The Spontaneously Hypertensive Rat (SHR)

Okamoto, Kozo

doi:10.1536/ihj.14.182

Cited by 104 publications

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“…In addition, others have shown a reduction in cerebral blood flow in conjunction with hypertension in SHR/SP with a marked decrease after 12 weeks, which is consistent with the timing we observed in hypoxic changes. [33][34][35] In conclusion, we used the SHR/SP with poor diet and carotid occlusion as a model for WM disease in VCI patients, and showed for the first time using direct pO 2 measurements with EPR a significant reduction in the O 2 in the deep WM. Our results suggest that changes in WM pO 2 may contribute to the selective injury in the deep WM unrelated to frank ischemic infarcts.…”

Section: Discussionmentioning

confidence: 83%

Tissue Oxygen is Reduced in White Matter of Spontaneously Hypertensive-Stroke Prone Rats: A Longitudinal Study with Electron Paramagnetic Resonance

Weaver

Jalal

Yang

et al. 2014

J Cereb Blood Flow Metab

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Small vessel disease is associated with white-matter (WM) magnetic resonance imaging (MRI) hyperintensities (WMHs) in patients with vascular cognitive impairment (VCI) and subsequent damage to the WM. Although WM is vulnerable to hypoxic-ischemic injury and O 2 is critical in brain physiology, tissue O 2 level in the WM has not been measured and explored in vivo. We hypothesized that spontaneously hypertensive stroke-prone rat (SHR/SP) fed a Japanese permissive diet (JPD) and subjected to unilateral carotid artery occlusion (UCAO), a model to study VCI, would lead to reduced tissue oxygen (pO 2 ) in the deep WM. We tested this hypothesis by monitoring WM tissue pO 2 using in vivo electron paramagnetic resonance (EPR) oximetry in SHR/SP rats over weeks before and after JPD/UCAO. The SHR/SP rats experienced an increase in WM pO 2 from 9 to 12 weeks with a maximal 32% increase at week 12, followed by a dramatic decrease in WM pO 2 to near hypoxic conditions during weeks 13 to 16 after JPD/UCAO. The decreased WM pO 2 was accompanied with WM damage and hemorrhages surrounding microvessels. Our findings suggest that changes in WM pO 2 may contribute to WM damage in SHR/SP rat model, and that EPR oximetry can monitor brain pO 2 in the WM of small animals. Keywords: brain oxygen; EPR oximetry; vascular cognitive impairment; white matter INTRODUCTION Brain cells poorly tolerate hypoxia, and even short periods of low oxygen (O 2 ) can initiate molecular pathways that are lethal to cells in both the gray and white matter (WM). Deep WM is a common site of hypoxic/ischemic injury in the elderly where it is associated with cognitive decline, gait disturbances, and focal ischemia leading to vascular cognitive impairment (VCI). Magnetic resonance imaging (MRI) reveals white-matter hyperintensities (WMHs) in the elderly located in the periventricular and subcortical regions, and considered to be due to strokes and secondary small vessel disease. An alternative mechanism is that the deep WM is vulnerable to hypoxia for a variety of reasons. Studies in humans suggest that there is impairment in the ability of the deep WM to respond to increased demand by raising cerebral blood flow or O 2 . 1 Although glutamate mediated excitotoxicity, inflammatory cytokines, and protease activation result in oligodendrocyte death in acute ischemic injury, the pathophysiology of WM injury in chronic vascular disease has not been fully explored. 2 Small vessel disease is associated with WMHs in patients with VCI; damage to small vessels causes an inflammatory response with disruption in the blood-brain barrier (BBB) associated with expression of matrix metalloproteinases (MMPs) and subsequent damage to the WM. Vascular dementia patients show expression of MMPs in regions of loss of myelin. [3][4][5]

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Section: Discussionmentioning

confidence: 83%

Tissue Oxygen is Reduced in White Matter of Spontaneously Hypertensive-Stroke Prone Rats: A Longitudinal Study with Electron Paramagnetic Resonance

Weaver

Jalal

Yang

et al. 2014

J Cereb Blood Flow Metab

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“…Experimental animals and diets Sixty inbred male stroke-prone spontaneously hypertensive rats (SHRSP), originally developed by Okamoto et al (1974), were used. The rats from our breeding were housed five animals in a cage in an animal laboratory (illuminated from 06 h 30 min to 18 h 30 min, room temperature 22-24°C).…”

Section: Methodsmentioning

confidence: 99%

Replacement of salt by a novel potassium‐ and magnesium‐enriched salt alternative improves the cardiovascular effects of ramipril

