Effect Of Allisartan On Blood Pressure Reduction And Organ Protection

INTRODUCTIONAngiotensinⅡAT1 receptor antagonist is the preference antihypertensive in clinical hypertension therapy. Losartan, as the represent of AngiotensinⅡAT1 receptor antagonist,is effective and low toxicity. However, in vivo P450 oxidation, there are 14% of losartan converts the hydroxyl function into a carboxylic acid. This metabolite is EXP3174, and it has a 10-to 40-fold higher potency compared to losartan and is noncompetitively bound to the AT1 receptor by interaction of the tetrazole with Lys in the trans-membrane helix 5 of the AT1 receptor. Compared with Losartan,in esterase hydrolysis Allisartan can be all convert EXP3174 no other metabolites.There are 7 experiments to evaluate Allisartan's safety and its effect on blood pressure and organ protection. In this research,6 animal models were used: Kunming mice, essential hypertension rat(SHR),2K1C renal artery hypertension rats and dogs,AngII induced hypertension Beagle dogs and healthy adults normal dogs.The spontaneously hypertensive rat (SHR) was developed from Wistar Kyoto (WKY) strain exhibiting spontaneously elevated blood pressure (BP) in 1963. SHR has been widely used as an experimental model of human essential hypertension.2K1C renal artery hypertension animal model is another importantal model of human hypertension. As Allisartan is one of angiotensinⅡreceptor antagonist, we set 2K1C renal artery hypertension rats and 2K1C renal artery hypertension dogs in this experiment research work to evaluate its effect.Beagle dogs, as classics animal model in pharmacology experiment has been used in the research to evaluate the BP reduction effect of Allisartan. After that, the Hemodynamics has also been done in normal dogs. High BP level is not the unique factor determining hypertensive end-organ damage. In addition, arterial baroreflex dysfunction is another feature of hypertension. So,besides BP reduction, enhance ABR function is also important in organ protection. The experiment of long-treatment with Allisartan is set to reveal its effect of organ protection.METHODSExperiment 1Female and male Kunming species Jimpy mice are evenly allocated to Allisartan group and losartan group. Using the KORBOR method,the experiment went on and explored the dosage range. At last,when the administration dosage was reach 10.0g/kg-BW yet no mouse was died in Allisartan group, however Losartan group mice were all died only with the 6.0g/kg-BW administration dosage,we concluded that Allisartan is more safe than Losartan and it was reach the maximum solubility and dosage-volume.Experiment 2Female SHR were randomly divided into 5 groups. They were respectively given 0.8% carboxymethylcellulose sodium (negative control), Allisartan (7.5,15,30mg/kg)and Losartan (30mg/kg, positive control). The drugs were once given via a catheter of gastric fistula. Blood pressure was recorded from one hour before drug administration for 7 hours in conscious freely moving rats. The present work found that every Allisartan three dosage group can significantly decrease SBP and DBP values in SHR,and with the same dose(30mg/kg) Allisartan is more effective to positive control grorp(losartan).Experiment 3Two-kidney-one-clip renal artery hypertension rats were made with male SD rats. Those systolic blood pressure(SBP) equal to or higher than 140mmHg were enrolled and divided randomly into5 groups. They were respectively given 0.8% carboxymethylcellulose sodium (negative control), Allisartan (7.5,15,30mg/kg)and Losartan (30mg/kg, positive control). The drugs were once given via a catheter of gastric fistula. Blood pressure was recorded from one hour before drug administration for 7 hours in conscious freely moving rats. The results reveal that every Allisartan three dosage group especially the mid-dosage group can steady and stepwise decrease BP values in 2K1C renal artery hypertension rats,but there's nothing influence to heart rate.Experiment 4Male 2K1C renal artery hypertension dogs were randomly divided into 4 groups. They were respectively given Allisartan (4,8,16mg/kg)and Losartan (16mg/kg, positive control). The drugs were once given via a catheter of gastric fistula. Blood pressure was recorded from half hour before drug administration for 3 hours in drugged state dogs. As the result,it was found that with the low dosage(4mg/kg) there's no effect on BP and HR at all, but on the opposition,BP decrease is notable in the mid(8mg/kg) and high(16mg/kg) dosage groups. Further more,the high dosage may also reduce HR in 2K1C renal artery hypertension dogs.Experiment 5Thirty male Beagle dogs were randomly diviede into 5 groups. They were respectively given 0.8% carboxymethylcellulose sodium (negative control), Allisartan (5,10,20mg/kg)and Losartan (20mg/kg, positive control). When the BP is about 180mmHg after an intravenous administration of AngII was in Beagle dogs,half hour blood pressure was recorded as the before drug administration control value.The drugs were once given via intragastric administration,then the BP and HR was recorded from 5min,15min,30min,1h,2h,3h for 4h in drugged state dogs. The results can be seen that every Allisartan three dosage group can steady and stepwise decrease BP values in Beagle dogs,and the dose-effect relationship is obviously. Compare with the Losartan, Allisartan is more significant in BP reduction. There's nothing influence to heart rate in all 5 groups.Experiment 6Female and male healthy adults normal dogs were randomly divided into 4 groups. They were respectively given 0.8% carboxymethylcellulose sodium (negative control), Allisartan (10,20mg/kg)and Losartan (20mg/kg, positive control). Catheter was put into the anesthetic dog's left ventricle and femoral artery,and hemodynamic parameters and myocardial mechanical parameters were measured before drug ingestion and after drug ingestion 30min,60min,90min,120min. We designed this study with anesthetic dog's hemodynamics to check the above 5 experiments'BP decrease effects of Allisartan. The results showed that,Allisartan could decrease the systolic blood pressure,but it didn't disturb the heart rate,LVSP, LVEDP and±dp/dt max.Experiment 7Sixty male SHR were randomly divided into 5 groups.Normal diet without drugs (negative control), Allisartan (7.5,15,30mg/kg)and Losartan (30mg/kg, positive control) were given in rat chow for 16 weeks in SHR. Blood pressure (BP) was then recorded during 4 hours in conscious state. After the determination of baroreflex sensitivity, rats were killed for organ-damage evaluation. In this work, chronic treatment with Allisartan, an obvious decreased on BP, ABR function enhancement and the organ protection was found in rats (SHR).CONCLUSIONThe toxicity test presented Allisartan is more safe than Losartan. Once dosage(short-treatment) with Allisartan lead BP reduction is obviously in SHR ,2K1C renal artery hypertension animal models(rats and dogs) and AngII induced hypertension Beagle dogs.The hemodynamics in anesthetic dogs shows that once dosage with Allisartan could decrease the systolic blood pressure,but didn't disturb the heart rate,LVSP, LVEDP and±dp/dt max.Besides the BP reduction, long-treatment with Allisartan obviously restored arterial baroreflex function and prevented organ damage,that means, Allisartan possessed obvious organ protection in SHR.