Stroke-resistant Spontaneously Hypertensive Rats Research Articles

Telmisartan promotes potential glucose homeostasis in stroke-resistant spontaneously hypertensive rats via peroxisome proliferator-activated receptor γ activation.

An angiotensin 2 type 1 receptor blocker (ARB) telmisartan possesses not only an anti-hypertensive effect but also an anti-metabolic syndrome effect due to peroxisome proliferator-activated receptor γ (PPAR-γ) activation. In the present study, we examined the effects of telmisartan on the angiotensin 2 type 1 receptor (AT1R), PPAR-γ, and insulin receptor (IR) in stroke-resistant spontaneously hypertensive rats (SHR-SR), comparing them with Wistar rats. Three-months-old SHR-SR rats were divided into three treatment groups, i.e., vehicle (SHR/Ve), low-dose telmisartan (0.3 mg/kg/day, SHR/Low), and high-dose telmisartan (3 mg/kg/day, SHR/High). Compared with Wistar rats, SHR/Ve increased the staining of AT1R, PPAR-γ and IR in the cerebral cortical neurons. On the other hand, telmisartan dose-dependently suppressed the excessive expression of AT1R and IR, but enhanced PPAR-γ activation. Low-dose telmisartan showed these effects even without lowering blood pressure (BP), while high-dose telmisartan lowered BP and showed further effects. The present study suggests that even a low dose of telmisartan decreased AT1R and IR, and increased PPAR-γ in the cerebral cortex of SHR-SR without lowering BP, probably by improving glucose homeostasis. The high dose of telmisartan showed further decreases in AT1R and IR, and further PPAR-γ activation while lowering BP, suggesting an additive benefit to lowering BP, namely the improvement of glucose homeostasis.

Telmisartan Reduces Progressive Oxidative Stress and Phosphorylated α-Synuclein Accumulation in Stroke-resistant Spontaneously Hypertensive Rats after Transient Middle Cerebral Artery Occlusion

Telmisartan is an angiotensin receptor blocker with high lipid solubility, also called metabosartan, which exerts a special protective effect on both acute brain damage and chronic neurodegeneration. We examined the effects of telmisartan on oxidative stress by advanced glycation end product (AGE) and 4-hydroxynonenal (4-HNE) assays and the accumulation of phosphorylated α-synuclein (pSyn) in the brain of stroke-resistant spontaneously hypertensive rats (SHR-SR). At the age of 12weeks, SHR-SR received transient middle cerebral artery occlusion (tMCAO) for 90minutes and were divided into the following 3 groups: the vehicle group, the low-dose telmisartan group (.3mg/kg/day), and the high-dose telmisartan group (3mg/kg/day, postoperatively). Immunohistologic analysis was performed when rats were 6, 12, and 18months old. AGE, 4-HNE, and pSyn-positive cells (per square millimeter) increased with age in the cerebral cortex and hippocampus of the vehicle group, in the low-dose telmisartan group, these parameters decreased without lowering blood pressure (BP), and in the high-dose telmisartan group, these parameters increased with lowering BP. The present study suggests that a persistent hypertension after tMCAO caused a progressive oxidative stress with the abnormal accumulation of pSyn, and that telmisartan reduced oxidative stress and the accumulation of pSyn without lowering BP (low dose) or improved these conditions with a reduction in BP (high dose) via its pleiotropic effects through a potential peroxisome proliferator-activated receptor gamma stimulation in the brain of SHR-SR.

Protective Effect of Telmisartan Against Progressive Oxidative Brain Damage and Synuclein Phosphorylation in Stroke-resistant Spontaneously Hypertensive Rats

Previously, we reported that reactive oxygen species and signaling molecules of angiotensin II produced lipid peroxides, degenerated proteins, and injured DNA after cerebral ischemia in normotensive Wistar rats. Here, we investigated the long-term effect of the angiotensin II type I receptor blocker telmisartan on oxidative stress and hyperphosphorylated α-synuclein accumulation in stroke-resistant spontaneously hypertensive rats (SHR-SR). At the age of 3months, SHR-SR were divided into 3 treatment groups: SHR-SR vehicle (SHR/Ve), SHR-SR low-dose telmisartan (.3mg/kg/day) (SHR/low), and SHR-SR high-dose telmisartan (3mg/kg/day) (SHR/high). Immunohistologic analyses were conducted in these groups and Wistar rats at the age of 6, 12, and 18months. The SHR/Ve group demonstrated more progressive increase in advanced glycation end product (AGE)-, 4-hydroxy-2-nonenal (4-HNE)-, and phosphorylated α-synuclein (pSyn)-positive cells in the cerebral cortex and hippocampus compared with the Wistar group at 18months. These expressions were reduced in the SHR/low group even without lowering blood pressure (BP), and expressions were dramatically suppressed in the SHR/high group with lowering of BP. These data suggest that persistent hypertension in SHR-SR strongly potentiate the markers of oxidative damage (AGEs and 4-HNE) and abnormal accumulation of pSyn, which were greatly suppressed by telmisartan in a dose-dependent manner without and with lowering of BP.

