| Objective Observe the anti-hpyertensive effects of TJ0711 racemicmodification and two Optical isomers via i.v and p.o administration in vivo.Through long-term administration,observe the effects to blood pressure and heart rate in R/S TJ0711 oral administration condition,and whether there is target organ protection effects.Methods 1.Single administration:In i.v administration experiment,took normal SD rats (equal male&female), Anesthetized them with urethane,then intubated carotid,used pressure transducer and Multi-channel physiological recorder to record blood pressure and heart rate.Vein injected TJ0711 with different dose,monitored the changes of BP and HR before and after i.v administration dynamically.In p.o administration experiment,chose normal Wistar rats and two-kidney-one-clip renal hypertensive rats(equal male&female), randomized them into TJ0711 groups with different doses,control group and model group.P.o administration,then measured the changes of BP and HR by tail-cuff method.Carvedilol was considered as positive control drug.According to the data,calculate ED50 of i.v and p.o administration.2.Long-term administration:Rinal hypertensive rats were randomly assigned into R/S TJ0711 groups with high,middle and low dose,control group and model group.Took sham operation Wistar rats as sham operation group.R/S TJ0711 p.o q.d.Measured BP and HR by tail-cuff method every week,and recorded them.Results 1. 1.Single administration:⑴TJ0711 i.v worked rapidly,blood pressure decreased in the maximum at 5min.The percentage of SBP decreased maximum of R/S TJ0711 were: -40.53%±11.45%,-28.15%±9.79%,-15.88%±8.68%,-12.06%±6.63% in 3mg/kg,1mg/kg,0.3mg/kg,0.1mg/kg dose. 0.1mg/kg i.v had significant antihypertensive effect. The percentage of SBP decreased maximum of R-TJ0711 were: -19.58 %±10.12%,-14.10%±6.58%,-8.31%±7.78% in 1mg/kg,0.5mg/kg,0.25mg/kg dose.The data in S-TJ0711 were -24.61%±6.19%,-14.01%±8.37%,-14.11%±8.20% in the same dose.The ED50 of TJ0711 to anesthetic rats i.v were: R/S TJ0711 0.156mg/kg,R-TJ0711 0.516mg/kg,S-TJ0711 0.267mg/kg at 5min; R/S TJ0711 0.237mg/kg,R-TJ0711 0.590mg/kg,S-TJ0711 0.378mg/kg at 10min. When i.v administration,heart rate slowed down as the dose increased.⑵TJ0711 oral administration approached SBP decreased maximum at 0.5h. The percentage of SBP decreased maximum of R/S TJ0711 p.o to normal rats were: 40mg/kg -21.26%±13.68%; 20mg/kg -17.01%±9.15%;10mg/kg -8.20%±7.32%;5mg/kg -3.01%±6.49%;the data of R-TJ0711 were: -18.90%±9.17%,-12.29%±8.28%,-9.14%±8.04%; S-TJ0711:-19.72%±8.60%,-12.67%±6.65%,-10.17%±5.97%。For RHR, the percentage of SBP decreased maximum of R/S TJ0711 p.o were: 40mg/kg -21.52%±7.65%; 20mg/kg -15.03%±10.54%;10mg/kg -13.16%±8.42%;the data of R-TJ0711 in the same doses were: -21.05%±6.20%,-15.44%±6.16%,-9.16%±9.00%;S-TJ0711: -19.57%±4.48%,-19.73%±7.08%and-16.29%±6.78%. The ED50 of TJ0711 to awake RHR p.o were: R/S TJ0711 28.89mg/kg,R-TJ0711 20.67mg/kg,S-TJ0711 20.25mg/kg.When oral administration,R/S and R-TJ0711 had little effect on HR;however,S-TJ0711 fastened HR.2.Long-term administration:The blood pressure of high dose and middle dose groups reduced from4th week.The MDA level of treated groups was significantly lower than model group`s.The data of Left Ventricular Weight Index(LVWI) and determination of hydroxyproline, of treated groups were lower than model group but not significantly.Conclusion Tj0711 is a Adrenalinβ-Receptor Blocker which has quick and strong antihypertensive effect,and have short duration.The effect-dose relations of R/S and R-TJ0711 are linear.When long-term used,it have antihypertensive effect,and it may have Vascular endothelial protection effect and may reverse left ventricular hypertrophy. |
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