-
Tatsuo Shimosawa,
Tomoyo Kaneko,
Xu Qingyou,
Yusei Miyamoto,
Mu Shengyu,
Hong Wang,
Sayoko Ogura,
Rika Jimbo,
Bohumil Majtan, Yuzaburo Uetake,
Daigoro Hirohama,
Fumiko Kawakami-Mori,
Toshiro Fujita,
Yutaka Yatomi
04/2012; , ISBN: 978-953-51-0552-7
-
ShengYu Mu,
Tatsuo Shimosawa,
Sayoko Ogura,
Hong Wang, Yuzaburo Uetake,
Fumiko Kawakami-Mori,
Takeshi Marumo,
Yutaka Yatomi,
David S Geller,
Hirotoshi Tanaka,
Toshiro Fujita
[show abstract]
[hide abstract]
ABSTRACT: How high salt intake increases blood pressure is a key question in the study of hypertension. Salt intake induces increased renal sympathetic activity resulting in sodium retention. However, the mechanisms underlying the sympathetic control of renal sodium excretion remain unclear. In this study, we found that β(2)-adrenergic receptor (β(2)AR) stimulation led to decreased transcription of the gene encoding WNK4, a regulator of sodium reabsorption. β(2)AR stimulation resulted in cyclic AMP-dependent inhibition of histone deacetylase-8 (HDAC8) activity and increased histone acetylation, leading to binding of the glucocorticoid receptor to a negative glucocorticoid-responsive element in the promoter region. In rat models of salt-sensitive hypertension and sympathetic overactivity, salt loading suppressed renal WNK4 expression, activated the Na(+)-Cl(-) cotransporter and induced salt-dependent hypertension. These findings implicate the epigenetic modulation of WNK4 transcription in the development of salt-sensitive hypertension. The renal β(2)AR-WNK4 pathway may be a therapeutic target for salt-sensitive hypertension.
Nature medicine 05/2011; 17(5):573-80. · 27.14 Impact Factor
-
Shengyu Mu,
Tatsuo Shimosawa,
Sayoko Ogura,
Hong Wang, Yuzaburo Uetake,
Fumiko Kawakami-Mori,
Takeshi Marumo,
Yutaka Yatomi,
David S Geller,
Hirotoshi Tanaka,
Toshiro Fujita
Nature medicine 01/2011; 17(8):1220. · 27.14 Impact Factor
-
Nippon rinsho. Japanese journal of clinical medicine 01/2011; 69 Suppl 1:197-200.
-
[show abstract]
[hide abstract]
ABSTRACT: Salt status plays a pivotal role in angiotensin-II-induced organ damage by regulating reactive oxygen species status, and it is reported that reactive oxygen species activate mineralocorticoid receptors.
To clarify the role of reactive oxygen species-related mineralocorticoid receptor activation in angiotensin-II-induced cardiac dysfunction, we examined the effect of the following: salt status; an MR antagonist, eplerenone; and an antioxidant, tempol in angiotensin-II-loaded Sprague-Dawley rats.
Angiotensin-II/salt-loading elevated blood pressure, and neither eplerenone nor tempol antagonized the rise in blood pressure significantly. Left ventricular diastolic function was monitored by measuring peak velocity of a mitral early inflow (E), the ratio of mitral early inflow to atrial contraction related flow (E/A), deceleration time of mitral early inflow and -dP/dt, the time constant (T), and filling pressure (left ventricular end-diastolic pressure) by echocardiography or cardiac catheterization. Despite the suppressed serum aldosterone, left ventricular diastolic function was deteriorated with angiotensin II/high salt, but not affected by angiotensin II/low salt. However, angiotensin-II/salt-induced cardiac dysfunction was restored by eplerenone and tempol. Nicotinamide adenine dinucleotide phosphateoxidase-derived superoxide formation was greater in the hearts of the angiotensin II/high-salt rats than of the angiotensin II/low-salt rats. The expression of the Na(+) -H(+) exchanger isoform 1, a target of mineralocorticoid receptor activation, was significantly increased in the angiotensin II/high-salt group. Both tempol and eplerenone inhibited the angiotensin-II/salt-induced upregulation of Na(+) -H(+) exchanger isoform 1.