Mitochondrial HMG-CoA synthase partially contributes to antioxidant protection in the kidney of stroke-prone spontaneously hypertensive rats

Objective Increased oxidative stress plays an important role in cardiovascular diseases including hypertension and stroke. Evidence has indicated that ketone bodies could exert antioxidative effects. We explored the role of renal mitochondrial 3-hydroxy-3-methylglutaryl-coenzyme A synthase (HMGCS2) expression, a key control site of ketogenesis, in stroke-prone spontaneously hypertensive rats (SHRSPs) and their ancestral hypertensive but stroke-resistant spontaneously hypertensive rats (SHRs). Methods Two groups of SHRSPs were fed a standard chow or standard chow supplemented with clofibrate (an agonist of HMGCS2 promoter), respectively, and SHRs fed with a standard chow were used as controls. The renal levels of HMGCS2, Akt, and phosphorylated protein kinase B (Akt) were measured by western blotting. Malondialdehyde, catalase, superoxide dismutase, and glutathione peroxidase were detected by assay kits. Results Compared with SHRs, lower HMGCS2 protein expression, enhanced phosphorylated Akt signal, higher malondialdehyde levels, and higher catalase activity were observed in kidney tissues in SHRSPs ( P < 0.05). No differences in superoxide dismutase and glutathione peroxidase activities were observed between SHRSPs and SHRs. Clofibrate treatment significantly upregulated renal HMGCS2 expressions, inhibited phosphorylation of Akt, and decreased malondialdehyde levels and catalase activities in SHRSP kidney tissues ( P < 0.05). Conclusion These results demonstrated the difference in HMGCS2 expression and oxidative stress in kidney tissues between SHRSPs and their SHR controls. The enhanced oxidative stress was partly due to the lower HMGCS2 expression regulated possibly by the Akt signaling pathway.

Chronic high‐salt diet reduces very low frequency blood pressure variability in stroke‐prone but not in stroke‐resistant rats

In previous studies we demonstrated that myogenic vascular function specifically affects very low frequency (VLF, 0.02–0.2 Hz) blood pressure variability (BPV) in rats. In addition, impaired cerebrovascular myogenic function has been associated with hemorrhagic stroke in stroke-prone spontaneously hypertensive rats (SHR-SP) on high-salt diet. Therefore, we hypothesized that VLF BPV is reduced in SHR-SP on high-salt diet but not in stroke-resistant spontaneously hypertensive rats (SHR-SR) or normotensive Wistar Kyoto rats (NT-WKY). NT-WKY (n=9), SHR-SR (n=14), and SHR-SP (n=13) received a high-salt diet (1% NaCl in drinking water) for 4 or 6 weeks before arterial blood pressure was recorded in conscious animals. Blood pressure values at the 4th and 6th week of high-salt diet were greater in SHR-SP than in SHR-SR and greater in SHR-SR than in NT-WKY. From the 4th to the 6th week of high-salt diet, VLF BPV tended to increase in NT-WKY (from 9.1±2.2 mmHg2 to 13.5±6.4 mmHg2, not sig.) and SHR-SR (from 14.6±1.4 mmHg2 to 21.6±2.0 mmHg2, not sig.). In contrast, VLF BPV significantly decreased during this time period in SHR-SP (from 20.2±2.8 mmHg2 to 11.8±3.8 mmHg2, p<0.05). These data suggest that reduced VLF BPV indicates impaired myogenic vascular function in SHR-SP on high-salt diet prior to hemorrhagic stroke. Supported by: AHA #0630329N

Pharmacological studies of alcohol susceptibility and brain monoamine function in stroke-prone spontaneously hypertensive rats (SHRSP) and stroke-resistant spontaneously hypertensive rats (SHRSR).

