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Failure to vasodilate in response to salt loading blunts renal blood flow and causes salt-sensitive hypertension. Cardiovasc Res 2021 01 01;117(1):308-319

Date

05/20/2020

Pubmed ID

32428209

Pubmed Central ID

PMC7797211

DOI

10.1093/cvr/cvaa147

Scopus ID

2-s2.0-85097807979   13 Citations

Abstract

AIMS: Salt-sensitive (SS) hypertension is accompanied by impaired vasodilation in the systemic and renal circulation. However, the causal relationship between vascular dysfunction and salt-induced hypertension remains controversial. We sought to determine whether primary vascular dysfunction, characterized by a failure to vasodilate during salt loading, plays a causal role in the pathogenesis of SS hypertension.

METHODS AND RESULTS: Mice selectively expressing a peroxisome proliferator-activated receptor I? dominant-negative mutation in vascular smooth muscle (S-P467L) exhibited progressive SS hypertension during a 4A week high salt diet (HSD). This was associated with severely impaired vasodilation in systemic and renal vessels. Salt-induced impairment of vasodilation occurred as early as 3a??days after HSD, which preceded the onset of SS hypertension. Notably, the overt salt-induced hypertension in S-P467L mice was not driven by higher cardiac output, implying elevations in peripheral vascular resistance. In keeping with this, HSD-fed S-P467L mice exhibited decreased smooth muscle responsiveness to nitric oxide (NO) in systemic vessels. HSD-fed S-P467L mice also exhibited elevated albuminuria and a blunted increase in urinary NO metabolites which was associated with blunted renal blood flow and increased sodium retention mediated by a lack of HSD-induced suppression of NKCC2. Blocking NKCC2 function prevented the salt-induced increase in blood pressure in S-P467L mice.

CONCLUSION: We conclude that failure to vasodilate in response to salt loading causes SS hypertension by restricting renal perfusion and reducing renal NO through a mechanism involving NKCC2 in a mouse model of vascular peroxisome proliferator-activated receptor I? impairment.

Author List

Wu J, Agbor LN, Fang S, Mukohda M, Nair AR, Nakagawa P, Sharma A, Morgan DA, Grobe JL, Rahmouni K, Weiss RM, McCormick JA, Sigmund CD

Authors

Justin L. Grobe PhD Associate Professor in the Physiology department at Medical College of Wisconsin
Pablo Nakagawa PhD Assistant Professor in the Physiology department at Medical College of Wisconsin
Curt Sigmund PhD Chair, Professor in the Physiology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Blood Pressure
Carotid Arteries
Disease Models, Animal
Hypertension
Kidney
Male
Mice, Inbred C57BL
Mice, Transgenic
Muscle, Smooth, Vascular
Mutation
Nitric Oxide
PPAR gamma
Renal Artery
Renal Circulation
Sodium Chloride, Dietary
Solute Carrier Family 12, Member 1
Vasodilation