AT(1) Receptor Antagonism Improves Structural, Functional, and Biomechanical Properties in Resistance Arteries in a Rodent Chronic Kidney Disease Model

作者：Quek Ko Jin; Ameer Omar Z; Phillips Jacqueline K^*

来源：American Journal of Hypertension, 2018, 31(6): 696-705.

DOI：10.1093/ajh/hpy021

• AT1 receptor blockade
• blood pressure
• chronic kidney disease
• endothelial function
• hypertension
• mesenteric resistance artery
• vascular stiffness

BACKGROUND
The renin-angiotensin system, in particular Angiotensin II (AngII), plays a significant role in the pathogenesis of hypertension in chronic kidney disease (CKD). Effects of chronic AT, receptor antagonism were investigated in a genetic hypertensive rat model of CKD, the Lewis polycystic kidney (LPK) rat.
METHODS
Mixed-sex LPK and Lewis control rats (total n = 31) were split between treated (valsartan 60 mg/kg/day p.o. from 4 to 18 weeks) and vehicle groups. Animals were assessed for systolic blood pressure and urine biochemistry, and after euthanasia, blood collected for urea and creatinine analysis, confirming the hypertensive and renal phenotype. Mesenteric resistance vasculature was assessed using pressure myography and histology.
RESULTS
Valsartan treatment improved vascular structure in LPK rats, increasing internal and external diameter values and reducing wall thickness (untreated vs. treated LPK: 53.19 +/- 3.29 vs. 33.93 +/- 2.17 mu m) and wall-lumen ratios (untreated vs. treated LPK: 0.52 +/- 0.09 vs. 0.16 +/- 0.01, all P < 0.0001). Endothelium dysfunction, as measured by maximal response to acetylcholine (R-max), was normalized with treatment (untreated vs. treated LPK: 6956 +/- 434 vs. 103.05 +/- 4.13, P < 0.05), increasing the relative contributions of nitric oxide and endothelium-derived hyperpolarization to vasorelaxation while downregulating the prostanoid contribution. Biomechanical properties also improved with treatment, as indicated by an increase in compliance, decrease in intrinsic stiffness and alterations in the artery wall composition, which included decreases in collagen density and collagen/elastin ratio.
CONCLUSIONS
Our results highlight the importance of Angll as a driver of resistance vessel structural, functional, and biomechanical dysfunction and provide insight as to how AT, receptor blockade exerts therapeutic efficacy in CKD.

• 出版日期2018-6