Effects Of Dual Inhibition Of Angiotensin ? Receptor-neprilysin On Nitric Oxide Synthase And Fibrosis In The Genital Tract Of Female Spontaneous Hypertensive Rats

Objective: Hypertension is the common chronic non-communicable disease and the most important risk factor for cardiovascular disease.Hypertension-mediated organ damage(HMOD)usually refers to damage to the heart,brain,kidney and peripheral blood vessels.Hypertension also causes spasms of small arteries,vascular endothelial damage,inflammation,oxidative stress,fibrosis and remodeling,the female genital tract is rich in blood vessels,similar damage will cause the corresponding pathophysiological damage.Our previous study proved that female hypertensive patients are more likely to develop sexual dysfunction than women with normal blood pressure,female genital tract can also be used as one of HMOD.The five major clinical categories of antihypertensive drugs include calcium channel blockers(CCB),angiotensin converting enzyme inhibitors(ACE-I),angiotensin receptor antagonists(ARB),diuretics and beta blockers.Previous studies of the effects of these drugs on sexual function in hypertensive women have been conducted.Angiotensin II-neprilysin inhibitor(Sacubitril/valsartan)is a first-in-class drug,it can not only block AT1 receptor,inhibit vasoconstriction,sympathetic excitation,inhibit aldosterone secretion,inhibit inflammation and oxidative stress,but also increase the level of natriuretic peptide,dilate blood vessels,reduce blood pressure,at the same time,it had the function of anti-tissue proliferation and anti-fibrosis,in theory,it should be stronger than the corresponding organ protection of ACE-I or ARB.Therefore,in this study,we investigated the effects of AT1 receptor and neprilysin double blocker(Sacubitril/valsartan)on oxidative stress and fibrosis indexin female hypertensive genital tract,the aim of this study was to explore whether it can improve the pathophysiology of genital tracts in female spontaneous hypertensive rats(SHR).Methods:16-week-old SPF-grade SHR were randomly divided into sacubitril / valsartan group,valsartan group,chlorothiazone groupand SHR group,and a normal control group(WKY group)with 10 rats in each group.During the three months period of administration,the drugs were given by gavage.The systolic blood pressure(SBP),diastolic blood pressure(DBP)and mean arterial blood pressure(MBP)were obtained by measuring rat tail artery pressure.After 12 weeks,all rats were operated on in aseptic operation,and their vaginal tissues were taken for the later experimental study.The oxidative stress index(eNOS,nNOS protein expression)was measured by Western blotting,and the degree of vaginal fibrosis was observed by HE staining and Masson staining.Results: 1.Changes of blood pressure in female SHR rats: Compared with SHR,both sacubitril/valsartan,valsartan and chlorothiazonegroups could significantly reduce blood pressure,including SBP,DBP and MBP,and compared with valsartan and chlorothiazone groups,the decrease of SBP insacubitril/valsartan group was more significant.2.Western blotting results: Compared with WKY group,the relative expression of eNOS,nNOS protein in vaginal tissue of SHR group was significantly lower than that of the control group,and there was significant difference between the two groups(P<0.01).Compared with SHR,the relative expression of eNOS,nNOS protein in sacubitril/valsartan group and valsartan group was significantly up-regulated(P<0.01),but there was no statistical significance in chlorothiazone group(P>0.05).3.HE staining results: The results of WKY group showed that the morphology of vaginal epithelium was basically normal,collagen fibers did not increase,and arranged neatly,no obvious pathological changes occurred,and the shape of vaginal vascular muscular layer was approximately normal.In SHR group,the thickness of vaginal epithelium was significantly increased,the keratinization was obvious,collagen fibers increased significantly,and arranged disorder,pathological changes were obvious.Vaginal vascular muscular layer presented pathological changes,such as vascular wall was thickened and lumen was stenosis.Both sacubitril/valsartangroup and valsartan group could reduce vaginal epithelial hyperplasia,cut down the increase of collagen fibers,but the degree was slightly different.Compared with valsartan group,sacubitril/valsartan group could significantly alleviate the increase of vaginal epithelium,collagen fiber and the degree of fibrosis.However,the effect of chlorthiazone on the reduction of vaginal fibrosis is not obvious.4.Masson staining results: Compared with SHR,the vaginal fiber content insacubitril/valsartan group decreased significantly(P < 0.05),and that in valsartan group decreased significantly(P < 0.05).Though the fiber content in chlorthiazone group was not significantly different from that in SHR group(P > 0.05).Conclusion: The causes of gentital tract fibrosis in female SHR rats are related to oxidative stress.Sacubitril/valsartan can inhibit oxidative stress and inflammation to some extent,improve vascular endothelial injury of gentital tract,reduce the degree of fibrosis,and thus ameliorate gentital tract remodeling in female SHR rats.