These findings demonstrate that mineralocorticoid receptor activation by oxidative stress can cause left ventricular diastolic dysfunction in a rat model of mild hypertension.
Journal of Hypertension 08/2008; 26(7):1453-62. · 4.02 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Potassium supplementation has a potent protective effect against cardiovascular disease, but the precise mechanism of it against left ventricular abnormal relaxation, relatively early functional cardiac alteration in hypertensive subjects, has not been fully elucidated. In the present study, we investigated the effect of potassium against salt-induced cardiac dysfunction and the involved mechanism. Seven- to 8-week-old Dahl salt sensitive rats were fed normal diet (0.3% NaCl) or high-salt diet (8% NaCl) with or without high potassium (8% KCl) for 8 weeks. Left ventricular relaxation was evaluated by the deceleration time of early diastolic filling obtained from Doppler transmitral inflow, the slope of the pressure curve, and the time constant at the isovolumic relaxation phase. High-salt loading induced a significant elevation of blood pressure and impaired left ventricular relaxation, accompanied by augmentation of reduced nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase activity in the cardiac tissue, measured by the lucigenin chemiluminescence method. Blood pressure lowering by hydralazine could not ameliorate NADPH oxidase activity and resulted in no improvement of left ventricular relaxation. Interestingly, although the blood pressure remained high, potassium supplementation as well as treatment with 4-hydroxy-2,2,6,6-tetramethyl-piperidine-N-oxyl, a superoxide dismutase mimetic, not only reduced the elevated NADPH oxidase activity but also improved the left ventricular relaxation. In conclusion, a high-potassium diet has a potent protective effect on left ventricular active relaxation independent of blood pressure, partly through the inhibition of cardiac NADPH oxidase activity. Sufficient potassium supplementation might be an attractive strategy for cardiac protection, especially in the salt-sensitive hypertensive subjects.
Hypertension 09/2006; 48(2):225-31. · 6.21 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The antiatherosclerotic effects of a calcium channel blockers have been attracting attention for some time. It is shown by the animal studies that especially dihydropyridine calcium channel blockers have the antiatherosclerotic effects by an anti-oxidative properties and the direct action on vascular cells in addition to an original decrease blood pressure, and the validity is being further proved by the results of randomized clinical trials such as PREVENT and CAMELOT.
Clinical calcium 11/2005; 15(10):1689-94.
-
[show abstract]
[hide abstract]
ABSTRACT: To assess the relationship between home blood pressure and left ventricular mass, we evaluated cardiac echocardiography in 297 hypertensive subjects (188 men and 109 women; mean age, 62.8+/-10.3 years) who were treated with amlodipine monotherapy over 1 year (mean dose, 5.5+/-2.3 mg/day). The morning hypertension group (n=57; 19.2%), who had a morning home systolic blood pressure (HSBP) > or =135 mmHg and an evening HSBP <135 mmHg, had a significantly greater left ventricular mass index (LVMI) concomitant with an increase in the homeostasis model assessment insulin resistance index (HOMA-IR) compared to the good control group (n=174; 58.6%), whose morning and evening HSBP were both <135 mmHg, and had a LVMI roughly equivalent to that of the poor control group (n=63; 21.2%), whose morning and evening HSBP were both > or =135 mmHg. By grouping of subjects according to the difference between morning and evening HSBP (delta HSBP), subjects with a delta HSBP> or =10 mmHg had a significantly greater LVMI than subjects with a delta HSBP <10 mmHg. Increases in LVMI in these patients were still significant after adjustment for age, gender, dose of amlodipine, alcohol consumption, body mass index, office systolic blood pressure, and morning and evening HSBP. In a stepwise multivariate regression analysis, delta HSBP (r2=36.2%, p <0.001), morning HSBP (r2=5.5%, p <0.001), HOMA-IR (r2=1.4%, p=0.016) and age (r2=1.0%, p=0.026) were determined to be significant contributing factors for LVMI. This regression model could explain 44.1% of LVMI variability. These results suggest that morning rise in blood pressure is a dominant predictor of left ventricular hypertrophy.
Hypertension Research 01/2005; 27(12):939-46. · 2.58 Impact Factor
