Ryoichi Horie

Possible role of nutritional factors in the incidence of cerebral lesions in stroke-prone spontaneously hypertensive rats.

The incidence of cerebral lesions in stroke-prone spontaneously hypertensive rats appears to depend on the severity of the hypertension and nutritional factors. Comparison of American and Japanese commercial rat diets revealed a much higher incidence of stroke in rats receiving the Japanese diet (88% vs 30% by 9 months of age). Analyses of the diets indicate that perhaps the most important difference in the two diets is the protein content. Based on complete amino acid analyses of the protein in these diets, it appears that the American diet contains about 22% protein as compared to about 15% for the Japanese diet. Minor differences in vitamin and mineral contents are not remarkable. Comparison of the findings in this experimental rat model with epidemiologic studies suggest that nutritional factors may also play a role in the incidence of stroke in humans.

Cardiac Hypertrophy in Early Hypertension

Studies of cardiac hypertrophy in spontaneously hypertensive rats have indicated that left ventricular hypertrophy occurred even in the prehypertensive stage. These findings suggested that other factors besides blood pressure levels, and including possibly a genetic predisposition to myocardial hypertrophy, could play a role in structural cardiovascular alterations in spontaneously hypertensive rats. More recent studies have confirmed these anatomic results; left ventricular hypertrophy was vectorcardiographically detected even in the prehypertensive stage in voth young stroke-prone rats and stroke-resistant spontaneously hypertensive rats. Further, a close relation was found between degree of left ventricular hypertrophy and vascular hypertrophy or hyperplasia; this suggests that early detection of left ventricular hypertrophy may be a useful indicator of the incipient stage of structural vascular changes in genetic hypertension.

Interrelationships between blood pressure, sodium, potassium, serum cholesterol, and protein intake in Japanese.

Interrelationships among blood pressure (BP), sodium (Na), potassium (K), dietary protein, and serum cholesterol level (Chol) were examined in 62% (1120) of 1818 Japanese inhabitants of both sexes aged over 30 years who lived in a rural village in Japan. Fasting single-spot urine specimens were collected in the morning to measure Na, K, urea nitrogen (UN), inorganic sulfate (SO4), and creatinine (Cr). The Cr ratios of Na, K, UN, SO4, Na/K, and SO4/UN were analyzed by multiple regression analysis to determine independent associations with BP together with age, obesity index, hematocrit (Hct), Chol, triglyceride (TG), and fasting serum glucose level (Glu). Except for Na/Cr in men, Na/Cr and Na/K were found to be independently and positively related to BP, particularly to systolic BP (SBP). In contrast, K/Cr and SO4/UN (an index related to the dietary score of sulphur-containing amino acids derived mainly from animal protein) were both negatively associated with SBP, and UN/Cr (an index of total protein intake) was positively associated with SBP in men. Chol was linked to BP negatively in men but positively in women. Age, obesity index, TG, and Hct were generally positively and significantly related to BP in both sexes. The results confirmed on epidemiological grounds the positive link of Na and the negative link of K to BP within a single population in Japan. They further suggest, although only in men, that there is a negative relationship of Chol and dietary animal protein with BP.

Abnormal Membrane Characteristics of Erythrocytes in Rat Models and Men with Predisposition to Stroke

Erythrocyte membrane characteristics were examined in normotensive Wistar-Kyoto rats (WK), stroke-resistant spontaneously hypertensive rats (SHRSR) and stroke-prone SHR (SHRSP). The membrane of SHRSP was more labile against osmotic shock than that of SHRSR or WK at the age of 2 months. This membrane fragility was not dependent on their blood pressure. The membrane permeability of lipophilic ion, tetraphenylphosphonium, was increased in 1-month old SHRSP. These membrane characteristics in SHRSP were partially dependent on cholesterol amount which was significantly decreased in SHRSP. The method determining the membrane fragility was applied to human erythrocytes. Two groups of people were selected from about 2,000 inhabitants under our community health control program. The erythrocytes from the group with stroke in their family history were more labile than erythrocytes from the corresponding group without stroke in their family history. This result suggests that the examination of these membrane characteristics may give us a new method to detect a genetic risk to hypertension or stroke-proneness also in human.

White matter lesions and alteration of vascular cell composition in the brain of spontaneously hypertensive rats

There have been few studies on the white matter lesions of spontaneously hypertensive rats (SHR). From the point of view of hypertension and arteriosclerosis, white matter lesions were examined in SHR and stroke-prone SHR (SHRSP), and were then compared with Wistar-Kyoto (WKY) rats. The vasculopathy was analyzed by morphometric immunohistochemistry for collagen and smooth muscle actin. Both SHR and SHRSP had hypertension at ⩾ 12 weeks of age, and the latter developed severe white matter lesions at 20 weeks. Immuno- histochemistry revealed proliferation of microglia in the white matter and an increase in smooth muscle actin in the vessels of SHRSP compared with the WKY rats and SHR, but there were no changes in the collagen. These results indicate a role of hypertension in the pathogenesis of white matter lesions. However, genetic difference may also be responsible since SHR and SHRSP showed similar hypertension.