Differences of alcohol drinking behavior, brain dopamine (DA) and serotonin (5-HT) levels and releases in the striatum were investigated in stroke-prone spontaneously hypertensive rats (SHRSP) and age-matched stroke-resistant spontaneously hypertensive rats (SHRSR). Voluntary alcohol (EtOH) consumption in SHRSP rats increased at 1 and 2 hours in the 4 hour time access. In the DA level, SHRSP showed decreases in the caudate-putamen (C/P) and dorsal raphe nucleus (DRN) compared with in SHRSR. 5-HT levels in the C/P, ventral tegmental area-subtantia nigra (V/S) and DRN of the SHRSP were decreased compared with that in SHRSR. The basal extracellular levels of 5-HT release in the C/P were increased in SHRSP as compared with those in SHRSR. K(+)- or EtOH-induced DA and 5-HT releases in the C/P of the SHRSP were a lower magnitude than those in SHRSR. Increased basal extracellular 5-HT releases showing low levels of 5-HT in the C/P of SHRSP mean an abnormality of serotonergic neuronal functions in a normal physiological condition. Higher voluntary alcohol drinking behavior, so called lower susceptibility to EtOH, in the SHRSP may be associated with the degenerated rewarding system including the DRN. These results suggest that the hypertensive state causes the dysfunction in the striatum of the brain rewarding system and induces the risk for increasing alcohol consumption to compensate for the alteration of serotonergic neurons.

Altered gene expression in cerebral capillaries of stroke-prone spontaneously hypertensive rats

Stroke-prone spontaneously hypertensive rats (SHRSP) are a well-characterized, genetic model for stroke. We showed earlier that the structure and function of the tight junctions in SHRSP blood–brain barrier endothelial cells is disturbed prior to stroke. To investigate the molecular events leading to endothelial dysfunction in SHRSP cerebral capillaries, we carried out suppression subtractive hybridization (SSH) in combination with a cDNA filter screening step. We identified two cDNA fragments that were upregulated in SHRSP, compared to stroke-resistant spontaneously hypertensive rats (SHR), and found open reading frames of 133 and 138 amino acids, respectively. These peptides did not match any known proteins in public databases. A third upregulated SHRSP cDNA fragment was identified as the rat sulfonylurea receptor 2B (SUR2B). We also isolated and cloned the cDNA of the rat homologue for the mouse G-protein signaling 5 (RGS5) regulator. This regulator was downregulated in SHRSP. We used in situ hybridization to show that rat RGS5 is expressed in the brain capillary endothelium and in the choroid plexus. Our findings may lead to the identification of new stroke-related genes.

Altered structure, regulation, and function of the gene encoding the atrial natriuretic peptide in the stroke-prone spontaneously hypertensive rat.

Through the genotype/phenotype cosegregation analysis of an F(2) intercross, from the crossbreeding of stroke-prone spontaneously hypertensive rats (SHRSP) and stroke-resistant spontaneously hypertensive rats (SHR), we previously identified a quantitative trait locus for stroke on rat chromosome 5 (STR2) that colocalized with the genes encoding atrial and brain natriuretic peptides (ANP and BNP) and conferred a stroke-delaying effect. To further characterize ANP and BNP as candidates for stroke, we performed additional studies. Comparative sequence analysis revealed point mutations in both the coding and regulatory regions of ANP, whereas no interstrain differences were found for BNP. In in vitro studies in COS-7 and AtT-20 cells that were performed to test the relevance of a G-->A substitution at position 1125, a Gly-->Ser transposition in the SHRSP pro-ANP peptide resulted in different posttranslational processing of the SHRSP ANP gene product that was also associated with higher cGMP production (P<0.05). Furthermore, an analysis of a 5' end mutation affecting a PEA2 regulatory binding site in the 5' untranslated regulatory sequence of SHRSP ANP demonstrated a significantly lower ANP promoter activation in endothelial cells (P<0.05 versus the SHR ANP). In addition, the expression of ANP was significantly reduced in the brain, but not in the atria, of SHRSP compared with SHR (P<0.0001). No differences were detected with regard to BNP expression. The present results reveal substantial differences in ANP, but not BNP, structure and product among SHR and SHRSP, which supports a role of ANP in the pathogenesis of stroke in the SHRSP animal model.

Hemodynamics and metabolism in stroke-prone spontaneously hypertensive rats before manifestation of brain infarcts.

