Lipophilic but not hydrophilic statin functionally inhibit volume-activated chloride channels by inhibiting NADPH oxidase in monocytes.

Volume-activated Cl- channels (VACCs) can be activated by hypotonic solutions and have been identified in many cell types. Here, we investigated the effects of different statins on VACCs in monocytes. Whole-cell patch clamp recordings demonstrated that a hypotonic solution induced 5-nitro-2- (3-phenylpropylamino) benzoic acid (NPPB)- and 4,4'-diisothiocyanatostilbene-2, 2'-disulfonic acid (DIDS)-sensitive VACC currents in human peripheral monocytes and RAW 264.7 cells. The VACC currents were inhibited by the lipophilic statin (simvastatin) but not by the hydrophilic simvastatin acid and pravastatin. A low-molecular-weight superoxide anion scavenger (tiron, 1 mM) and inhibitor of NADPH oxidase (DPI 10 µM) was able to abolish the VACC currents. A hypotonic solution increased the reactive oxygen species (ROS) detected by the fluorescence of dichlorodihydrofluorescein (DCF), which was abolished by tiron and DPI. NPPB, DIDS, and simvastatin but not pravastatin decreased the fluorescence of DCF. Simvastatin could not further decrease VACC currents when pretreated with tiron or DPI, whereas exogenous H2O2 (100 µM), increased the VACC currents and overcame the blockade of VACC currents by simvastatin. Functionally, hypotonic solution increased the TNF-α mRNA expression, which could be decreased by tiron, DPI, NPPB, DIDS and simvastatin but not pravastatin. However, simvastatin could not decrease the TNF-α expression further when pretreatment with tiron, DPI, NPPB or DIDS. We conclude that lipophilic (simvastatin) rather than hydrophilic statin inhibit VACCs and decrease hyposmolality induced inflammation in monocytes by inhibiting NADPH oxidase.

Possible beneficial effect of olmesartan medoxomil on left atrial function in patients with hypertension : noninvasive assessment by acoustic quantification.

BACKGROUND AND OBJECTIVE: Hypertension alters the diastolic properties of the left ventricle and results in deterioration in the structure and function of the left atrium. We aimed to evaluate whether olmesartan medoxomil has an effect on left atrial function in hypertensive patients. METHODS: Fifty hypertensive patients and 20 controls were included in the study. Hypertensive patients were treated with olmesartan medoxomil for 8 weeks. Before and after treatment, study participants were examined by acoustic quantification and tissue Doppler imaging. Left atrial reservoir function was assessed by end-diastolic volume (EDV), end-systolic volume (ESV), reservoir volume (RV) and peak filling rate (PFR). Left atrial booster pump function was assessed by atrial emptying volume (AEV), atrial emptying fraction (AEF) and peak atrial emptying rate (PAER). Left atrial conduit function was assessed by rapid emptying volume (REV), rapid emptying fraction (REF), REV/AEV ratio, and the ratio of peak rapid emptying rate and PAER (PRER/PAER). RESULTS: Atrial RV and PFR were significantly increased in hypertensive subjects (48.30 +/- 19.28 mL vs 34.35 +/- 14.26 mL, p < 0.001; 267.26 +/- 126.52 mL/s vs 206.81 +/- 107.17 mL/s, p < 0.05) compared with controls, while the REV/AEV ratio was decreased in hypertensive patients compared with controls (2.86 +/- 0.85 vs 3.69 +/- 2.13, p < 0.001). After therapy with olmesartan medoxomil, atrial RV (48.30 +/- 19.28 mL vs 40.50 +/- 17.59 mL) and PFR decreased (267.26 +/- 126.52 mL/s vs 220.40 +/- 108.56 mL/s, p < 0.05) and the REV/AEV ratio increased (2.86 +/- 0.85 vs 3.14 +/- 0.43, p < 0.05) in hypertensive patients. CONCLUSION: Our novel findings indicate that left atrial function is impaired in hypertensive patients, and that olmesartan medoxomil can improve left atrial function in this context. Our study also showed that acoustic quantification is useful for non-invasive evaluation of the benefits of treatment on left atrial function.

Cilnidipine improves left-ventricular midwall function independently of blood pressure changes in Chinese patients with hypertension.

Despite normal indices of left-ventricular (LV) chamber function, patients with hypertension are thought to have depressed LV midwall systolic shortening. This study was designed to investigate effects of short-term therapy with cilnidipine on LV midwall fractional shortening (mFS) in Chinese patients with hypertension. Thirty-seven patients with mild to moderate essential hypertension underwent a 2 week placebo run-in period, then received 5-10 mg/day of cilnidipine orally for 8 weeks. At the end of the placebo period and treatment, patients were examined by echocardiogram, measuring and calculating LV ejection fraction (EF), LV endocardial fraction shortening (eFS), and LV mFS. Compared with the normotensive group, the hypertensive group had a significantly higher eFS (P < 0.05) and EF (P < 0.01), both at the end of the placebo period and at 8 weeks; mFS of patients with hypertension was lower at the end of the placebo period (P < 0.05), but at the end of 8 weeks mFS was not different than that of the control group (P = 0.963). After cilnidipine treatment, EF and eFS did not change (P > 0.05); however, absolute mFS and corrected mFS were increased significantly (P < 0.01). Moreover, changes of mFS showed no correlation with changes of blood pressure (P > 0.05). Midwall fractional shortening is more reliable and sensitive than conventional systolic function measures in assessment of systolic function; cilnidipine can improve left-ventricular systolic function (mFS) independently of blood pressure changes in Chinese patients who have hypertension.

Effects of cilnidipine on fibrinolysis in chinese hypertensive patients.

BACKGROUND: Hypertension is an important risk factor for myocardial infarction and stroke. Accumulating data support the association of blood pressure and impairment of fibrinolysis in hypertensive patients. Fibrinolysis plays a pivotal role in atherogenesis, but there are few studies that focus on evaluating the effect of calcium channel antagonists on fibrinolysis in hypertensive patients, and the results are controversial. The aim of this study was therefore to investigate the effects of cilnidipine on fibrinolysis in Chinese hypertensive patients. METHODS: This study was an open-label, paired trial that included 43 patients with mild-to-moderate hypertension. After a 2-week placebo washout period, patients were treated with cilnidipine 5mg daily for 8 weeks. Venous blood was taken before and after treatment between 8am and 9am, after an overnight fast. Plasma tissue plasminogen activator (tPA) antigen and plasminogen activator inhibitor type 1 (PAI-1) antigen were measured by ELISA and plasma angiotensin II was measured by radioimmunoassay. RESULTS: After treatment with cilnidipine for 8 weeks, plasma tPA antigen level increased significantly (from 12.12 +/- 6.77 ng/mL pre-treatment to 16.12 +/- 11.89 ng/mL post-treatment, p < 0.05), and the PAI-1 antigen level remained unaffected. There were no significant changes in plasma angiotensin II. Systolic and diastolic blood pressures were significantly decreased without changes in heart rate. CONCLUSIONS: These data suggest that in hypertensive patients, a population with impaired fibrinolysis, cilnidipine may improve the fibrinolytic balance, and that cilnidipine is effective in treating hypertension without causing reflex tachycardia.