient Outward Potassium Channel Activator NS5806 Attenuates Cardiac Hypertrophy In A Pressure-overload Mouse Model

Objective: Prolonged action potential duration(APD) induced by delayed ventricular repolarization is the most conspicuous electrophysiological change in pathological cardiac hypertrophy. However, the cause-effect relationship between electrical and hypertophic of which the correlation with cardiac remodelling is currently still unclear. The transient outward potassium channel regulated K+ current(I_to) is the main outward ion current in the early stage of action potential polarization, and also the major component of small rodents’ repolarization currents. This study was to investigate the possible influence of intervened electrophysiological remodelling on the tissue hypertrophic remodelling by observing the effect of outward potassium channel opener NS5806 on the mice’s cardiac hypertrophy induced by pressure overload.Methods: The mice’s cardiac hypertrophy induced by thoracic aortic banding. At 3 weeks after surgery,mice TAB models were confirmed through measuring ventricular wall thickness and blood flow velocity at constriction site by high resolution in vivo micro ultrasound imaging system. Subjects was randomly grouped into sham, TAB group, and NS5806 group; morever,the NS5806 group is divided into low dose, middle dose and high dose(of 25, 50, and 100 mg kg-1 respectively). Following 4 week of intraperitoneal injection in the mice, ECG was recorded for anesthetized mice, so as echocardiography checking cardiac function, Left ventricular mass index(LVW/BW) was also assessed by morphology measurement. Histological studies were performed on HE and Masson detaining dissected heart samples. The m RNA expression of ANP, β-MHC, Procollagen I_ and TGF-β were measured with RT-PCR which to quantify transcriptional level of biomarkers associate with cardiac fibrosis.Resutls: ① I_ndicated by measured results of Echocardiography at 3 weeks after surgery. Compared to Sham, model group has a significantly increased in pulsed wave doppler spectra of the transmitral flow velocity E peak velocity of stenotic jet velocity(P < 0.01). Left ventricular posterior wall thickness both in diastole and systole(LVPWs and LVPWd), interventricular septum thickness(I_Vs) were increased, while left ventricular end diastolic dimension(LVd) was no difference in TAB compared to sham(with P < 0.01 for each). Which indicated that TAB in this experimental condition result in heart hypertrophy and the model is successful. There was no significant difference among the experimental groups before therapy.②Echocardiographic measurements were performed on mice at the end of drug treatment, Model group has a significantly decreased left ventricle, increased ventricular wall thickness and significantly reduced LVI_Ds and larger LVW/BW(with P < 0.01 for each). Whereas significant attenuation was observed in any dosed group. ③Compared to sham, TAB had a prolonged QT inteval, depressed J point(P < 0.01), part of which was also observed to have inverted t wave. I_t was led to significant decrease in these parameters compared with TAB after 4 weeks treatment(P < 0.01). I_n contrast, dosed groups had a significantly elevated J point, showing dose-dependent shortened Q-T interval. ④At the end of drug treatment, body weight was similar among the experimental groups. The ratio of LV weight to body weight(LVW/BW), an index of LV hypertrophy, was increased greatly, it was significant attenuated in NS5806 group. ⑤The significant increasing cardiomyocyte cross-section area was observed by cardiomyocytic HE staining(P < 0.01) whereas the Masson staining indicates the interstitial and collagen increases significantly. Whereas low, median, and high dose all had a significantly ameliorated cardiomyocyte fibrosis. Significantly increased m RNA level of ⑥hypertrophy associated biomarker ANP、β-MHC、Procollagen I_ was found in model group by utilizing RT-PCR(P < 0.01), in which, the middle and high dose was significantly inhibited(P < 0.01).Conclusion: As for aforementioned results it is very likely to conclude that I_to activator reverse the cardiac hypertrophy induced by pressure overload, and also, indicate that the pathological prolonged APD might be the important factor causing cardiac hypertrophic remodelling.