AT1 receptor antagonism improves structural, functional, and biomechanical properties in resistance arteries in a rodent chronic kidney disease model

Ko Jin Quek; Omar Z. Ameer; Jacqueline K. Phillips

doi:10.1093/ajh/hpy021

AT₁ receptor antagonism improves structural, functional, and biomechanical properties in resistance arteries in a rodent chronic kidney disease model

Ko Jin Quek, Omar Z. Ameer, Jacqueline K. Phillips^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

7 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	696-705
Number of pages	10
Journal	American Journal of Hypertension
Volume	31
Issue number	6
DOIs	https://doi.org/10.1093/ajh/hpy021
Publication status	Published - Jun 2018

Bibliographical note

A corrigendum exists for this article and can be found in the American Journal of Hypertension (2018) Vol 31(6), at https://doi.org/10.1093/ajh/hpy048

Keywords

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

Access to Document

10.1093/ajh/hpy021

Cite this

@article{28f338cb023f42249741699d1b6a7071,

title = "AT1 receptor antagonism improves structural, functional, and biomechanical properties in resistance arteries in a rodent chronic kidney disease model",

abstract = "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 (Rmax), 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.",

keywords = "AT1 receptor blockade, blood pressure, chronic kidney disease, endothelial function, hypertension, mesenteric resistance artery, vascular stiffness",

author = "Quek, {Ko Jin} and Ameer, {Omar Z.} and Phillips, {Jacqueline K.}",

note = "A corrigendum exists for this article and can be found in the American Journal of Hypertension (2018) Vol 31(6), at https://doi.org/10.1093/ajh/hpy048",

year = "2018",

month = jun,

doi = "10.1093/ajh/hpy021",

language = "English",

volume = "31",

pages = "696--705",

journal = "American Journal of Hypertension",

issn = "0895-7061",

publisher = "OXFORD UNIV PRESS INC",

number = "6",

}

TY - JOUR

T1 - AT1 receptor antagonism improves structural, functional, and biomechanical properties in resistance arteries in a rodent chronic kidney disease model

AU - Quek, Ko Jin

AU - Ameer, Omar Z.

AU - Phillips, Jacqueline K.

N1 - A corrigendum exists for this article and can be found in the American Journal of Hypertension (2018) Vol 31(6), at https://doi.org/10.1093/ajh/hpy048

PY - 2018/6

Y1 - 2018/6

N2 - 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 (Rmax), 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.

AB - 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 (Rmax), 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.

KW - AT1 receptor blockade

KW - blood pressure

KW - chronic kidney disease

KW - endothelial function

KW - hypertension

KW - mesenteric resistance artery

KW - vascular stiffness

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U2 - 10.1093/ajh/hpy021

DO - 10.1093/ajh/hpy021

M3 - Article

C2 - 29425281

SN - 0895-7061

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JO - American Journal of Hypertension

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