V ascular endothelial cells play an important role in the regulation of vascular tone through the release of both vasorelaxing and vasoconstricting factors.1 Apart from the release of vasorelaxant factors such as nitric oxide and prostaglandins, endothelial cells relax the vascular smooth muscle cells through the generation of endothelium-dependent hyperpolarization (EDH). With respect to EDH, there is consensus that the activation of the small-and intermediate-conductance of Ca 2+ -activated K + channels (SK Ca and IK Ca ) located on endothelial cells results in the generation of EDH. [2][3][4][5][6][7][8] In rat mesenteric arteries, the electric transmission of EDH to the adjacent smooth muscle cells via myoendothelial gap junctions (MEGJs) plays a central role in EDH-mediated responses. [9][10][11] Several recent studies have suggested that Ca 2+ influx through endothelial transient receptor potential vanilloid 4 channel (TRPV4), a member of the TRP family of nonselective cation channels, plays a crucial role in EDHmediated hyperpolarization via the downstream activation of SK Ca and IK Ca in specific beds. 12,13 Although the mechanisms through which TRPV4 interact with SK Ca /IK Ca are not well understood, recent studies have suggested that, in specific beds, Ca 2+ influx through TRPV4 directly activates nearby IK Ca and SK Ca at the myoendothelial microdomain signaling sites to generate EDH. 12.13 In rat mesenteric arteries, it has been reported that the relative contribution of EDH in the acetylcholine-induced relaxations decreases as the vessel size increases.14 Although some previous studies reported little or no EDH-mediated relaxations in the superior mesenteric arteries of the rat, 15,16 acetylcholine evoked robust and consistent EDH-mediated Abstract-Endothelium-dependent hyperpolarization (EDH)-mediated responses are impaired in hypertension, but the underlying mechanisms have not yet been determined. (TRPV4) is a prerequisite for the activation of SK Ca /IK Ca in endothelial cells in specific beds. Here, we attempted to determine whether the impairment of EDH in hypertension is attributable to the dysfunction of TRPV4 and S/IK Ca , using isolated superior mesenteric arteries of 20-week-old strokeprone spontaneously hypertensive rats (SHRSP) and age-matched Wistar-Kyoto (WKY) rats. In the WKY arteries, EDHmediated responses were reduced by a combination of SK Ca /IK Ca blockers (apamin plus TRAM-34; 1-[(2-chlorophenyl) diphenylmethl]-1H-pyrazole) and by the blockade of TRPV4 with the selective antagonist RN-1734 or HC-067047. In the SHRSP arteries, EDH-mediated hyperpolarization and relaxation were significantly impaired when compared with WKY. GSK1016790A, a selective TRPV4 activator, evoked robust hyperpolarization and relaxation in WKY arteries. In contrast, in SHRSP arteries, the GSK1016790A-evoked hyperpolarization was small and relaxation was absent. Hyperpolarization and relaxation to cyclohexyl-[2-(3,5-dimethyl-pyrazol-1-yl)-6-methyl-pyrimidin-4-yl]-amine, a selective SK Ca activator, we...

BackgroundWe have previously demonstrated that antihypertensive treatment with renin‐angiotensin system inhibitors restores the impaired endothelium‐dependent hyperpolarization (EDH)–mediated responses in spontaneously hypertensive rats (SHRs). Herein, we investigated whether the angiotensin II receptor–neprilysin inhibitor sacubitril/valsartan (LCZ696) would improve reduced EDH‐mediated responses and whether LCZ696 would exert additional effects on endothelium‐dependent and endothelium‐independent vasorelaxation compared with an angiotensin II type 1 receptor blocker alone during hypertension.Methods and Results SHRs were treated for 3 months with either LCZ696 or valsartan, from the age of 8 to 11 months. Age‐matched, untreated SHRs and Wistar‐Kyoto rats served as controls. Membrane potentials and contractile responses were recorded from the isolated superior mesenteric arteries. Acetylcholine‐induced, EDH‐mediated responses were impaired in untreated SHRs compared with Wistar‐Kyoto rats. EDH‐mediated responses were similarly improved in the LCZ696‐ and valsartan‐treated SHRs. No difference was observed in acetylcholine‐induced, nitric oxide‐mediated relaxations among the 4 groups. Endothelium‐independent relaxations in response to a nitric oxide donor, sodium nitroprusside, and those to levcromakalim, an ATP‐sensitive K+‐channel opener, were similar among the 4 groups; however, the sensitivities to levcromakalim were significantly higher in both LCZ696‐ and valsartan‐treated SHRs.Conclusions LCZ696 appears to be as effective as valsartan in improving the impaired EDH‐mediated responses during hypertension. LCZ696 and valsartan exert similar beneficial effects on endothelium‐independent relaxation via enhanced sensitivity of the ATP‐sensitive K+ channel. However, the dual blockade of renin‐angiotensin system and neutral endopeptidase with LCZ696 does not appear to provide additional benefit over valsartan alone on vasomotor function in mesenteric arteries of SHRs.

