Modulation Of Biphenyl Tetrazoles Angiotensin Ⅱ Antagonists EXP3174 On The Angiotensin Ⅱ Type 1 Receptors In Sympathectomy Rats

Background and Objective:EXP3174 ,the active metabolite of Losartan, an angiotensin II type 1 receptor antagonist, bear a resemblance in its chemical structure to Losartan. It targets at ATi receptor with high specificity and affinity, and block almost all of the effects of angiotensin II mediated by ATi without affecting the metabolism of bradykinin. Compared with its parent compound, EXP3174 is more potent and has a longer terminal half-life and is considered to be a good angiotensin II type 1 receptor antagonist.Since there is complicated inter-accommodation between sympathetic system and renin-angiotensin system ,we investigated the modulation of EXP3174 on the angiotensin receptors in sympathectomy rats to understand the effects of sympathectomy on the angiotensin receptors,and the effects of EXP3174,a biphenyl tetrazoles angiotensin II antagonist,on the angiotensin receptors.Methods:1. Sympathectomy :destroy the newborn-rats' sympathetic nerve end with 6-OHDA;Tyramine injection to test the extent the sympathetic nerve end destroyed.2. Inspect the influence of sympathectomy on the development of blood pressure and heart rate using tail-cuff methods.3. Inspect the influence of sympathectomy and biphenyl tetrazoles angiotensin II antagonist on the pressor role of Ang II using direct intra-arterial measurement.4. Contraction studies to inspect the influence of sympathectomy and biphenyl tetrazoles angiotensin II antagonist on the vasoconstrictive role of Angll.5. Radioimmunoassay to inspect the effect of sympathectomy on the plasma concentration of angiotensin II.6. Radio ligend-receptor binding assay to determine the influence of sympathectomy and biphenyl tetrazoles angiotensin II antagonist on the specific binding of [3H]-Ang II to ATj receptors in myocardium.7. RT-PCR to determine the influence of sympathectomy and biphenyl tetrazoles angiotensin II antagonist on the mRNA expression of ATi receptors in vessel smooth muscle or vessel smooth muscle cells.Results:1. Reactions to tyramine was decreased more than 70% in the sympathectomy rats.2. There was no difference in blood pressure ,heart rate and plasma concentration of Ang II between perfect rats and sympathectomy rats, but the pressor and vasoconstrictive role of Ang II were enhanced in sympathectomy rats.3. There was an enhancement on the expression of ATi receptors in vessel smooth muscle in sympathectomy rats,as well as the enhancement of specific binding of [3H]-AngII to ATj receptors in myocardium.But there was no difference in their Kp.4. Losartan and EXP3174 dose-dependent decreased the pressor and vasoconstrictive role of Ang II .Losartan shifted the Ang II-induced pressor and contractile response curve to the right in a parallel fasion but didn't reduce the maximal response, while EXP3174 did it in a nonparallel fasion and reduced the maximal response .5. Losartan increased the KD of specific binding of [3H]-AngII to AT1 receptors in myocardium,but couldn't decrease the maximal binding. While EXP3174 not only increase the Ko,but also decrease the maxmal binding.6. Losartan couldn't influence the expression of ATi receptors in vessel smooth muscle cells,while EXP3174 could derease it dose-dependently.7. A reduction was found in the antagonistic action of Losartan and EXP3174 on the pressor role of Ang II in sympathectomy rats,but it did not exist in the action on vasoconstrictive role of Ang II ,specific binding of [3H]-Ang II to ATi receptors in myocardium and expression of ATi receptors.Conclusions:1. Sympathectomy might destroy more than 70% of the function of sympathetic nerve.2. In sympathectomy rats, blood pressure and heart rate didn't reduce because of the rise in the expression of ATi receptors.3. Losartan blocked ATj receptors in a surmountable fasion,while EXP3174 did it in an insurmountable fasion.4. EXP3174 could derease the expression of ATY receptors in vessel smooth muscle cells d...