Mari Michimata

Prognostic significance of the nocturnal decline in blood pressure in individuals with and without high 24-h blood pressure: the Ohasama study.

Objective To examine the relationship between the normal nocturnal decline in blood pressure and the risk of cardiovascular mortality in individuals with and without high 24-h blood pressure values. Methods We obtained 24-h ambulatory blood pressure readings from 1542 residents of Ohasama, Japan, who were aged 40 years or more and were representative of the Japanese general population. We then followed up their survival for a mean of 9.2 years. The relationship was analysed using a Cox proportional hazards model adjusted for possible confounding factors. Results There was a linear relationship between the nocturnal decline in blood pressure and cardiovascular mortality. On average, each 5% decrease in the decline in nocturnal systolic/diastolic blood pressure was associated with an approximately 20% greater risk of cardiovascular mortality. There were no significant interactions for the risk between 24-h systolic/diastolic blood pressure values and continuous values for the nocturnal decline in blood pressure (P for interaction > 0.6). Even when 24-h blood pressure values were within the normal range (< 135/80 mmHg, average 118/69 mmHg), diminished nocturnal decreases in systolic/diastolic blood pressure were associated with an increased risk of cardiovascular mortality. Conclusions This is the first study to demonstrate that a diminished nocturnal decline in blood pressure is a risk factor for cardiovascular mortality, independent of the overall blood pressure load during a 24-h period, in the general population.

Prognostic significance of blood pressure and heart rate variabilities: the Ohasama study

To investigate the association between cardiovascular mortality and short-term variabilities in blood pressure and heart rate, we performed a long-term prospective study of ambulatory blood pressure monitoring in Ohasama, Japan, starting in 1987. We obtained ambulatory blood pressure and heart rate in 1542 subjects ≥40 years of age. Blood pressure and heart rate variabilities were estimated as a standard deviation measured every 30 minutes by ambulatory monitoring. There were 67 cardiovascular deaths during the follow-up period (mean=8.5 years). The Cox proportional hazards model, adjusted for possible confounding factors, demonstrated a significant increase in cardiovascular mortality, with an increase in daytime systolic ambulatory blood pressure variability. A similar trend was observed in daytime diastolic and nighttime ambulatory blood pressures. Cardiovascular mortality rate increased linearly, with a decrease in daytime heart rate variability. Subjects in whom the daytime systolic ambulatory blood pressure variability was larger than third quintile and the daytime heart rate variability was lower than the mean−SD were at extremely high risk of cardiovascular mortality. The blood pressure and heart rate variabilities obtained every 30 minutes by ambulatory blood pressure monitoring were independent predictors for cardiovascular mortality in the general population.

Expression of S‐100 protein is related to neuronal damage in MPTP‐treated mice

S‐100β is a calcium‐binding protein expressed at high levels in brain and is known as a marker of brain damage. However, little is known about the role of S‐100β protein during neuronal damage caused by 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP). To determine whether S‐100β protein is induced in glial cells after MPTP treatment, we investigated the expression of S‐100 protein immunohistochemically, using MPTP‐treated mice. We also examined the change of neurons and glial cells in mice after MPTP treatment. The present study shows that tyrosine hydroxylase (TH) immunoreactivity decreased gradually in the striatum and substantia nigra from 1 day after MPTP treatment. Thereafter, TH‐immunopositive cells and fibers decreased in the striatum and substantia nigra at 3 days after MPTP treatment. In contrast, S‐100‐immunopositive cells and glial fibrillary acidic protein (GFAP)‐immunopositive cells increased markedly in the striatum and substantia nigra at 3 days after MPTP treatment. Seven days after MPTP treatment, S‐100‐immunopositive cells decreased in the striatum and substantia nigra. However, the number of GFAP‐immunopositive cells increased in these regions. In double‐labeled immunostaining with anti‐S‐100 and anti‐GFAP antibodies, S‐100 immunoreactivity was observed only in the GFAP‐positive astrocytes. These results provide evidence that astrocytic activation may play a role in the pathogenesis of MPTP‐induced degeneration of dopaminergic neurons. Furthermore, the present study demonstrates that S‐100 protein is expressed selectively by astrocytes, but not by microglia, after MPTP treatment. These results provide valuable information for the pathogenesis of the acute stage of Parkinsons disease. GLIA 42:307–313, 2003.

Device for the self-measurement of blood pressure that can monitor blood pressure during sleep.

Sponsorship: This work was supported by Research Grants from the Takeda Medical Foundation, the Japan Arteriosclerosis Prevention Fund ( ) ( ) JAPF, 2000 and the Mitsui Life Social Welfare Foundation 1998 , by Research Grants of Kosei Kagaku Kenkyuhi, 1996 and 1997, of Junkankibyo ( ) Itaku Kenkyuu 11C-5 , 1999, and Rojin Hoken Jigyo, 1998 and 1999, from the Ministry of Health and Welfare, and by a Research Grant for Scientific ( ) ( ) Research 10470102 and a Research Grant for JSPS’ Research T.O. from the Ministry of Education, Science and Culture of Japan.

