Hidemi Nonaka

Alterations of Circadian Expressions of Clock Genes in Dahl Salt-Sensitive Rats Fed a High-Salt Diet

Abstract—In mammals, behavioral and physiologic processes display 24-hour rhythms that are regulated by a circadian system consisting of central and peripheral oscillators. Because various cardiovascular functions show diurnal variations and abnormal patterns of circadian blood pressure variation carry a high risk of cardiovascular complications, we investigated whether the expression of clock genes is altered in an animal model of hypertension. In Dahl salt-sensitive rats fed a high-salt (4% NaCl) diet for 6 weeks (DS-H), radiotelemetry monitoring showed increased amplitude of circadian variations in blood pressure. The ratio of heart weight to body weight and the ratio of kidney weight to body weight were higher in DS-H. Echocardiographic data showed that the wall thickness of the left ventricle was greater in DS-H. Northern blot analysis and single cosinor analysis revealed that the amplitudes of circadian expression changes of the clock genes (mPer2, Bmal1, and dbp) in the heart, liver, and kidney were significantly decreased in DS-H rats compared with a normal-salt-diet group, except for Bmal1 in the liver. The circadian expression changes of plasminogen activator inhibitor-1, a clock-regulated gene, were attenuated in the hearts of DS-H. The present results demonstrate that DS-H show altered circadian expression of peripheral clock genes. Detailed analyses of the relation between circadian expression of clock genes and blood pressure regulation might reveal a role for chronologic therapy of cardiovascular disease.

Vascular endothelial cell-derived endothelin-1 mediates vascular inflammation and neointima formation following blood flow cessation

AIMS Although endothelin-1 (ET-1) has been suggested to contribute to the pathogenesis of neointima formation and atherosclerosis, the individual roles of ET-1 derived from certain cell types in this disease remain unclear. In this study, we determined the role of vascular endothelial ET-1 on vascular inflammation and neointima formation using vascular endothelial ET-1-knockout [ET-1(f/f); Tie2-Cre (+)] mice. METHODS AND RESULTS Intimal hyperplasia was induced by complete ligation of the left carotid artery in 12-week-old male ET-1(f/f);Tie2-Cre (+) mice (n = 35) and the wild-type (WT) littermates (n = 34). Following this intervention, neointima formation was reduced in ET-1(f/f);Tie2-Cre (+) mice compared with the WT mice, independent of the difference in blood pressure. This reduction was associated with a decrease in inflammatory cell recruitment to the vessel wall, which was accompanied by reduced expression levels of endothelial adhesion molecules as well as chemokines and a decrease in vascular smooth muscle cell proliferation. CONCLUSION The results of our study provide direct evidence for the role of vascular endothelial ET-1 in mediating vascular inflammation and neointima formation following vascular injury in addition to promoting vasoconstriction and cell proliferation. Furthermore, this study suggests a strategy for the efficient design of ET receptor antagonists with targeted inhibition of ET-1 signalling in vascular endothelial cells.

Oral taurine supplementation prevents fructose-induced hypertension in rats

Taurine is known to have antihypertensive and lipid-lowering effects in some experimental models and patients. On the other hand, intracellular free calcium and magnesium play important roles in regulating the tonus of blood vessels and insulin sensitivity. We examined the effect of oral taurine supplementation on blood pressure, serum metabolic parameters, and platelet cytosolic free calcium ([Ca2+]i) and magnesium ([Mg2+]i) concentration in fructose-fed Sprague-Dawley rats. Systolic blood pressure and platelet [Ca2+]i were significantly higher in rats fed a 60% fructose diet. Oral taurine supplementation (1% in drinking water) completely prevented the elevation of blood pressure and an increase in platelet [Ca2+]i, but exacerbated hyperinsulinemia, hypertriglyceridemia, and a decrease in platelet [Mg2+]i. In conclusion, taurine may ameliorate fructose-induced hypertension in rats by preventing an increase in intracellular free calcium concentration. The blood pressure-lowering effect of taurine appeared to be independent from its effect on glucose and lipid metabolism in this model.

Comparison of medium-dose losartan/hydrochlorothiazide and maximal-dose angiotensin II receptor blockers in the treatment of Japanese patients with uncontrolled hypertension: the Kobe-CONNECT Study.

The objective of this study is to examine the effects of thiazide diuretics, plus medium-dose losartan versus maximal-dose angiotensin II receptor blockers (ARBs) on blood pressure (BP) in Japanese patients with uncontrolled hypertension despite the use of medium-dose ARBs. Hypertensive patients in whom BP was inadequately controlled by treatment with medium-dose ARBs alone or with calcium-channel blockers were enrolled. Patients were randomly assigned to a fixed-dose combination of 50 mg per day losartan and 12.5 mg per day hydrochlorothiazide (HCTZ; n=98), or to a maximal dose of current ARBs (n=95). The reduction in office BP from baseline was significantly larger in the losartan/HCTZ group than in the maximal-dose ARB group (systolic BP −22.7±13.7 vs. −11.7±13.0 mm Hg, diastolic BP −9.6±10.9 vs. −4.5±11.0 mm Hg; P<0.01, respectively). The proportion of patients in whom the therapeutic target BP was achieved was greater in the losartan/HCTZ group than in the maximal-dose ARB group (59.2 vs. 26.3%; P<0.001). Both early-morning and evening BP were controlled more effectively over 1 year of treatment in the losartan/HCTZ group than in the maximal-dose ARB group (the mean BP difference between the groups, early-morning: 5.6 mm Hg (P=0.001), evening: 3.8 mm Hg (P=0.049)). Adverse changes in serum potassium and uric acid were observed in the losartan/HCTZ group; however, both changes were very slight, and the values were still within the normal range. The concomitant usage of losartan and HCTZ had no influence on glucose metabolism and lipid profiles. Declines in plasma N-terminal pro-brain natriuretic peptide levels and urinary albumin excretion were observed in the losartan/HCTZ group, but not in the maximal-dose ARB group. Switching from medium-dose ARBs to losartan plus HCTZ reduced both office and home BP efficiently in patients with uncontrolled hypertension.

High Salt Intake Elevated Blood Pressure but not Changed Circadian Blood Pressure Rhythm in Otsuka Long-Evans Tokushima Fatty (OLETF) Rat

We examined the effect of high salt intake on mean arterial pressure and circadian blood pressure rhythm in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model of type II diabetes mellitus. Mean arterial pressure, fasting blood glucose, and fasting plasma insulin in OLETF rats were higher than those in LETO rats, their normoglycemic controls. The amplitude of circadian blood pressure rhythm in LETO rats was smaller than that in OLETF rats. High salt intake elevated blood pressure and exacerbated hyperinsulinemia, but did not change the circadian blood pressure rhythm in OLETF rats.