Naohisa Hosomi

Predictors of Intracerebral Hemorrhage Severity and Its Outcome in Japanese Stroke Patients

Objective: The aim of this investigation was to determine the factors influencing acute intracerebral hemorrhage severity on admission and clinical outcomes at discharge. Methods: Sixty acute stroke hospitals throughout Japan participated in the Japan Standard Stroke Registry Study (JSSRS), documenting the in-hospital course of 16,630 consecutive patients with acute stroke from January 2001 to March 2004. We identified 2,840 adult patients from the JSSRS who had intracerebral hemorrhage. Results: Intracerebral hemorrhage severity on admission was strongly related to age, previous stroke history, and hemorrhage size in a monotone fashion [χ2(9) = 374.5, p < 0.0001]. Drinking history was also predictive of intracerebral hemorrhage severity on admission, but the association was not monotone. Interestingly, intracerebral hemorrhage severity on admission was increased in nondrinking and heavy drinking compared to mild drinking (p < 0.05). Unsuccessful outcome (modified Rankin scale score = 3–6) was related to age, previous stroke history, hemorrhage size, and intracerebral hemorrhage severity on admission [χ2(9) = 830.4, p < 0.0001]. Mortality was related to hemorrhage size, intraventricular hemorrhage, intracerebral hemorrhage severity on admission, and surgical operation [χ2(7) = 540.4, p < 0.0001]. Conclusion: We could find four varied factors associated with intracerebral hemorrhage severity and its outcomes. Interestingly, intracerebral hemorrhage severity tended to be greater in nondrinking and heavy drinking than mild drinking. Additionally, surgical operation decreased intracerebral hemorrhage mortality.

Comparison of central blood pressure and cardio-ankle vascular index for association with cardiac function in treated hypertensive patients

Recent automated applanation tonometry can measure radial pulse wave-derived central blood pressure (CBP), which has shown a prognostic value independently of peripheral blood pressure. However, CBPs clinical significance has not been fully established. We examined the associations between CBP and cardiac structure and function by comparing them with those of arterial stiffness assessed by cardio-ankle vascular index (CAVI) in treated hypertensive patients. Enrolled in the study were 102 patients (71±7u2009years) with treated hypertension. The transmitral early-to-atrial velocity ratio (E/A), peak systolic (S′), early diastolic (E′) mitral annular velocities and the Tei index were measured as indexes of cardiac function derived from conventional and tissue Doppler echocardiography. Left ventricular mass index (LVMI) was measured as an index of LV hypertrophy. CBP and CAVI were measured just after echocardiographic examination. CBP, but not CAVI, correlated with LVMI (r=0.306, P<0.01). Although CBP correlated only with the Tei index (r=0.201, P<0.05), CAVI correlated with E/A (r=−0.387, P<0.001), S′ (r=−0.270, P<0.01), E′ (r=−0.362, P<0.01) and the Tei index (r=0.339, P<0.01). Stepwise regression analysis revealed that neither CBP nor CAVI was independently associated with E/A, S′ or E′. However, CAVI, but not CBP, was independently associated with the Tei index (β coefficient=0.311, P<0.001), reflecting both LV systolic and diastolic function. In conclusion, CBP may be suitable for detecting LV hypertrophy. In contrast, CAVI may be suitable for detecting LV dysfunction. This difference, suggesting the clinical value of each parameter, should be kept in mind when we use CBP and CAVI for assessing arteriosclerosis in treated hypertension.

Inhibitory effects of a dihydropyridine calcium channel blocker on renal injury in aldosterone-infused rats.