Guidelines for the management of hypertension have recommended strict control of blood pressure to help prevent cardiovascular disease. The aim of the present study was to evaluate the current status of blood pressure control and trends over the past two decades. Four hundred patients treated for hypertension at Kyushu University Hospital were included in the present study. Blood pressure levels and prescribed antihypertensive drugs were examined in 2011. The average blood pressure was 129/74 mmHg, and the number of prescribed antihypertensive drugs was 2.2. Angiotensin II receptor antagonists, angiotensin-converting enzyme inhibitors, calcium channel blockers, diuretics, alpha-blockers, and beta-blockers were prescribed in 66%, 5%, 78%, 21%, 12%, and 27% of the cases, respectively. Systolic blood pressure was significantly higher, and diastolic blood pressure was significantly lower in patients aged 80 years or older compared with the younger patients (<80 and ≥80 years, 128/75 mmHg and 133/68 mmHg, respectively). The number of prescribed antihypertensive drugs was similar between the two groups. Sixty-five patients were continuously treated for 20 years. The average blood pressure of these patients significantly decreased from 142/87 mmHg in 1991 to 128/71 mmHg in 2011, accompanied with an increase in the number of antihypertensive drugs from 1.6 in 1991 to 2.7 in 2011. These findings suggest that the revised guidelines for the management of hypertension may have contributed to increased awareness and better management of blood pressure levels.

It has been shown that obstructive sleep apnea (OSA) is related to hypertension and cardiovascular disease; however, the prevalence of OSA in general population and the impact of it on blood pressure especially in Japan has not been well determined. We have conducted a screening test for OSA from 2003 to 2011. In addition, a cross-sectional analysis was performed in 2012 to determine the association of OSA and cardiovascular risk factors in Japanese men (18-69 years of age; mean age, 44.4 ± 0.2). The study group consisted of 2208 male employees, and OSA was evaluated by using the 4% oxygen desaturation index and apnea-hypopnea index (AHI). The prevalence of mild-to-moderate (5≤AHI<30) and severe (AHI≥30) OSA in the studied subjects were 7.1%, and 6.1%, respectively. Among the 135 severe OSA subjects, 105 (77.8%) had been treated with continuous positive airway pressure. Both systolic and diastolic blood pressures (DBP) were significantly increased in the subjects with severe OSA compared with those without OSA. These associations in DBP remained observed after adjustment for age, body mass index (BMI), estimated glomerular filtration rate, HbA, current alcohol intake, current smoking habits, and OSA treatment. DBP in severe OSA subjects were significantly increased in 1807 subjects who were not treated for hypertension or OSA. However, the levels of blood pressures were not decreased by OSA treatment. These results suggest that the prevalence of OSA is relatively high in middle-aged Japanese men and that blood pressures were elevated in the subjects with severe OSA.

Many studies have demonstrated that increased carotid intima-media thickness (IMT) is related to future cardiovascular events and is influenced by cardiovascular risk factors such as sex, hypertension, diabetes, and hypercholesterolemia. Although aging is a well-known risk factor for an increase in carotid IMT, few studies have investigated which factors influence carotid IMT in the very elderly. In the present study, we investigated the relationship of pulse pressure (PP), blood pressure (BP), and its variability (six consecutive visits) with carotid IMT among 240 high-risk elderly in whom risk factors were managed clinically (average age was 79 ± 5 years). In the simple correlation, mean systolic BP (SBP) had a positive correlation with IMT and max IMT (P = .012 and P = .045), as did PP (P = .018 and P = .004), but did not diastolic BP or standard deviation of BP and coefficient of variation of BP. In multiple regression analyses, mean SBP and mean PP were each determinants of both IMT and max IMT, when each parameter was added separately to the regression model. We concluded that high SBP and wide PP still have an influence on increased carotid IMT in the very elderly Japanese patients.

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