The Effect Of Different Dosing Schedule Of Perindopril On Circadian Rhythm Of Urine Rennin-angiotensin System In Spontaneously Hypertensive Rats

Objective:Biological rhythm are an universal phenomenon.Biological rhythm can divided into 3 types on the basis of their cycle lengths: 1.Circadian rhythm(or Diurnal rhythm)with a period of approximately 24 hours;2.Ultradian rhythm,with a period significantly shorter than 24 hours,changes frequency more than once a day;3.Infradian rhythm,with a period longer than 24 hours.In human and animal,circadian rhythm is the most common phenomenon and comphensively better under stood.It has been found that the human blood pressure presents with typical circadian rhythm.Abnormal blood pressure rhythm not only contribute to the target organ damage,such as heart,brain,kidney but also increase the morbidity and mortality of cardiovascular events.The regulation of blood pressure circadian rhythm depends on many factors,which the renin-angiotensin system(RAAS),may plays important roles.The RAAS regulates blood pressure,water,electrolytes and maintain environmental stability of the important system in the human body.Recent studies found that the local RAAS,especially kidney RAAS plays an important role in the occurrence and development of hypertension.Animal trials suggested that urine and renal AGT and Ang? levels were positively correlated,it may be an important index of intra-renal RAAS activity.In this study,the urinary of spontaneously hypertensive rats were collecting by different time(6:00,12:00,18:00,24:00),we investigated the circadian rhythm of RAAS in the urinary and the effects of different time administrating perindopril on circadian rhythm of urine RAAS.Methods:Thirty age-matched male SHR(with body weight 250-300g)were included in this study.They were raised in the animal center of Hebei General Hospital.Then they were divided randomly into three groups according to the dosing time with 10 SHR in each group: rats that were administrated with perindopril at 07:00 in the morning were designed as the “ M group ”;rats that treated with perindopril at 19:00 were designed as the “ N group ”;rats that not treated with perindopril were designed as the “ control group ” or “ C group ”.Perindopril-treated group was gorged 2mg/Kg/d.The animals were adaptive fed one week before the experiment.When the metabolism of rats were stable and they adopted to the surrounding environment,measuring the systolic blood pressure(SBP)of the rats with rat-tail manometer once every four weeks.After 8 weeks,we measured rats systolic blood pressure and AGT,Ang?,PRA and ALD concentrations in the urinary in different time of the same day acrossing 24 hours.After the rats were death,take the rats heart,removal of large blood vessels residual and dry with paper,then weighed the left ventricular weight to calculate the heart weight index and invest cardiac pathology tissue specimens.Cosinor fitting analysis and zero amplitude test were introduced to analyze the chronobiological feature of RAAS of SHR in every group.The compare of circadian values among 3 groups was managed based on Analysis of Variance(ANOVA),and P<0.05 was defined as statistically different borderline.Results:1 The levels of PRA in urinary were higher in group M and N than those in C group by using ANOVA(P<0.01).The levels of PRA in urinary were no significant difference between group M and N(P=0.265).The levels of AGT,Ang?and ALD in urionary were lower in group M and N than those in C group(P<0.01).The levels of AGT,Ang?and ALD in urinary were no significant difference between group M and N(P=0.265,P=0.07,P=0.127,respectively).2 Before the experiment,the blood pressure of each group was no difference by using ANOVA(P>0.05).After 8 weeks,the SBP of M and N were lower than that in C group(P<0.01).The SBP were no significantl difference between group M and N(P=0.751).3 The left ventricular mass and heart weight index of SHR were lower in group M and N than those in C group(P<0.01).The rats of left ventricular mass,heart weight index were no significant difference between group M and N(P=0.510,P=0.497).The myocardial fibers loosely arranged,irregular,fibroblasts significant proliferation,collagen fibers thicker in control group.The myocardial fibers mitigation,myocardial cell arranged more regular in group M and N.4 Based on cosinor fitting analysis and zero amplitude test,circadian rhythm were found in all the 3 groups,and the curves and characteristic values of AGT,Ang?,PRA and ALD in urinary show significantly diurnal variation,with the peak times at 1:11,5:18,7:57,0:51,respectively in group C;The results also showed in both group M and N present with circadian variation,with the peak times at 12:13,7:46,17:23,4:30 and14:40,11:45,13:27,7:01,with somewhat behind of control group.Conclusions:1 Administrating perindopril at different time schedule,the levels of PRA in urinary in SHR were higher in group M and N than those in C group.The levels of AGT,Ang?,ALD in urinary were lower in group M and N than those in control group.2 AGT,Ang?,PRA and ALD in urinary showed significantly diurnal variation.Circadian rhythm of AGT,Ang?,PRA and ALD were altered at different perindopril-treated time schedules(mainly reflected in the shift of acrophase),administrating perindopril at different time can alter the diurnal variation of above indices at some extent,which can shift the acrophase of cosinor curves early,especially after the morning dose.It suggested that different perindopril-treated time schedule might affect the diurnal variation RAAS system components.3 Administrat perindopril at different time significantly lower the blood pressure,but the SBP had no significant difference between M and N group.4 Administrat perindopril at different time can reduce the left ventricular weight and heart weight index,suggests that perindopril can improve myocardial remodeling.In conclusion,the results suggested that the AGT,Ang?,PRA,ALD all showed typical circadian rhythm.Administrat perindopril at different time enable alter the diurnal variation of above indices at some extent,which can shift the acrophase of cosinor curves early,especially after the morning dose.Different time medication for SHR rats cardiac remodeling prevention effect is the same.