Protective effects of neuronal nitric oxide synthase inhibitor in mouse brain against MPTP neurotoxicity: an immunohistological study

We recently reported that neuronal nitric oxide synthase (nNOS) inhibitor, 7-nitroindazole, can protect against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity in mice. It protected against both dopamine depletions and tyrosine hydroxylase (TH) positive neuron decreases in the mouse brain. In the present study, we further examined whether 7-nitroindazole can also protect against the alterations of TH-, microtubule-associated protein 2a,b (MAP2)-, glial fibrillary acidic protein (GFAP)-, parvalbumin (PV)-, dopamine transporter (DAT)-, nNOS- or endothelial NOS (eNOS)-positive cells, in comparison with pargyline as a relatively selective inhibitor of the monoamine oxidase-B (MAO-B). The present study showed that nNOS inhibitor as well as MAO-B inhibitor has a dose-dependent protective effect against MPTP-induced striatal dopamine and DOPAC depletion in mice. Furthermore, the present study revealed that 7-nitroindazole and pargyline can protect the alterations of immunohistochemical changes in the striatum and substantia nigra after MPTP treatment. These protective effects may be, at least in part, produced by the reduction of neuronally derived NO and peroxynitrite caused by MPTP. Our results also demonstrate that MPTP can cause functional damage of interneurons in the substantia nigra. These results suggest the possibility that nNOS inhibitors as well as MAO-B inhibitors may be therapeutically useful in neurodegenerative diseases such as Parkinsons disease. Thus our present results provide valuable information for the pathogenesis of degeneration of the nigrostriatal dopaminergic neuronal pathway.

Aldosterone synthase gene (CYP11B2) C-334T polymorphism, ambulatory blood pressure and nocturnal decline in blood pressure in the general Japanese population: the Ohasama Study.

Objective The C-344T polymorphism in the 5′-flanking region of the aldosterone synthase (CYP11B2) gene has been suggested to be associated with hypertension and disturbed circadian blood pressure (BP) rhythm through its effect on aldosterone synthesis. However, previous findings on this topic have been inconsistent. Design A cross-sectional study. Subjects and methods We investigated the CYP11B2 C-344T genotype in 802 subjects, aged 40 and over, in a Japanese community, who gave written informed consent and were monitored for 24 h ambulatory BP. Results The frequencies of the CC, CT, and TT genotypes in these Japanese subjects were 0.14, 0.44, and 0.42, showing a higher frequency of the T allele (0.64) than in Caucasians. Although there was no significant difference in 24 h ambulatory BP levels among the genotypes, the nocturnal decline in BP was significantly greater in the CC homozygous subjects than in other subjects (P = 0.0065 for systolic and P = 0.031 for diastolic decline in nocturnal BP). Detailed analyses demonstrated that this association was significant only in aged (60 years and over) or male subjects. The prevalence of previous cardiovascular disease was significantly less in these subjects with the CC genotype than in those with the TC and TT genotypes, although age, body mass index, male gender, smoking, use of alcohol and antihypertensive medication did not differ among the three genotypes. There was no significant difference among the three genotypes in biochemical and hormonal parameters. Conclusion Although the C-344 T polymorphism of CYP11B2 did not directly influence the level of 24 h BP, the CC genotype was associated with decreased nocturnal BP in elderly or male Japanese. Since prevalence of previous cardiovascular disease was significantly less in homozygous CC subjects, greater nocturnal BP decline in this genotype appears to be beneficial in the circadian BP rhythm.

Angiotensin converting enzyme I/D polymorphism and hypertension : the Ohasama study

Objective Angiotensin-converting enzyme (ACE) I/D polymorphism in intron 16 of the ACE gene was analyzed in a general Japanese population in relation to self-blood pressure (BP) measurement at home (home BP) and ambulatory BP monitoring (ABPM) to determine the association between genetic variants of this polymorphism and hypertension. Design A cross-sectional study. Methods and results We genotyped the ACE I/D polymorphism in 1245 subjects with home BP and 803 subjects with ABPM in Ohasama, a rural community in Japan. All the subjects were 40 years of age and over, and gave written informed consent for the present genetic analysis. Hypertensive subjects were defined as those receiving antihypertensive drugs and those who had a home BP higher than 135 mmHg in systole and/or higher than 85 mmHg in diastole. The frequencies of the II, ID, and DD genotypes in these Japanese subjects were 0.45, 0.45, and 0.10, indicating a lower frequency of the D allele (0.33) than in Caucasians. There was no significant difference of BP level, prevalence of hypertension or nocturnal decline in BP among the genotypes. There were no differences in the prevalence of previous cardiovascular disease, age, body mass index, male gender, smoking, or biochemical and hormonal parameters among the three genotypes. Conclusion The present results indicate the absence of direct effects of the ACE D-allele on BP level, prevalence of hypertension, prevalence of cardiovascular disease, and circadian BP variation. We conclude there is little association between ACE I/D polymorphism and hypertension in the general Japanese population.

