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AIM:To investigate the protective effect of zacopride (ZAC) on the pressure-overload left ventricular remodeling in the rats induced by coarctation of abdominal aorta.METHODS:Male Sprague-Dawley (SD) rats with pressure overload were induced by the coarctation of abdominal aorta.The model rats were intraperitoneally administered with ZAC, chloroquine (Chlor) , and zacopride+chlorquine (ZAC+Chlor).The study duration was 8 weeks.The cardiac structure and function were assessed by echocardiography.The heart weight/body weight (HW/BW) ratio and the left ventricular weight/body weight (LVW/BW) ratio were calculated.The changes of structure and shape in myocardial tissue were observed with HE staining.The ultrastructure of the myocytes was observed under transmission electron microscope.The inward rectifier potassium channel (IK1) protein expression was determined by Western blot.The mRNA expression of Kir2.1 was detected by RT-PCR.RESULTS:Compared with vehicle group, ZAC improved cardiac function, as indicated by the decreased left ventricular end-diastolic dimension (LVEDD) and left ventricular end systolic dimension (LVESD) (P<0.05) , and the increased left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) (P<0.01).The HW/BW and LVW/BW ratios were significantly decreased, and the cross-sectional area of the cardiomyocytes was significantly less in ZAC group than that in vehicle group (P<0.01).The ultrastructure of the myocytes was significantly improved.Chlor blocked the protective effect of zacopride on the pressure-overload left ventricular remodeling.The protein level ofmRNA expression of Kir2.1 in the cardiac tissues in ZAC group were significantly increased compared with vehicle group (P<0.01).CONCLUSION:ZAC significantly attenuates pressure overload-induced ventricular remodeling in rats.
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Aim To examine the effect of zacopride,a specific inward rectifier potassium channel(IK1)agonist,on L-thyroxine(T4)-induced ventricular remodeling and the underlying mechanism.Methods SD rats were randomly divided as control,L-thyroxine(L-thy,1 mg·kg-1·d-1,ig,10 d)model,L-thy +zacopride(5,15,50 μg·kg-1,respectively,ip),L-thy+zacopride(15 μg·kg-1)+chloroquine(7.5 μg·kg-1,ip)and L-thy+captopril(100 mg·kg-1·d-1,drinking water)groups.Echocardiography and cardiac hypertrophic indexes were measured to confirm the establishment of the ventricular remodeling model.The changes of IK1 and L-calcium current(ICa-L)were detected by whole cell patch clamp technique.The confocal microscopy and fluorescent indicator Fluo-4 were applied to examine the intracellular Ca2+ concentration([Ca2+]i)of isolated adult rat ventricular myocytes.Results L-thyroxine induced left ventricular hypertrophy with increased ratio of heart weight(HW)to body weight(HW·BW-1),ratio of left ventrical weight(LVW)to body weight(LVW·BW-1),left ventricular dimension in diastole(LVIDd),left ventricular dimension in systole(LVIDs),interventricular septum thickness(IVS)and decreased ejection fraction(EF),fractional shortening(FS)(P<0.01).Patch clamp data suggested IK1 was downregulated,while ICa-L was upregulated(P<0.01).In isolated adult cardiomyocytes,L-thyroxine increased the cell area and [Ca2+]i(P<0.01).Zacopride treatment obviously alleviated cardiac remodeling,improved cardiac function,reversed the changes of IK1 and ICa-L,and significantly attenuated intracellular calcium overload(P<0.01).The optimum dose of zacopride in vivo was 15 μg·kg-1 at which the effect was compared favourably with captopril,a classical anti-remodeling agent.Low-dose IK1 atagonist chloroquine could reverse the effect of zacopride(P<0.01).Conclusion Via activating IK1,zacopride could significantly decrease Ca2+ influx and intracellular calcium overload thereby inhibiting L-thyroxine-induced cardiac ventricular remodeling.
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Objective: To investigate the effect with its possible mechanisms of zacopride on vasodilatation of isolated coronary arterial rings in experimental rats. Methods: The tension of vasodilatation of isolated coronary arterial rings of male SD rats was recorded by Powerlab and DMT system. The rats were divided into 4 groups: +Endo (vehicle) group, +Endo (zacopride) group and -Endo (vehicle) group, –Endo (zacopride) group.n=6 in each group. The vasodilatation effects of zacopride on KCl (60 mmol/L) and U46619 (10-6 mol/L) pre-constricted arterial ring were recorded; the effects of different agents on zacopride caused vasodilatation were studied. Results: In both +Endo (zacopride) and –Endo (zacopride) groups, zacopride showed a dose dependent vasodilatation effect on coronary ring pre-constricted by KCl and U46619. The maximum vasodilatation effect of zacopride in KCl treated+Endo (zacopride) group was (90.15 ± 6.38) %, in U46619 treated-Endo (zacopride) group was (81.67 ± 4.97 ) %; the maximum vasodilatation effect of zacopride in KCl treated-Endo (zacopride) group was (85.48±5.04) %, in U46619 treated–Endo (zacopride) group was (79.65 ± 3.51) %, compared to each corresponding vehicle group, allP0.05. Conclusion: Zacopride had vasodilatation effect on coronary arterial ring which was pre-constricted by KCl and U46619, which might be related to the channel of IK1.
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Aim To investigate the inhibitory effects of zacopride(Zac) on arrhythmia induced by isoproterenol ( ISO) and the underlying mechanisms in rats. Meth-ods ①ECGs were recorded in anesthetized rats in vi-vo to observe the effects of zacopride on arrhythmia in-duced by ISO. ② Intracellular microelectrode tech-nique was used to investigate the effects of zacopride on resting membrane potential, delayed afterdepolariza-tions ( DADs) and triggered activity ( TA) induced by ISO combined with 3. 6 mmol·L-1 CaCl2 in right ven-tricular papillary muscle of rats. Results ① In ISO group rats, ventricular premature beats ( VPB ) oc-curred frequently with ST-segment depression. Com-pared with ISO group, the incidence of VPB in ISO+Zac group decreased from 100% to 50% ( n=6 , P<0. 05 ) and the total number of VPB recorded in 1 hour significantly reduced from 1 574 ± 521 to 33 ± 40 ( n=6,P<0. 05). ② Zacopride at 1 μmol·L-1 could hy-perpolarize the resting membrane potential of right ven-tricular papillary muscle in normal rat from ( -74. 42 ± 1. 95 ) mV to ( -78. 50 ± 2. 07 ) mV ( n =6 , P <0. 05). ③ Zacopride at 1 μmol·L-1 significantly de-pressed the DADs and TA induced by ISO combined with 3. 6 mmol·L-1 CaCl2 in right ventricular papilla-ry muscle. The incidence of DADs decreased from 93. 75% in rats in ISO group to 25% in ISO +Zac group ( n =16 , P <0. 05 ) , and this antiarrhythmic effect could be reversed by 1 μmol·L-1 BaCl2 . Conclusions Zacopride, a selective IK1 channel ago-nist , can significantly inhibit cardiac arrthymia induced by ISO in rats, the mechanism of which is mainly at-tributed to zacopride-induced hyperpolarization of the resting membrane potential and subsequent suppression of DADs and TA via enhancing IK1 . These results pro-vide further evidence that to enhance IK1 moderately may be a feasible pathway for antiarrthymic therapy.
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0.05).Zacopride at concentration of 1.0 ?mol/L showed the most potent activity on IK1 with approximately 30% increment both in inward current and outward current(P