SUMMARY The predilection sites of cerebrovascular lesions (cerebral hemorrhage and/or softening) were studied in 1,278 strokeprone spontaneously hypertensive rats (SHRSP). The precise supply to the main cerebral arteries was determined by trypan blue injections and microangiography. The three major territories were the anteromedial cortex, the occipital cortex, and the basal ganglia. A common angioarchitectural characteristic of these three areas was the blood supply through "recurrent branching" from the main stream. In the basal ganglia, where there is a preponderance of lesions, the arteries responsible for these lesions belonged to the lateral group of lenticulostriate arteries. The primary pre-stroke arterial lesions were further studied microangiographically in SHRSP killed at the time the initial symptoms of stroke were detected. These points were located at the "boundary zone" of the main cerebral arteries. Our findings indicated the importance of these two angioarchitectural minor loci as the basis for functional or organic circulatory disturbances that may cause stroke. Since these local factors of stroke are common in the cortex and basal ganglia of rats and basal ganglia of humans, these SHRSP are regarded as good pathogenetic models for studies on stroke in humans.

As oxidative stress plays a crucial role in the development and pathogenesis of hypertension, we analyzed the redox (reduction/oxidation) status in tissues from Wistar-Kyoto rats (WKY), spontaneously hypertensive rats (SHR), and stroke-prone SHR (SHRSP). Expressions of 8-hydroxy-2'-deoxyguanosine, a marker for oxidative stress-induced DNA damage, and protein carbonylation, a marker for oxidation status of proteins, were enhanced in aorta, heart, and kidney from SHR and SHRSP compared with WKY. The expression of redox regulating protein, thioredoxin (TRX), estimated by immunohistochemistry and western blot, and expression of TRX gene estimated by real-time RT-PCR were markedly suppressed in those tissues from SHR and SHRSP compared with WKY. Induction of TRX was impaired after angiotension II treatment in peripheral blood mononuclear cells isolated from SHR and SHRSP compared with those isolated from WKY. Although previous reports have shown that TRX is induced by a variety of oxidative stress in tissues, the present study shows the impaired induction of TRX in tissues from genetically hypertensive rats despite the relative increment of oxidative stress. Redox imbalance in essential organs may play a crucial role in the development and pathogenesis of hypertension.

SUMMARY Regional cerebral blood flow (rCBF) was repeatedly measured by the hydrogen clearance method in the frontal cortex of stroke-prone spontaneously hypertensive rats (SHRSP) at the age of 50 days and thereafter. When SHRSP rats developed severe hypertension (over 200 mg Hg at the age of 60 days) rCBF began to decrease abruptly in the frontal cortex -one of the three predilection sites of stroke in these rats. In contrast, such a reduction in rCBF was not noted in either stroke-resistant spontaneously hypertensive rats (SHRSR) which developed moderate hypertension (under 200 mg Hg), or in Wistar-Kyoto rats (WK) with normal blood pressure (under 150 mm Hg).A similar marked reduction of rCBF with severe hypertension (over 200 mm Hg) was also detected in apoplectic gene-free renal infarction hypertensive rats (RHR) experimentally produced from agematched WK animals. Blood samples were obtained through an implanted femoral artery canula without disturbing the nonanesthetized SHRSP, SHRSR and WK rats. Arterial blood gas analysis (PacOj, Pao 2 and pH) showed no significant differences at the age of 5 months in any of these rats.Chemical cerebrovascular reactivity, that is, an increase in rCBF in response to CO a inhalation, showed no significant difference among SHRSP rats from the age of 50 days to 5 months. However, it markedly decreased in SHRSP rats at the age of 9 months and thereafter (the average age of male SHRSP rats which develop stroke is 9 months).The present study showed stroke did not occur in antihypertensive agent-treated SHRSP rats. In these SHRSP rats rCBF did not decrease as long as blood pressure was well-controlled.RECENTLY, there has been increasing clinical interest in studies on cerebral blood flow (CBF) in cerebrovascular disease. Methods for CBF measurement have made rapid progress since the introduction of the nitrous oxide technique, first developed by Kety and Schmidt.1 ' 2 In patients with stroke there have been reported changes in regional cerebral blood flow (rCBF) at various stages. Many investigators have observed rCBF reduction after patients developed stroke. 36 However, the causal relation between CBF and stroke, and especially between CBF and hypertension, have never been elucidated.To clarify this relation, a number of experimental approaches have been tried. "8 Among these, some emphasize clinical data, others add new experimental data and still others have developed new theories, for example, "hypertension breakthrough." 9 ' 10As previously reported, a stroke-prone spontaneously hypertensive rat (SHRSP) was successfully developed in our laboratory at Kyoto University." More than 80% of these SHRSP rats spontaneously develop stroke (cerebral hemorrhage and/or cerebral softening). In our previous report, we confirmed the pathogenetic similarity of stroke in SHRSP rats and humans. 12 In the present studies, using our original SHRSP rats, we tried to elucidate the causal relation between rCBF and stroke.Methods SHRSP rats used in this study were of the A 4 strain among the F^.M...