Cerebral alterations in a MPTP-mouse model of Parkinson’s disease – an immunocytochemical study

Summary. We investigated the immunohistochemical alterations of neuronal nitric oxide synthase (nNOS), endothelial NOS (eNOS), tyrosine hydroxylase (TH), microtuble-associated protein 2a,b (MAP 2), glial fibrillary acidic protein (GFAP), parvalbumin (PV), and dopamine transporter (DAT) in the striatum and substantia nigra following the application of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice. TH-, MAP 2- and DAT-immunoreactive cells were decreased gradually in the striatum and substantia nigra from 1 day up to 7 days after MPTP treatment, as well as the reduction of the striatal dopamine, DOPAC and HVA content. The number of GFAP-immunoreactive astrocytes increased gradually in the striatum and substantia nigra from 1 day up to 7 days after MPTP treatment. Striatal nNOS-immunoreactive cells were unchanged in MPTP-treated mice. In the substantia nigra, intense immunoreactivity of nNOS-positive cells increased 5 hr after MPTP treatment. Thereafter, the immunoreactivity of nNOS-positive cells decreased gradually from 1 day up to 7 days after MPTP treatment. eNOS-immunopositive cells were unchanged in the striatum and substantia nigra. These results demonstrate that nNOS may play a key role in the development of MPTP neurotoxicity. Our findings also indicate that MPTP can cause the functional damage of interneurons in the substantia nigra, but not in the striatum.

Predictive values of automated blood pressure measurement: what can we learn from the Japanese population - the Ohasama study.

BackgroundMeasurements of ambulatory blood pressure (ABP) and of home blood pressure (HBP) as an adjunct to casual/clinic blood pressure (CBP) measurements are currently widely used for the diagnosis and treatment of hypertension. We have monitored a rural cohort of people from the population of Ohasama, Japan, with respect to their prognosis and have previously reported that ABP and HBP are superior to CBP for the prediction of cardiovascular mortality. One reason that CBP is a poor predictor of prognosis is that it incorporates several biases, including the white-coat effect. Methods and resultsWe examined the prognostic significance of white-coat hypertension for mortality and found that the relative hazard for the overall mortality of patients with white-coat hypertension was significantly lower than that for true hypertension. Short-term blood pressure variability has recently attracted attention as a cause of target-organ damage and cardiovascular complications. Our results confirmed that short-term blood pressure variability (as measured every 30 min) was independently associated with cardiovascular mortality. In addition, research has recently focused on isolated systolic hypertension and pulse pressure as independent risk factors for poor cardiovascular prognosis. The Ohasama study also clearly demonstrated that isolated systolic hypertension and increased pulse pressure, as assessed by HBP, were associated with an increase in the risk of cardiovascular mortality. Circadian blood pressure variation is characterized by a diurnal elevation and a nocturnal decline in blood pressure. We therefore compared morbidity from stroke between dippers (subjects who show an ordinal nocturnal dipping of blood pressure) and non-dippers (those with a diminished nocturnal dipping or nocturnal elevation of blood pressure [inverted dippers]) in the Ohasama study. The incidence of stroke increased with an increased length of observation in dippers using antihypertensive medication but not in non-dippers using antihypertensive medication. In contrast, the relative hazard for mortality increased in non-dippers and inverted dippers. These results suggest a cause-and-effect relationship for both dippers and non-dippers. ConclusionThe Ohasama study showed that the level and variability of hypertension as assessed by ABP and HBP are independent predictors of cardiovascular mortality. It also demonstrated an independent association between the prognosis of hypertension and each component of ABP and HBP, indicating the prognostic significance of these blood pressure measurements.

Therapeutic effect of neuronal nitric oxide synthase inhibitor (7-nitroindazole) against MPTP neurotoxicity in mice

Effects of neuronal nitric oxide synthase (nNOS) inhibitor (7-nitroindazole), nonselective NOS inhibitor (NG-nitro-L-arginine methyl ester; L-NAME), and monoamine oxidase inhibitor (pargyline) were studied on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice. The mice received four intraperitoneal injections of MPTP at 1-h intervals. A significant depletion in dopamine and DOPAC concentration was observed in the striatum from 1 day after MPTP treatment. The pretreatment of 7-nitroindazole and pargyline, but not L-NAME, dose-dependently protected against MPTP-induced depletion in dopamine content 3 days after MPTP treatment. Our histochemical study also showed that 7-nitroindazole and pargyline can prevent a marked decrease in the nigral cells and a marked increase in astrocytes in striatum 7 days after MPTP treatment. The protective effect of 7-nitroindazole against MPTP-induced dopamine and DOPAC depletion in the striatum was not attenuated by intraperitoneal pretreatment with L-arginine. Furthermore, the posttreatment of 7-nitroindazole or pargyline protected against MPTP-induced depletion of dopamine content. These results demonstrate that the protective mechanism by which 7-nitroindazole counteracts MPTP neurotoxicity in mice may be due not only to inhibition of nNOS, but also to MAO-B inhibition. Furthermore, our study suggests that the posttreatment of 7-nitroindazole and pargyline can prevent a significant decrease in dopamine levels in the striatum of MPTP-treated mice. These findings have important implications for the therapeutic time window and choice of nNOS or MAO inhibitors in patients with Parkinsons disease.