Genomic screening of hybrids from stroke-prone (SHR-SP) and stroke-resistant spontaneously hypertensive rats (SHR) identified a STR1 locus on the rat chromosome 1, which correlates with the susceptibility to cerebral stroke but not with hypertension. The authors examined whether this genetic abnormality is associated with hemodynamic or metabolic alterations in the brain that can be detected before the manifestation of brain infarction. Starting at 6 weeks of age, SHR-SP were fed with a salt-rich diet to accelerate arterial hypertension. At the age of 12 weeks, animals developed functional symptoms and were age-matched with symptom-negative SHR-SP to differentiate between presymptomatic and postsymptomatic changes. Brains were investigated by multiparametric imaging comprising quantitative double-tracer autoradiography of CBF and cerebral protein synthesis (CPS); bioluminescence imaging of regional ATP, glucose, and lactate content; and umbelliferone fluoroscopic imaging of tissue pH. None of the animals exhibited focal hemodynamic or biochemical abnormalities. In symptom-negative SHR-SP, global CBF was 1.1+/-0.3 mL x g(-1) x min(-1), cortical CPS was 10.1+/-3.1 nmol x g(-1) x min(-1), and cortical ATP, glucose, lactate, and pH levels were in the normal range. In SHR-SP with functional symptoms, ATP, glucose, and lactate levels also were normal, but tissue pH exhibited periventricular alkalosis, CBF was significantly reduced to 0.7+/-0.2 mL x g(-1) x min(-1) (P < 0.001), and cortical CPS was significantly reduced to 6.7+/-2.1 nmol x g(-1) x min(-1) (P < 0.001). The decline in brain perfusion of SHR-SP correlated significantly with both the severity of functional deficits and the decline of protein synthesis. Our observations demonstrate that SHR-SP had already developed functional symptoms before the manifestation of overt brain infarcts and that the symptoms are initiated by a decline in global CBF and cortical CPS. Genetic abnormalities in SHR-SP are associated with a diffuse vascular process that results in global decompensation of blood flow well before the onset of focal brain infarction.

Changes in various tissues in the arterial wall of spontaneously hypertensive rats.

1. Using stroke-prone spontaneously hypertensive rats (SHRSP), stroke-resistant spontaneously hypertensive rats (SHRSR) and Wistar-Kyoto rats (WKY), vascular complications and the longevity of rats were investigated. 2. SHRSP aged more than 9.5 months tended to suffer from severe vascular complications such as periarteritis nodosa (PN) of mesenteric artery, while SHRSR very rarely showed severe vascular complications and WKY did not show any complications, because of the different level of systolic blood pressure. 3. Among some tissues PN tended to occur early in the small arteries of the testes and then in mesenteric artery, when these tissues of SHRSP were investigated microscopically. 4. Concerning the influence of systolic blood pressure on arterial smooth muscle layer, the deviation force of this layer was larger in SHRSR compared to WKY (44.7 times in Y axis), which was calculated mathematically and physically using computer analysis. 5. The arterial wall area of PN was enlarged, resulting in the low ratio of lumen/wall. The ratio of arterial lumen/wall was lower in SHRSP when compared to the age-matched WKY. 6. In search for myocardial ischaemia, ECG was recorded. There were positive correlations between PQ interval or SV1 + RV5 and age in the three strains of rats. ST depression more than 1 mm on ECG was most prevalent in old SHRSP, indicating probably the presence of myocardial ischaemia.

Indirect systolic and mean blood pressure determination by a new tail cuff method in spontaneously hypertensive rats

A new tail cuff method for determining systolic and mean blood pressure in rats was developed based on photoelectric detection of tail arterial blood flow and pulsatile volume oscillation. Indirect systolic and mean blood pressure measured by this method correlated well with direct systolic and mean blood pressures recorded by a transducer and polygraph after carotid artery cannulation in stroke-resistant spontaneously hypertensive rats (SHR), stroke-prone SHR and normotensive Wistar Kyoto rats. Blood pressures were sharply, and transiently raised for about 1 min when rats were picked up by an investigator to be placed in a hot box or immobilized in a restrainer for measuring blood pressure. Therefore, blood pressures should be measured at least 1 min after the rats are put in a restrainer. This new tail cuff method for measuring blood pressure provides reliable mean blood pressure readings in conscious rats.

