Increased role of E prostanoid receptor-3 in prostacyclin-evoked contractile activity of spontaneously hypertensive rat mesenteric resistance arteries

As a critical step toward understanding the role of abnormal intracellular Ca2+ release via the ryanodine receptor (RyR2) during the development of hypertension-induced cardiac hypertrophy and heart failure, this study examines two questions: 1) At what stage, if ever, in the development of hypertrophy and heart failure is RyR2 hyperphosphorylated at Ser2808? 2) Does the spatial distribution of RyR2 clusters change in failing hearts? Using a newly developed semiquantitative immunohistochemistry method and Western blotting, we measured phosphorylation of RyR2 at Ser2808 in the spontaneously hypertensive rat (SHR) at four distinct disease stages. A major finding is that hyperphosphorylation of RyR2 at Ser2808 occurred only at late-stage heart failure in SHR, but not in age-matched controls. Furthermore, the spacing between RyR2 clusters was shortened in failing hearts, as predicted by quantitative model simulation to increase spontaneous Ca2+ wave generation and arrhythmias.

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Electrical stimulation of the gastrocnemius muscle in the spontaneously hypertensive rat increases the pain threshold: role of different serotonergic receptors

Acta Physiologica Scandinavica ◽

10.1111/j.1748-1716.1990.tb08824.x ◽

1990 ◽

Vol 138 (2) ◽

pp. 125-131 ◽

Cited By ~ 26

Author(s):

P. HOFFMANN ◽

J. O. SKARPHEDINSSON ◽

M. DELLE ◽

P. THORÉN

Keyword(s):

Electrical Stimulation ◽

Gastrocnemius Muscle ◽

Pain Threshold ◽

Spontaneously Hypertensive Rat ◽

Spontaneously Hypertensive ◽

Serotonergic Receptors ◽

Hypertensive Rat ◽

Stimulation Of

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Endoplasmic reticulum stress inhibition blunts the development of essential hypertension in the spontaneously hypertensive rat

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00523.2018 ◽

2019 ◽

Vol 316 (5) ◽

pp. H1214-H1223 ◽

Cited By ~ 6

Author(s):

Safaa Naiel ◽

Rachel E. Carlisle ◽

Chao Lu ◽

Victor Tat ◽

Jeffrey G. Dickhout

Keyword(s):

Blood Pressure ◽

Endoplasmic Reticulum ◽

Essential Hypertension ◽

Er Stress ◽

Spontaneously Hypertensive Rat ◽

Resistance Arteries ◽

Spontaneously Hypertensive ◽

Functional Changes ◽

Hypertensive Rat ◽

Hypertension Development

Essential hypertension is the leading cause of premature death worldwide. However, hypertension’s cause remains uncertain. endoplasmic reticulum (ER) stress has recently been associated with hypertension, but it is unclear whether ER stress causes hypertension. To clarify this question, we examined if ER stress occurs in blood vessels before the development of hypertension and if ER stress inhibition would prevent hypertension development. We used the spontaneously hypertensive rat (SHR) as a model of human essential hypertension and the Wistar-Kyoto (WKY) rat as its normotensive control. Resistance arteries collected from young rats determined that ER stress was present in SHR vessels before the onset of hypertension. To assess the effect of ER stress inhibition on hypertension development, another subset of rats were treated with 4-phenylbutyric acid (4-PBA; 1 g·kg−1·day−1) for 8 wk from 5 wk of age. Blood pressure was measured via radiotelemetry and compared with untreated SHR and WKY rats. Mesenteric resistance arteries were collected and assessed for structural and functional changes associated with hypertension. Systolic and diastolic blood pressures were significantly lower in the 4-PBA-treated SHR groups than in untreated SHRs. Additionally, 4-PBA significantly decreased the media-to-lumen ratio and ER stress marker expression, improved vasodilatory response, and reduced contractile responses in resistance arteries from SHRs. Overall, ER stress inhibition blunted the development of hypertension in the SHR. These data add evidence to the hypothesis that a component of hypertension in the SHR is caused by ER stress. NEW & NOTEWORTHY In this study, 4-phenylbutyric acid’s (4-PBA’s) molecular chaperone capability was used to inhibit endoplasmic reticulum (ER) stress in the small arteries of young spontaneously hypertensive rats (SHRs) and reduce their hypertension. These effects are likely mediated through 4-PBA's effects to reduce resistant artery contractility and increase nitric oxide-mediated endothelial vasodilation through a process preventing endothelial dysfunction. Overall, ER stress inhibition blunted the development of hypertension in this young SHR model. This suggests that a component of the increase in blood pressure found in SHRs is due to ER stress. However, it is important to note that inhibition of ER stress was not able to fully restore the blood pressure to normal, suggesting that a component of hypertension may not be due to ER stress. This study points to the inhibition of ER stress as an important new physiological pathway to lower blood pressure, where other known approaches may not achieve blood pressure-lowering targets.

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Abstract P160: Role of Uncoupling Protein 2 in Stroke Susceptibility of Stroke-prone Spontaneously Hypertensive Rat

Hypertension ◽

10.1161/hyp.66.suppl_1.p160 ◽

2015 ◽

Vol 66 (suppl_1) ◽

Author(s):

Speranza Rubattu ◽

Maria Cotugno ◽

Franca Bianchi ◽

Sara Di Castro ◽

Rosita Stanzione ◽

...

Keyword(s):

Oxidative Stress ◽

Protein Expression ◽

Mitochondrial Dysfunction ◽

Spontaneously Hypertensive Rat ◽

Uncoupling Protein ◽

Uncoupling Protein 2 ◽

Spontaneously Hypertensive ◽

Hypertensive Rat ◽

Ucp2 Expression

Mitochondrial dysfunction causes severe cellular derangements potentially underlying tissue injury and consequent diseases. Evidence of a direct involvement of mitochondrial dysfunction in hypertensive target organ damage is still poor. The gene encoding Uncoupling Protein 2 (UCP2), a inner mitochondrial membrane protein, maps inside stroke QTL/STR1 in stroke prone spontaneously hypertensive rat (SHRSP). We explored the role of UCP2 in stroke pathogenesis of SHRSP. Male SHRSP, stroke resistant SHR (SHRSR) and reciprocal STR1/congenic rats were fed with stroke permissive Japanese style diet (JD). A group of SHRSP received JD plus fenofibrate (150 mg/kg/die). Rats were sacrificed at stroke occurrence. Additional SHRSR and SHRSP rats were sacrificed at 1, 3, 6, 12 months of age upon regular diet. SBP, BW, proteinuria, stroke signs were monitored. Brains were used for molecular analysis (UCP2 gene and protein expression, Nf-kB protein expression, oxidative stress quantification) and for histological analyses. As a result, brain UCP2 expression was reduced to 20% by JD only in SHRSP (showing 100% stroke occurrence by 7 weeks of JD). Fenofibrate protected SHRSP from stroke and upregulated brain UCP2 (+ 100%). Congenic rats carrying STR1/QTL showed increased (+100%) brain UCP2 expression, as compared to SHRSP, when resistant to stroke, and, viceversa, decreased (-50%) brain UCP2 levels, as compared to SHRSR, when susceptible to stroke. Brain UCP2 expression progressively decreased with aging only in SHRSP, down to 15% level at one year of age (when SHRSP showed spontaneous stroke). Both brain Nf-kB expression and oxidative stress levels increased when UCP2 expression was downregulated, and viceversa. Histological analysis showed both ischemic and haemorrhagic lesions at stroke occurrence. Our results highlight a role of UCP2 in stroke predisposition associated to hypertension in an animal model of complex human disease.

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