Mervaala

Paakkari

Laakso³

et al. 1994

British J Pharmacology

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1The influence of salt (sodium chloride; NaCl) (an additional 6% in the diet) and that of a novel sodium-reduced, potassium-, magnesium-, and L-lysine-enriched salt alternative on the cardiovascular effects of ramipril was studied in stroke-prone spontaneously hypertensive rats in a 6-week study. The intake of sodium chloride was adjusted to the same level by adding the salt alternative at a 1.75 times higher amount than regular salt. 2 Salt produced a marked rise in blood pressure and induced cardiac hypertrophy and significant mortality, while the salt alternative neither increased blood pressure nor caused any mortality and produced less cardiac hypertrophy than salt. 3 Ramipril treatment at a daily dose of 3 mg kg' normalized blood pressure and prevented the development of cardiac hypertrophy of rats on control diet. These effects of ramipril were blocked by the addition of salt but were only slightly attenuated by the addition of the salt alternative. The mortality in -the salt group was prevented by ramipril. 4 Responses of mesenteric arterial rings in vitro were examined at the end of the study. Salt, but not the salt alternative, increased vascular contractile responses to noradrenaline. Ramipril treatment improved the arterial relaxation responses to acetylcholine and to sodium nitroprusside. The vascular relaxation enhancing effect of ramipril was blocked by salt but only slightly attenuated by the salt alternative. 5 Ramipril treatment did not significantly increase plasma renin activity in the presence or in the absence of salt supplementation. The salt alternative did not cause hyperkalaemia, either alone or in combination with ramipril treatment. 6 Both salt supplementations, irrespective of ramipril treatment, induced a six to eight fold increase in the urinary excretion of calcium. There was an expected 90 to 140% rise in the urinary excretion of magnesium and 200% rise in the urinary excretion of potassium in the salt alternative group. Salt also produced an approximately 50% increase in magnesuria. 7 Our findings suggest that replacement of salt by the potassium-, magnesium-and L-lysine-enriched salt alternative improves the cardiovascular effects of ramipril. In the present study the beneficial effect was related to the increased intakes of potassium and/or magnesium and L-lysine from the salt alternative because the amount of sodium chloride was the same.

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“…Experimentally, various rat strains, such as spontaneously hypertensive stroke-prone rats (SHRSP) that develop spontaneous cerebral infarction or hemorrhage have been developed (Okamoto et al, 1974). Also, genetically engineered mice that typically over-express or have a specific gene deleted (knock-out) have been developed to study the cause-and-effect relationships in specific injury pathways (Chan et al, 1995).…”

Section: Genetic Aspects Of Stroke and Head Traumamentioning

confidence: 99%

Pathophysiology of Cerebral Ischemia and Brain Trauma: Similarities and Differences

Bramlett

Dietrich

2004

J Cereb Blood Flow Metab

567

358

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Summary: Current knowledge regarding the pathophysiology of cerebral ischemia and brain trauma indicates that similar mechanisms contribute to loss of cellular integrity and tissue destruction. Mechanisms of cell damage include excitotoxicity, oxidative stress, free radical production, apoptosis and inflammation. Genetic and gender factors have also been shown to be important mediators of pathomechanisms present in both injury settings. However, the fact that these injuries arise from different types of primary insults leads to diverse cellular vulnerability patterns as well as a spectrum of injury processes. Blunt head trauma produces shear forces that result in primary membrane damage to neuronal cell bodies, white matter structures and vascular beds as well as secondary injury mechanisms. Severe cerebral ischemic insults lead to metabolic stress, ionic perturbations, and a complex cascade of biochemical and molecular events ultimately causing neuronal death. Similarities in the pathogenesis of these cerebral injuries may indicate that therapeutic strategies protective following ischemia may also be beneficial after trauma. This review summarizes and contrasts injury mechanisms after ischemia and trauma and discusses neuroprotective strategies that target both types of injuries.

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The Spontaneously Hypertensive Rat (SHR)

Abstract: have been donated to laboratories and institutions all over the world. They are now being preferably used as one of the best animal models for hypertension research. The establishment of inbred strains of SHR was reported to Japan Ex

Cited by 104 publications

References 0 publications

Tissue Oxygen is Reduced in White Matter of Spontaneously Hypertensive-Stroke Prone Rats: A Longitudinal Study with Electron Paramagnetic Resonance

Tissue Oxygen is Reduced in White Matter of Spontaneously Hypertensive-Stroke Prone Rats: A Longitudinal Study with Electron Paramagnetic Resonance

Replacement of salt by a novel potassium‐ and magnesium‐enriched salt alternative improves the cardiovascular effects of ramipril

Pathophysiology of Cerebral Ischemia and Brain Trauma: Similarities and Differences

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