Pathogenic Mechanisms and Prevention of Stroke in Stroke-prone Spontaneously Hypertensive Rats

Publisher Summary The establishment of stroke-prone spontaneously hypertensive rats (SHRSP), of which more than 80% died of stroke, has led to extensive study on the mechanisms of cerebrovascular lesions. Studies have revealed that hypertension is the most important systemic factor for stroke. Other possible factors are the alteration of the physical characteristics of the arterial wall, and involvement of humoral factors such as renin. Further, the angioarchitectural studies have clarified that the predilection sites of stroke are the boundary zone of the three main cerebral arterial supplies and the areas fed by recurrent arteries. This chapter presents the assay of norepinephrine in the brain quantitatively or by fluorescent histochemical methods. regional cerebral blood flow (rCBF) tends to increase under hypertensive state below 200 mm Hg but decreases abruptly in SHRSP with severe hypertension over 220 mm Hg.

Stroke-prone SHR (SHRSP) as a model for osteoporosis

Since previous studies on SHRSP showed various abnormalities in Ca metabolism, aged SHRSP together with age-matched Wistar-Kyoto (WKY) were examined for bone mineral density and contents as well as bone histomorphometry and mechanical properties. SHRSP and WKY, 10 rats of each group at the age of 7 to 8 months were sacrificed with or without tetracycline and calcein labellings for the estimation of mineral appositional rate. Both femurs, tibia and the 1st lumbar vertebra were extirpated from each rat; one femur was used for mineral density and content analyses and the other was used for analyzing mechanical properties by three point-bending and torque methods (Maruto, MZ500D). Mineral density and cortical thickness index were decreased significantly in SHRSP compared with WKY, and Ca contents were decreased as well. Correspondingly femurs from SHRSP were proven to be fragile in the maximum bending stress. Undecalcified histological sections of tibial proximal epiphysis histomorphometrically indicated bone volume and trabecular thickness were significantly decreased in SHRSP. These findings together with others indicate SHRSP can be a good model for spontaneous osteoporosis in man.

Biochemical aspects of salt-induced, pressure-independent left ventricular hypertrophy in rats.

SummaryIn an attempt to investigate the effect of chronic salt loading on heart size and biochemical composition, sixty 3-month-old male Wistar-Kyoto rats (WKY) were equally divided into two groups: One group was given 1% NaCl in drinking water, and the other group was given tap water as the control. After 7 months, five randomly selected rats from each group were examined for body weight (BW), indirect blood pressure (BP), hematocrit (Hct), and organ weights. Ventricles of the heart, aorta, and mesenteric arteries were biochemically analyzed for collagen (C) and noncollagenous protein (NC) and deoxyribonucleic acid (DNA).Although there was no difference between the salt and control groups in BP (129±3 mmHg vs. 125±4 mmHg, mean ± SE), BW (376±8 g vs. 372±5 g) and Hct (42.8%±1.0% vs. 44.3%±0.8%), left ventricular weight (857±19 mg vs. 788±8 mg) and kidney weight (2.59±00.9 g vs. 2.31±0.05 g) were both significantly (P<0.01) greater in the salt group, whereas the weights of the right ventricle, aorta, and adrenal glands were equal. Biochemical analysis showed significant increase in NC/DNA ratio and total collagen content as well as decreased DNA concentration in the left ventricle of the salt group compared with the control, suggesting hypertrophy rather than hyperplasia of myocardial cells with concomitant activation of collagen synthesis.Since the manner of reactive collagen production appeared different from that reported for spontaneously hypertrophic rats (SHR) or in hypoxia- or aortic constriction-induced cardiac hypertrophy, some unique mechanism may be involved in salt-induced cardiac hypertrophy.

Genetic Markers in Spontaneously Hypertensive Rats

Establishment of various models for hypertensive diseases such as spontaneously hypertensive rats (SHR) and stroke-prone SHR (SHRSP) clarified the importance of genetic factors in the pathogenesis of these diseases and further accelerated studies on their genetic mechanisms. Although various biochemical abnormalities have been detected and can be used as biochemical markers in these models, they have not been always closely related to blood pressure in F2 generation obtained by cross breeding between SHR and normotensive Wistar-Kyoto rats. Recent studies indicate that biomembrane abnormalities detected in erythrocytes and other membranes of SHR and SHRSP may not only be biochemical markers but also related to the pathogenesis of hypertensive diseases.

Intralymphocytic free calcium and magnesium in stroke-prone spontaneously hypertensive rats and effects of blood pressure and various antihypertensive agents.

1. Free Ca2+ ([Ca2+]i) and Mg2+ ([Mg2+]i) were measured in peripheral lymphocytes from stroke‐prone spontaneously hypertensive rats (SHRSP) and normotensive Wistar‐Kyoto rats (WKY) at the age of 5, 7 and 17 weeks, from various antihypertensive agents‐treated SHRSP, and from secondary hypertensive WKY.