Objectives Recent in-vitro studies demonstrated that dihydropyridine calcium channel blockers have direct mineralocorticoid receptor antagonistic activity. The present study was conducted to examine the effects of a dihydropyridine calcium channel blocker, azelnidipine, on aldosterone-induced oxidative stress and renal injury. Methods and results Uninephrectomized rats subjected to 6 weeks treatment with aldosterone (0.75 μg/h, subcutaneous) and 1% NaCl (in drinking water) showed higher systolic blood pressure (SBP), urinary excretion of protein (UproteinV), glomerular cell proliferation and renal interstitial fibrosis than vehicle (2% ethanol)-infused rats. Aldosterone-induced renal injury was associated with increased renal cortical content of thiobarbituric acid-reactive substances (TBARS), NAD(P)H oxidase complex formation and mRNA expression of NAD(P)H oxidase membrane components (p22phox and gp91phox). Administration of azelnidipine [3 mg/kg per day, orally (p.o.)] markedly attenuated the aldosterone-induced increases in SBP, UproteinV, renal cortical tissues TBARS content, NAD(P)H oxidase complex formation, mRNA levels of p22phox and gp91phox, and morphological changes. In aldosterone-infused rats, treatment with a nonspecific vasodilator, hydralazine (5 mg/kg per day in drinking water) resulted in a reduction in SBP similar to azelnidipine; however, it did not affect any renal parameters. Treatment with azelnidipine suppressed aldosterone/mineralocorticoid receptor-dependent but not mineralocorticoid receptor-independent superoxide production in cultured rat mesangial cells. Conclusion These data suggest that dihydropyridine calcium channel blockers may elicit marked amelioration of aldosterone-induced renal injury through their inhibitory effects on NAD(P)H oxidase-dependent oxidative stress.

Influences of Hypertension and Diabetes on Normal Age-Related Changes in Left Ventricular Function as Assessed by Tissue Doppler Echocardiography

Although the impact of hypertension (HT) and type 2 diabetes mellitus (DM) on left ventricular (LV) function has recently been studied using tissue Doppler echocardiography (TDE), there are few studies discriminating between the impact of the disease and that of normal aging on LV function. The purpose of the present study was to elucidate the LV function in patients with HT and DM in various age strata in order to assess the independent roles of HT and DM on normal age-related changes in cardiac function. The population of the study consisted of four groups: 20 control subjects (Control), 20 patients with hypertension alone (HTN), 20 patients with type 2 diabetes alone (DM), and 20 patients with both hypertension and diabetes (HTN+DM) in each of five age strata—the 40s, 50s, 60s, 70s, and 80s. The strain and strain rate, which reflected both LV systolic and diastolic function, were assessed by TDE. The strain and strain rate decreased with advancing age in healthy control subjects and in all the patient groups. The strain and strain rate in the HTN group and the DM group showed lower values than those in the healthy control subjects in each age stratum. Furthermore, the strain and strain rate in the HTN+DM group showed the lowest values among all four groups in each age stratum. These results indicate that LV function as assessed by TDE demonstrates age-related deterioration with normal aging. Although HT or DM affects normal age-related changes in LV function, the co-existence of HT and DM has a more harmful effect on the normal age-related changes than HT alone or DM alone.

The expression of P-glycoprotein is increased in vessels with blood-brain barrier impairment in a stroke-prone hypertensive model

Aims: We previously reported that the blood‐brain barrier (BBB) function was impaired in vessels in the hippocampus in 3‐month‐old stroke‐prone spontaneously hypertensive rats (SHRSP). In this study, we examined gene and protein expressions of P‐glycoprotein, a representative efflux transporter of cerebral vessels, in the BBB‐damaged hippocampal vessels of SHRSP and in the vessels of Wistar Kyoto (WKY) rats as controls, to clarify roles of the efflux transporter in the BBB‐damaged vessels. Methods: The expression of P‐glycoprotein in hippocampal and cortical samples was examined by real‐time quantitative reverse transcriptase‐polymerase chain reaction (RT‐PCR), Western blotting and immunoelectron microscopic techniques. Results: Real‐time RT‐PCR and Western blotting analyses revealed that the gene and protein expressions of P‐glycoprotein were increased in the hippocampal samples of 3‐month‐old SHRSP compared with hippocampal samples of 3‐month‐old WKY rats or with cortical samples of SHRSP. The gene expression of P‐glycoprotein was also increased in the hippocampal samples of 4‐week‐old SHRSP. Immunoelectron microscopic examination revealed that immunosignals of P‐glycoprotein were seen in the luminal and ab‐luminal cytoplasmic membranes of endothelial cells and the basal lamina, that the labelling density of P‐glycoprotein in the vessel wall was higher in the hippocampus of 3‐month‐old SHRSP than in other groups and that the immunosignals of P‐glycoprotein were occasionally co‐located with those of albumin. Conclusions: These findings indicate that the expression of P‐glycoprotein is increased in BBB‐damaged hippocampal vessels in hypertensive SHRSP compared with those in WKY rats.