A new approach to the prevention of hypertensive cardiovascular diseases by controlling the proliferation of vascular smooth muscle cells.

Cholera toxin subunit B suppressed the proliferation of cultured vascular smooth muscle cells from the thoracic aorta of Wistar-Kyoto rats (WKY), stroke-resistant spontaneously hypertensive rats (SHR) and stroke-prone SHR (SHRSP). Since cholera toxin subunit B did not stimulate cyclic AMP accumulation in vascular smooth muscle cells, the effect of cholera toxin subunit B might be due to another mechanism. Cholera toxin subunit B bound to the surface of vascular smooth muscle cells and was rapidly incorporated into them. The morphological structure of vascular smooth muscle cells was transformed from the synthetic type to the non-synthetic type, in which microfilaments and intermediate filaments were abundantly formed, while rough endoplasmic reticulum was decreased after CTB treatment.

New establishment of hypertensive diabetic animal models: Neonatally streptozotocin-treated spontaneously hypertensive rats

Hypertensive diabetic animal models have been developed by injecting streptozotocin (STZ) in neonatal stroke-resistant spontaneously hypertensive rats (SHRSR) and stroke-prone SHR (SHRSP) at the age of two days. After the treatment, the animals showed mild insulin deficiency and mild hyperglycemia at the age of three to four months. Diabetic nephropathy was produced particularly in STZ-treated SHRSR at the age of six months. The effect of neonatal STZ injection on hyperglycemia varied among normotensive Wistar-Kyoto rats (WKY), SHRSR, and SHRSP; SHRSR showed the highest glucose levels, SHRSP showed intermediate levels, and WKY was the lowest. All STZ-treated SHRSR showed glycosuria, while glycosuria was not observed in the treated SHRSP and WKY. Histologic study indicated that these strain differences were partly ascribed to differences in islet B-cell sensitivity to toxic effects of STZ. The development of hypertension was not accelerated in these SHRSR and SHRSP compared with respective nontreated controls. Since STZ-treated SHRSR develop mild diabetic symptom with hypertension and develop mild diabetic glomerulosclerosis, they are good models for studying vascular complications or other problems relating to the synergism between hypertension and diabetes mellitus.

Influence of duration of antihypertensive treatment on experimental cerebral ischemia in SHRSR

Nicardipine hydrochloride, which is one of the Ca2+ antagonists, was administered to two SHRSR (stroke-resistant spontaneously hypertensive rats) groups. In one group it was administered for 3 weeks (short-term T-SHR) and in the other for 8-10 weeks (long-term T-SHR). The degree of cerebral ischemia induced by BLCL (bilateral common carotid artery ligation) was investigated in the two groups as well as in two corresponding controls (U-SHR). The brain metabolites. (ATP, lactate, c-AMP) and brain water content were analysed 4h after BLCL, and histopathological changes were observed by scanning electron microscopy (SEM) 3h after BLCL. The influence. of duration of antihypertensive treatment and the ameliorating effect of the long-term treatment on experimental cerebral ischemia were discussed in this report.ATP level in the short-term T-SHR group was higher than that in the U-SHR group after BLCL. However, there was no significant difference in lactate and c-AMP levels between these two groups. The brain water.content in the occipital region after BLCL in the. short-term T-SHR group was significantly lower than that in the U-SHR group, but there was no difference in the frontal region between the two groups. In the long-term T-SHR group, ATP and c-AMP levels were significantly higher than in the U-SHR group, and the lactate level was significantly lower. Furthermore the brain water content after BLCL in the long-term T-SHR group was significantly lower than in the USHR group in both the frontal and occipital portions. There was a more significant amelioration of the brain metabolism and brain edema after BLCL in the long-term T-SHR group than in the shortterm T-SHR group.From the observation of SEM in the brain vessels after BLCL, the short-term and long-term TSHR groups showed less propagation of microvilli on the endothelial surface than either U-SHR group. Vasoconstriction was observed in these U-SHR groups. The marginal folds were shown to remain in both the short-term and long-term T-SHR groups after BLCL. However, in this histopathological study, the vascular endothelial ischemic changes of the brain vessels were much less in the long-term T-SHR group than in the short-term T-SHR group.These results indicate that long-term antihypertensive treatment significantly contributed to the amelioration of ischemia.

