| Objective:To study the effects of ARBs combined by anti-aldosterone therapy on the contractive and dilational functions of the coronary artery and intra-renal artery in the male elderly hypertensive rats;To investigate the effects of combined anti-aldosterone therapy on the vessels and kidney fibrosis in elderly hypertensive rats and mechanisms underlying.Methods:The male elderly spontaneously hypertensive rats(SHR)were divided into 3 groups randomly,6 in each group: SHR group,L group(losartan 20 mg/(kg?d))and L+A group(losartan 20 mg/(kg?d)and antisterone 10 mg/(kg?d)at the same time).Six WKY rats,age and sex-matched,were taken as control group(WKY group).The rats in SHR group and WKY group were given normal saline.SHR group,L group,L+A group and WKY group were treated for 4 weeks by gavage after 4 weeks of adaptation.The blood pressures of each group before and after the intervention were recorded.The constriction and relaxation functions of the isolated arterial rings taken from the heart and kidneys were tested with the Multi Myogragh system.Western blotting,real-time PCR and histological tests were used to evaluate the vascular and kidney fibrosis associated protein and mRNA expressions.Results:The SBPs in SHR group was higher than that in WKY group significantly(P<0.05).Compared with SHR group,the SBPs in L group and L+A group were decreased significantly(P<0.05).The SBPs in L+A group was decreased significantly compared to L group(P<0.05).LVPW changed typically according to data from echocardiography.The LVPWD and LVPWS of SHR group were thickened than those of WKY group significantly(P<0.05).The LVPWD of SHR L group was lower than that of SHR group significantly(P<0.05).The LVPWS of SHR L+A group was lower than that of SHR L group significantly(P<0.05).For different organs,the reactions of arterioles to KCl were diverse: under the certain condition of 100mmol/L KCl solution,the constrictions of coronary arteries of L group and L+A group were decreased than that of SHR group significantly(P<0.05).The constrictions of intra-renal arteries(RA)of L+A group was decreased significantly compared to those of L group(P<0.05).The constrictions of RA of SHR group was decreased significantly(P<0.05)compared to those of WKY group.The constrictions of RA of L group and L+A group were increased than that of SHR group significantly(P<0.05).The constrictions of RA of L+A group was increased significantly compared to those of L group(P<0.05).The endothelium-dependent vasodilatation of the intra-renal artery in SHR was impaired and the myogenic vasodilatation of the RA in SHR was weaken,which were repaired after treatment by losartan.The ratio of transforming growth factor-β1(TGF-β1)48 kDa/180 kDa decreased significantly in SHRs compared to WKYs,and was increased significantly in SHR LA group(P<0.05).Compared with the WKY group,the expressions of RA matrix metalloproteinase-2(MMP-2)mRNA was increased in SHRs compared to WKYs significantly(P<0.05),and TGF-β1,CTGF,Smad-2 and Smad-3 mRNA were decreased in SHRs compared to WKYs significantly(P<0.05).When treated with losartan and antisterone,SHR showed reduced levels of TGF-β1,MMP-2,CTGF,Smad-2 and Smad-3 mRNA significantly(P<0.05).Positive rate(%)of mineralocorticoid receptors(MR)expression in kidneys were increased significantly in the SHR group compared with the WKY group(P<0.05),and collagen volume fraction(CVF)in masson staining were increased significantly in the SHR group compared with the WKY group(P<0.05).When SHRs were treated with losartan and antistorene,positive rate and CVF were decreased significantly(P<0.05),SHR L group compared to SHR group and SHR L+A group compared to SHR group.Conclusion:Based on ARBs,the combination of aldosterone receptor blockers could adjust the function of arterioles of heart and kidneys,which could further benefit target organ protection during anti-hypertensive treatment.Short-term combination of anti-aldosterone treatment to ARBs has renal and vascular-protective effects against fibrosis.The mechanism underlying is still to be investigated. |
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