RAGE, LDL receptor, and LRP1 expression in the brains of SAMP8

SAMP8, senescence-accelerated mice with age-related deficits in memory and learning, are known to show age-related increases of amyloid precursor protein (APP) expression and to be under elevated oxidative stress. The receptor for advanced glycation end product (RAGE) is a representative influx transporter of APP or amyloid-beta (A beta) protein in cerebral vessels, while low-density lipoprotein receptor (LDLR) and LDL-related protein 1 (LRP1) are efflux transporters. These receptors play roles not only in clearance of A beta protein but also in control of oxidative stress. In this study, we examined the gene and protein expressions of these receptors, by real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), Western blotting, and immunohistochemical techniques. SAMR1 mice with lower expression of APP were as controls. The gene and protein expressions of RAGE were lower in SAMP8 brains than in SAMR1. Those of LDLR were higher in SAMP8 brains than those of SAMR1. There were no differences in the expressions of LRP1 between SAMP8 and SAMR1. Immunosignals of RAGE and LDLR were seen in the cytoplasm of CD34-positive endothelial cells and also in astrocytes, in both strains of mice. These findings suggest that the lower expression of RAGE and the higher expression of LDLR may contribute to clearance of toxic substances and, in addition, be related to elevated oxidative stress in SAMP8 brains.

Age-related changes in P-glycoprotein expression in senescence-accelerated mouse.

P-glycoprotein, the gene product of ATP-binding cassette, sub-family B (Abcb1), is a representative efflux transporter of cerebral vessels. It was recently reported that the expressions of P-glycoprotein and Abcb1 gene were increased in hippocampal vessels with blood-brain barrier (BBB) damage in stroke-prone hypertensive rats. SAMP8, senescence-accelerated mice with age-related deficits in memory and learning, are known to show age-related damage of BBB. Accordingly, in this study, we examined the P-glycoprotein expression and the gene expression (Abcb1a/b) by real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), Western blotting, and immunohistochemical techniques. SAMR1, which has a spontaneous retroviral insertional mutation in Abcb1a gene, was used to assess the effects of Abcb1a gene mutation. The brain samples of SAMR1 showed decreased expressions of P-glycoprotein and Abcb1a genes and increased expression of Abcb1b gene, compared with those of SAMP8 mice. The P-glycoprotein expression increased with aging in the brain samples of SAMP8, but not in those of SAMR1. The gene expressions of Abcb1a and Abcb1b increased with aging in the brain samples of SAMP8. Immunosignals of P-glycoprotein were seen in vessel walls, mainly in the cytoplasm of CD34-positive endothelial cells and partially in astrocytes, in all mice. These findings indicate that the expressions of Abcb1a and Abcb1b genes and their gene products, P-glycoprotein, were increased with aging in SAMP8, suggesting age-related response to prevent toxic substance from accumulating in the brains of SAMP8.

Abcb1a and Abcb1b expression in senescence-accelerated mouse (SAM)

It was recently reported that some strains of senescence-accelerated mouse (SAM) including SAMR1 had a spontaneous retroviral insertional mutation in the ATP-binding cassette, sub-family B, member 1A (Abcb1a) gene, while other strains including SAMP8 had not. The Abcb1 gene product, P-glycoprotein, is a representative efflux transporter of cerebral vessels. In this study, using brain samples of SAMR1, Abcb1a gene-mutant mice, and of SAMP8 without that mutation, we examined the gene expression of some representative ATP-binding cassettes, such as Abcb1a, Abcb1b, Abcc, and Abcg2, and the protein expression of P-glycoprotein by real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), Western blotting, and immunohistochemical techniques. The gene expression of Abcb1a was decreased in the brain samples of SAMR1 compared with those of SAMP8, while that of Abcb1b was increased in the samples of SAMR1 compared with those of SAMP8. There were no differences in the gene expression of Abcc and Abcg2 between the samples of SAMR1 and SAMP8. The protein expression of P-glycoprotein was decreased in the brain samples of SAMR1 compared with those of SAMP8. Immunosignals of P-glycoprotein were seen in vessels walls, mainly CD34-positive endothelial cells and partially astrocytic cells, in both mice. These findings indicate that SAMR1, Abcb1a-mutant mice, showed decreased expression of Abcb1a gene and P-glycoprotein and increased gene expression of Abcb1b, compared with those of SAMP8 without that mutation, suggesting no clear effect of increased gene expression of Abcb1b on decreased expression of P-glycoprotein. The combination of SAMR1 and SAMP8 may be a good tool to investigate which transporter, Abcb1a or Abcb1b, can be used in drug delivery into the brain.