| Objective:To explore and compare long-term blood pressure and renal protective effect by transient prehypertensive treatment in spontaneously hypertensive rats with losartan and amlodipine.Methods:(1)72 4-week-old SHR were allocated to three groups at random as followed(24 rats in each group):①Placebo control(normal sodium ig.)(SHR);②Losartan(20mg/kg/d ig.)(SHR-LOS);③Amlodipine(10mg/kg/d ig.)(SHR-AML).24 age and weight matched male normotensive WKY rats were set as normal control.Treatment lasted 6 weeks then were stopped. Blood pressure were measured every 4 weeks from 10-week-old.(2)Blood and 24-h urine were collect at age 14,30,46 weeks and then creatine and urea nitrogen in serum, AngⅡand aldosterone in plasma, creatine and albumin in urine were measured, the creatinine clearance rate and 24-h albuminuria were calculated.(3)Rats were killed at age 14,30,46 weeks,8 rats each group.The kidneys were generally embedded with paraffin.PAS pigmentized the slices of kidney and then calculated GSI in a blinded manner using a cumulative semiquantitative scoring.Stained the collagen in slice of kidney by Nitroxanthic acid-Sirius Red and then renal interstitium fibrosis was assessed.Part of remaining renal tissue was homogenated and AngⅡand aldosterone in renal tissue were measured.Took the other part of renal tissue as samples and then compared the expression levels of AT1R and TGF-β1 mRNA in these samples among all groups by RT-PCR.Results: (1)Losartan and amlodipine treatment reduced the blood pressure.After drug withdrawal blood pressure of SHR-LOS increased slowly but remained obviously lower than SHR until age 46 weeks(P<0.05).In contrast blood pressure of SHR-AML increased rapidly after drug withdrawal and there were no statistical significance compared with SHR from age 30 weeks(P>0.05).(2)There were no statistical significance in creatine and urea nitrogen of serum,creatinine clearance rate and 24-h albuminuria among all groups at age 14 weeks.Compared with WKY,creatinine clearance rate decreased but 24-h albuminuria increased in progress in SHR (P<0.05). After drug withdrawal creatinine clearance rate of SHR-LOS decreased slowly but remained higher than SHR, 24-h albuminuria increased slowly but remained higher than SHR(P<0.05).The creatinine clearance rate of SHR-AML decreased rapidly after age 30 weeks and was lower than WKY or SHR-LOS at age 46 weeks(P<0.05).The 24-h albuminuria of SHR-AML increased after age 30 weeks and was no statistical significance compared with SHR at age 46 weeks(P>0.05).(3)There were no statistical significance in plasma AngⅡand aldosterone between SHR and WKY at age 14 and 30 weeks.The above two indexes inceased in SHR and were higher than WKY at age 46 weeks.AngⅡin plasma was obviously higher in SHR-LOS and SHR-AML than in SHR and WKY.In contrast the plasma AngⅡwere lower than SHR and WKY at 30 and 46 weeks.The plasma AngⅡin SHR-AML were no statistical significance compared with SHR from age 30 weeks(P>0.05).Aldosterone in plasma were lower in SHR-LOS than SHR(P<0.05)and there were no statistical significance between SHR-AML and SHR(P>0.05).AngⅡand aldosterone in local renal tissue were obviously higher in SHR than WKY at every age points(P<0.05).In SHR-LOS group AngⅡand aldosterone in local renal tissue were lower than SHR at age 14,30,46 weeks(P<0.05),meanwhile there were no statistical significance between SHR-AML and SHR(P>0.05).(4)In SHR group GSI and renal interstitium fibrosis were higher than WKY at every age points. After drug withdrawal GSI and renal interstitium fibrosis of SHR-LOS increased slowly but remained obviously lower than SHR until age 46 weeks(P<0.05). In contrast GSI and renal interstitium fibrosis of SHR-AML increased rapidly after drug withdrawal and were obviously higher than WKY or SHR-LOS(P<0.05)but lower than SHR(P<0.05).(5)Expression of AT1R and TGF-β1 mRNA in kidney of SHR were obviously increased when compared with WKY (P<0.05).Expression of AT1R mRNA in kidney of SHR-LOS were increased at age 14 weeks but decreased at age 30 and 46 weeks when compared with SHR(P<0.05).Expression of TGF-β1 mRNA in kidney of SHR-LOS were increased through whole trial.There were no significance change of expression of AT1R mRNA in kidney between SHR-AML and SHR at every age points(P>0.05).There was a sligh decreased change of expression of TGF-β1 mRNA in kidney of SHR-AML compared with SHR at the age 14 weeks(P<0.05),but at age 30 and 46 weeks there were no statistical significance compared with SHR(P>0.05).Conclusions:(1)Transient prehypertensive treatment in young spontaneously hypertensive rats with losartan may lead to prolong blood pressure reduction and exert nephroprotection effects up to age 46 weeks.(2)Transient prehypertensive treatment in young spontaneously hypertensive rats with amlodipine is less effective on long-term blood pressure control and nephroprotection than transient losartan treatment. |
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