Establishment Of Rat Model With Aortic Dissection Induced By β-aminopropionitrile Combined With Angiotensin Ⅱ And Its Complications

Objective:To establish the aortic dissection（AD）model of Sprague-Dawley（SD）rats induced by beta-aminopropionitrile（BAPN）combined with AngiotensinⅡ（Ang-Ⅱ）,and to explore the optimal dose and combination of administration for establishing the AD model of SD rats.Meanwhile,the success rate of modeling under different drug conditions and its influence on different tissues and organs were analyzed.Methods:Forty-eight Three-week-old male SD rats were randomly divided into 8 groups（Group A-Group H）for experiment:Group A（0.25%BAPN drinking water administration）,Group B（0.4%BAPN drinking water administration）,Group C（0.8%BAPN drinking water administration）,Group D(1g·kg^-1·d^-1BAPN drinking water administration),Group E(1g·kg^-1·d^-1BAPN drinking water administration),Group F(1g·kg^-1·d^-1BAPN drinking water administration+1?g·kg^-1·min^-1saline osmotic pump infusion),Group G(1g·kg^-1·d^-1BAPN drinking water administration+1?g·kg^-1·min^-1 Ang-Ⅱosmotic pump infusion)and Group H（control group）.The experimental period of group A,B,C,D,F and G was 5 weeks,and the experimental period of group E and H was 7 weeks（including adaptive feeding for 1week）.All rats were free to eat and drink.The diet,water intake,mental state and body weight of rats were monitored daily.In the course of the experiment,if the rats died,they were immediately dissected,separated and retained the whole aorta.Rats still alive at the time point of each group were sacrificed by excessive pentobarbital sodium,and the whole aorta was separated and retained.The changes of aorta were observed from the pathological and morphological characteristics after the appropriate cross-section was intercepted and stained with H＆E.Results:1.Effect of BAPN on survival rate and incidence of AD:After BAPN intervention for 4 weeks,the survival rates of rats in group A,B,C,D,E,F,G and H were 83.3%（5/6）,50%（3/6）,100%（6/6）,100%（6/6）,83.3%（5/6）,83.3%（5/6）,100%（6/6）and 100%（6/6）,respectively.The incidence of AD in each group was 0.Five days after the placement of capsule osmotic pump,the survival rates of group F and group G were83.3%（5/6）and 0（0/6）,respectively,and the incidence rates of AD were0（0/6）and 100%（6/6）,respectively.Among them,83.3%（5/6）of rats in group G died of AD rupture,and 16.7%（1/6）of rats died of AD formation.After 6 weeks of BAPN intervention,the survival rate was33.3%（2/6）,the incidence of AD was 16.7%（1/6）,and the mortality rate of AD was 100%（1/1）.2.Effects of BAPN on diet,water intake and body weightThe effect of BAPN on the diet of rats:After the intervention with BAPN,the diet of rats in each group A,B and D showed a downward trend,and the downward trend in group B was the most obvious.The diet of rats in group C showed a slight upward trend,but it was still significantly lower than that in group H.When the experimental time node was reached,the dietary amounts of groups A,B,C,D and H were8.35 g/d,2.60 g/d,19.70g/d,6.17g/d and 27.77g/d,respectively.The effect of BAPN on water intake of rats:After the intervention with BAPN,the water intake of rats in groups A,B and D showed a downward trend,and the downward trend in group B was the most obvious.The water intake of rats in group C showed a slight upward trend,but it was still significantly lower than that in group H.When the experimental time node was reached,the water intakes of groups A,B,C,D and H were 16.25ml/d,5.35ml/d,28.65ml/d,37.73ml/d and 53.27ml/d,respectively.The effect of BAPN on the body weight of rats:After the intervention with BAPN,the body weight growth rates of rats in groups A,B,C and D were significantly slower than those in group H.Among them,BAPN had the greatest effect on group B,followed by groups A and D,and had the smallest effect on group C.When the experimental time node was reached,the average weight of groups A,B,C,D and H was 114.30g,98.93g,195.43g,133.55g and 293.90g,respectively.Changes in drug uptake in groups A,B,C,and D:The drug uptake in groups A,B,C and D was group C>group D>group B>group A.However,with the change of body weight and water intake of rats,the drug intake of each group A,B and C gradually decreased,and the drug intake of each group was group C>group D>group A>group B when the experimental time node was reached.3.Effect of BAPN on aortic tissue:In this study,only group E and group G successfully induced the formation of AD in rats,and the incidence rates of AD in group E and G were 16.7%（1/6）and 100%（6/6）,respectively.H＆E staining showed that the aortic intima was thickened,the elastic fibers were broken,and the arrangement was disordered,accompanied by inflammatory cell infiltration.The pathological morphological changes were similar to those of human AD.4.Effects of BAPN on other systems:Rats in group H had normal mental state throughout the experiment;after the intervention with BAPN for 1 week,rats in group A-G gradually showed mental state depression and lack of sensitivity to external stimuli.The incidence of intestinal obstruction in rats in groups A,B and E was 16.7%（1/6）,33.3%（2/6）and16.7%,respectively.The incidence of hip varus in group E was 16.7%（1/6）.Conclusion:1.The AD model in SD rats can be stably established by the induction of BAPN(1g·kg^-1·d^-1,drinking water administration)combined with Ang-Ⅱ(1?g·kg^-1·min^-1,osmotic pump infusion),which will provide a stable carrier for further study of the pathogenesis and therapeutic targets of AD.2.BAPN could significantly inhibit the diet of rats,but the inhibition degree was not positively correlated with the dosage.BAPN could significantly inhibit the water intake of rats,but the degree of inhibition was not completely positively correlated with the dosage.BAPN could significantly inhibit the weight gain of rats,but the inhibition degree was not completely positively correlated with the dosage.3.BAPN（or combined with Ang-Ⅱ）can lead to the proliferation of fibrous tissue in the aortic vascular wall of rats with vitreous and mucinous changes,a large number of red blood cell infiltration,elastic fiber rupture,disorder,with false lumen thrombosis.4.BAPN can not only affect the aortic tissue of rats,but also affect the mental state,gastrointestinal system and bone and joint system of rats.This is also an unstable factor in the establishment of AD model in SD rats.How to balance the effect of BAPN on other organs and tissues in the establishment of AD model remains to be further studied.