Endoplasmic reticulum stress inhibition reduces hypertension through the preservation of resistance blood vessel structure and function.
Our purpose was to determine if endoplasmic reticulum stress inhibition lowers blood pressure (BP) in hypertension by correcting vascular dysfunction.



The spontaneously hypertensive rat (SHR) was used as a model of human essential hypertension with its normotensive control, the Wistar Kyoto rat. Animals were subjected to endoplasmic reticulum stress inhibition with 4-phenylbutyric acid (4-PBA; 1 g/kg per day, orally) for 5 weeks from 12 weeks of age. BP was measured weekly noninvasively and at endpoint with carotid arterial cannulation. Small mesenteric arteries were removed for vascular studies. Function was assessed with a Mulvany-Halpern style myograph, and structure was assessed by measurement of medial-to-lumen ratio in perfusion fixed vessels as well as three-dimensional confocal reconstruction of vessel wall components. Endoplasmic reticulum stress was assessed by quantitative real time-PCR and western blotting; oxidative stress was assessed by 3-nitrotyrosine and dihydroethidium staining.



4-PBA significantly lowered BP in SHR (vehicle 206.1 ± 4.3 vs. 4-PBA 178.9 ± 3.1, systolic) but not Wistar Kyoto. 4-PBA diminished contractility and augmented endothelial-dependent vasodilation in SHR small mesenteric arteries, as well as reducing media-to-lumen ratio. 4-PBA significantly reduced endoplasmic reticulum stress in SHR resistance vessels. Normotensive resistance vessels, treated with the endoplasmic reticulum stress-inducing agent, tunicamycin, show decreased endothelial-dependent vasodilation; this was improved with 4-PBA treatment. 3-Nitrotyrosine and dihydroethidium staining indicated that endoplasmic reticulum stress leads to reactive oxygen species generation resolvable by 4-PBA treatment.



Endoplasmic reticulum stress caused endothelial-mediated vascular dysfunction contributing to elevated BP in the SHR model of human essential hypertension.
aDepartment of Medicine, Division of Nephrology bDepartment of Medicine, Division of Respirology, McMaster University and St. Joseph's Healthcare Hamilton, Hamilton, Ontario, Canada.
Rachel E
RE
Carlisle
Kaitlyn E
KE
Werner
Victoria
V
Yum
Chao
C
Lu
Victor
V
Tat
Muzammil
M
Memon
Yejin
Y
No
Kjetil
K
Ask
Jeffrey G
JG
Dickhout
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D006973:Hypertension / Q000503:physiopathology*; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D009119:Muscle Contraction; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D010654:Phenylbutyrates / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017382:Reactive Oxygen Species / Q000378:metabolism; D014415:Tunicamycin / Q000494:pharmacology; D014655:Vascular Resistance; D014664:Vasodilation / Q000187:drug effects
D010654:Phenylbutyrates; D017382:Reactive Oxygen Species; D014415:Tunicamycin; C075773:4-phenylbutyric acid