Development of New Animal Model for Hypertension with Diabetes

Hypertensive diabetic animal models have been developed by injecting streptozotocin (STZ) in neonatal stroke-resistant spontaneously hypertensive rats (SHRSR) and stroke-prone SHR (SHRSP) at the age of 2 days. They showed mild insulin deficiency and mild hyperglycemia at the age of 3 to 4 months, but strain difference in the susceptibility was noted; the incidences of diabetes were higher in SHRSR and SHRSP than in Wistar-Kyoto rats (WKY).

Prevention of nephrosclerosis and cardiac hypertrophy by captopril treatment of spontaneously hypertensive rats.

The relationship between hypertension and cardiovascular damage was assessed in three groups of spontaneously hypertensive rats (SHR): 1. stroke prone SHR (SHR-SP) treated orally with an angiotensin I converting enzyme inhibitor (captopril) (100-400 mg/L in the drinking water) from 6 to 35 weeks of age, 2. SHR-SP maintained on tap water until 30 weeks of age, 3. stroke resistant SHR (SHR-SR) maintained on tap water. The controls were Wister Kyoto rats (WKY) maintained on tap water. Captopril-treated SHR-SP showed blood pressure lower than that of untreated SHR-SP, similar to SHR-SR. The ratio of heart weight to body weight was 0.55% in SHR-SP, 0.39% in captopril-treated SHR-SP, 0.46% in SHR-SR, and 0.39% in WKY. The kidneys of SHR-SP showed glomerular sclerosis, glomerular fibrosis, tubular casts, interstitial cell infiltration and vascular wall thickening or hyperplasia of the small arteries and arterioles. The severe glomerular sclerosis was mostly distributed in the inner and middle portions of cortex. Immunohistological study showed IgG, C3 and fibrinogen in the glomeruli and arterioles in SHR-SP. In captopril-treated SHR-SP, similar to SHR-SR, only minor histological changes were seen and there was no deposition of IgG, C3 or fibrinogen. No changes were seen in WKY. Thus, it was concluded that nephrosclerosis and cardiac hypertrophy in SHR-SP are prevented by captopril. The role of the renin-angiotensin and kallikrein-kinin systems in organ pathogenesis in SHR-SP is discussed.

Aging and Dietary Effect on Glucose Tolerance (GT) in Stroke-Resistant Spontaneously Hypertensive Rats (SHRSR)

GT was examined in SHRSR at various ages. The GT was the lowest at the age of 2-3 months and improved at the age of 5-6 months. GT in SHRSR fed on a high fructose diet (HFD) or a high sucrose diet (HSD) was significantly lower as compared to that in SHRSR fed on a normal diet (ND).

The effect of vitamin E on platelet kinetics of stroke-prone spontaneously hypertensive rats (SHRSP).

The platelet survival time was shortened in stroke-prone spontaneously hypertensive rats (SHRSP) at 10 weeks of age on feeding the regular diet but it was normalized on administering the vitamin E-supplemented diet. Platelet survival time was normal in stroke-resistant spontaneously hypertensive rats (SHRSR) at 10 weeks of age on feeding the regular diet but it was shortened when supplying the vitamin E-free diet. The maximal uptake of 75Se-selenomethionine by platelets was increased in SHRSP at 10 weeks of age on feeding the regular diet. It was further increased in SHRSP on feeding the vitamin E-free diet. On the other hand, the increased maximal uptake of 75Se-selenomethionine by platelets was normalized in SHRSP on feeding both the vitamin E-supplemented diet and the vitamin E-supplemented diet after administering the vitamin E-free diet. Therefore, we concluded that the deficiency of vitamin E brought about the shortening of platelet survival time and enhanced platelet production.

Effect of acute and chronic reduction of cerebral blood flow on glucose metabolite levels in SHRSP.

Glucose metabolites in the rat brain were measured under various stages of ischemia. In acute ischemia induced by bilateral carotid artery ligation, phosphocreatine and ATP levels were significantly decreased and lactate levels were significantly increased in stroke-prone spontaneously hypertensive rats (SHRSP). These extreme changes were not observed in normotensive Wistar-Kyoto rats (WKY) and stroke-resistant spontaneously hypertensive rats (SHRSR), under the same conditions. In chronic ischemia induced by long-lasting regional cerebral blood flow reduction due to severe hypertension, similar changes were observed only in SHRSP at the advanced stage. The levels of glucose metabolites in the brain were confirmed to be well maintained within control ranges even though the cerebral tissues were subjected to the chronic ischemia related to severe hypertension.

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.