SUMMARYThe 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. INCREASED blood pressure appears to be one of the primary risk factors related to the incidence of hemorrhagic stroke in humans.' It was of interest therefore when Yamori et al, 2 reported the development of a rat strain that had very high blood pressure and a high incidence of stroke. This strain was derived from the spontaneously hypertensive rats (SHR) developed by Okamoto and Aoki 3 and exhibited an 80% to 90% incidence of cerebral lesions during the first year of life. This stroke-prone substrain is designated SHRSP and uniformly develops arterial blood pressure of over 200 mm Hg by 6 months of age. In 1975, this substrain was established in the breeding colonies of the National Institutes of Health (NIH) and used for studies on the pathogenesis of hypertension in this genetic model. It has subsequently become apparent to us that the incidence of cerebral lesions in the SHRSP in our laboratory was dramatically lower than that reported in Japan. The mean blood pressures observed in From the Section on Biochemical Pharmacology, HypertensionEndocrine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland (Dr. Lovenberg); the Department of Pathology, Shimane Medical University, Izumo, Japan (Drs. Yamori, Horie, Fujiwara, Nara, and Tanase).Present address for Dr. the NIH-SHRSP were significantly higher than in the SHR and were similar to the values reported for SHRSP in Japan. These observations suggested that perhaps environmental factors interacted with the genetic traits for hypertension to account for the high incidence of stroke in this strain of rats in Japan. We therefore undertook experiments to determine if the different incidence of stroke could be related to the diet. Materials and MethodsMale SHRSP rats were obtained from the Animal Production section of the NIH at 5 weeks of age and were assigned randomly to Groups 1 and 2 that were to receive either the Japanese rat diet (Funahashi-SP diet, Funahashi Farm, Funahashi City, Chiba Prefecture, Japan) or the NIH open formula diet (Ralston-Purina, Inc., St. Louis, Missouri). These groups were fed ad libitum and received tap water. Starting at 6 ...

MASAHIRO KIHARA, JUN FUJIKAWA, MICHIYA OHTAKA, MASAYUKI MANO, YASUO NARA, RYOICHI HORIE, TOKUGORO TSUNEMATSU, SHINYA NOTE, MASAICHI FUKASE, AND YUKIO YAMORI SUMMARY Interrelationships among blood pressure (BP), sodium (Na), potassium (K), dietary protein, and serum cholesterol level (Choi) 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 (SO 4 ), and creatinine (Cr). The Cr ratios of Na, K, UN, SO 4 , Na/K, and SO4/UN were analyzed by multiple regression analysis to determine independent associations with BP together with age, obesity index, hematocrit (Hct), Choi, triglyceride (TG), and fasting serum glucose level (Glu). Except for Na7 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 sulphurcontaining 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. Choi 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 Choi and dietary animal protein with BP. (Hypertension 6: 736-742, 1984) KEY WORDS • sodium • potassium • animal protein • cholesterol hypertension * multivariate analysis