[Sleep apnea and hypertension].

Obstructive sleep apnea (OSA) is strongly associated with hypertension. The seventh report of the joint national committee (JNC-VII) guidelines have placed OSA at the top of the list to induce secondary hypertension. Severe OSA patients revealed the high prevalence of hypertension. Compared with normal subjects, patients with OSA had a higher 24-hour blood pressure, especially nighttime blood pressure. More recently, prospective data showed that sleep apnea syndrome was an independent risk for onset of hypertension. There is a lot of evidence that demonstrates that treating OSA using continuous positive airway pressure (CPAP) is an effective for management of OSA.

Relationship between chronic kidney disease and sleep blood pressure in patients with sleep apnea syndrome.

Chronic kidney disease (CKD) is common disease in patients with sleep apnea syndrome (SAS), which is considered to be responsible for secondary and nocturnal hypertension. In this study, we assessed blood pressure (BP) changes in SAS patients with CKD. Of 460 Japanese outpatients with suspected SAS who underwent ambulatory BP monitoring within 3 months of overnight polysomnography, 198 patients (172 males and 26 females) who were not receiving treatment with antihypertensives or nitroglycerin were enrolled. The estimated glomerular filtration rate (eGFR) was calculated, and the patients were stratified into the high (H; eGFR≥60 ml min⁻¹ per 1.73 m²) or the low (L; eGFR<60 ml min⁻¹ per 1.73 m²) group. The patients in the L group were significantly older than those in the H group (P<0.001), and body mass index was significantly smaller in the L group than in the H group (P=0.025). The rate of patients treated with statin (P=0.030) and the levels of both triglyceride (P=0.006) and creatinine (P<0.001) differed significantly between the two groups. The sleep data, 24-h BP, awake BP and morning BP showed no significant differences between the two groups. However, sleep systolic and diastolic BPs were significantly higher in the L group (122.5±16.7 mm Hg and 81.1±12.2 mm Hg, respectively) than in the H group (117.1±11.8 mm Hg, P=0.033; and 76.1±9.5 mm Hg, P=0.012, respectively). SAS patients with CKD had elevated sleep BP. This result suggests that appropriate treatments for both SAS and CKD prevent sleep BP elevation, which is considered a risk factor for the onset risk of a cardiovascular event.

Imaging of structural changes in endothelial cells and thrombus formation at the site of FeCl(3)-induced injuries in mice cremasteric arteries.

AIM: We investigated thrombus formation at the site of functional injury to endothelial cells by FeCl(3). METHODS: After preparation of cremasteric arteries of mice, controlled endothelial injury was induced by application of FeCl(3). Endothelial cells were rendered fluorescent by addition of FITC (fluorescein isothiocyanate)-labeled isolectin B4. Circulating platelets and leukocytes were made fluorescent by rhodamine 6G. Three-dimensional (3D) growth of thrombi was visualized in real time. Effects of aspirin and clopidogrel pre-treatments on the growth of thrombi were investigated in vivo as well as in an ex vivo flow chamber system. RESULTS: Endothelial cells were tightly bound to each other to protect local thrombus formation. Platelets started to adhere to endothelial cells when FeCl(3) was applied. Three-dimensional growth of thrombi, which takes 10.6+/-7.5 minutes for complete occlusion in control, can be visualized with our imaging system. Aspirin pre-treatment at the dose tested did not influence either endothelial injury or platelet thrombus growth, while clopidogrel pretreatment significantly inhibited 3D growth and prolonged occlusion time up to 64.6+/-25.3 minutes (100 mg/kg). A similar inhibiting effect of clopidogrel was reproduced in ex vivo flow chamber experiments. CONCLUSIONS: We have developed an in vivo system to detect thrombus formation after functional damage to the endothelium.

Nicorandil attenuates FeCl(3)-induced thrombus formation through the inhibition of reactive oxygen species production.

BACKGROUND: Although nicorandil has a number of beneficial cardiovascular actions, its effects on endothelial cells in the context of thrombosis have not been elucidated. METHODS AND RESULTS: Arterial thrombosis was induced by endothelial injury caused by FeCl(3) in the mouse testicular artery. Thrombus growth led to complete occlusion 12 min after endothelial injury in control mice. The antiplatelet agent, tirofiban, and nicorandil significantly slowed the growth of thrombi, resulting in arterial occlusion after 58 min and 55 min, respectively. In the absence of endothelial cells, nicorandil did not inhibit platelet aggregation. Diazoxide and high-dose isosorbide dinitrate both showed a similar effect to that of nicorandil. The beneficial effect of nicorandil was prevented by 5-hydroxydecanoate, but not by L-NAME. The production of reactive oxygen species by FeCl(3) treatment was measured with the specific fluorescent probe, dihydrorhodamine 123. After FeCl(3) treatment, nicorandil significantly inhibited the increase in fluorescence. In further experiments, incubation of human umbilical vein endothelial cells with nicorandil did not change the endothelial nitric oxide synthase (eNOS) mRNA levels, eNOS phosphorylation or nitrite production. CONCLUSIONS: Nicorandil attenuates FeCl(3)-induced thrombus formation in the mouse testicular artery, which suggests that it may inhibit the generation of reactive oxygen species by FeCl(3)-treated endothelial cells through activation of the mitochondrial ATP-sensitive potassium channels.

Important regulatory role of activated platelet-derived procoagulant activity in the propagation of thrombi formed under arterial blood flow conditions.

BACKGROUND: The functional links between the activation of platelets and the coagulation system have not been clarified. METHODS AND RESULTS: Immobilized collagen fibrils were perfused with human blood containing fluoresceinated platelets in the presence of various concentrations of thrombin inhibitor. Coagulant activity around platelet thrombi was detected using a FITC-conjugated antibody against the fibrin monomer complex (F-405). Intra-cytosolic calcium ion concentrations ([Ca(2+)](i)) in individual platelets and the volume of thrombi were detected with an ultrafast confocal laser microscope equipped with a piezo-motor control unit. The volume of platelet thrombi formed after 8 min of blood perfusion in the presence of 10, 25, 50, and 100 micromol/L argatroban was 7.69+/-0.46 microm(3), 6.61+/-1.96 microm(3), 3.63+/-1.54 microm(3), and 1.67+/-0.75 microm(3), respectively. There was a positive correlation between the volume of platelet thrombi and the amount of fibrin monomer complex produced around them. The [Ca(2+)](i) of the platelets forming the thrombi oscillated between a minimum of 92.0+/-57.4 nmol/L, 120.1+/-68.1 nmol/L, and a maximum of 217.6+/-131.5 nmol/L, 367.6+/-189.1 nmol/L, respectively, in the presence of 100 and 10 mumol/L argatroban. CONCLUSIONS: The results suggest a crucial role of coagulant activity in both the generation of fibrin and the growth of platelet thrombi.

Validation of the Friedewald Equation for Evaluation of Plasma LDL-Cholesterol.

In most clinical laboratories, low density lipoprotein (LDL) cholesterol is usually estimated indirectly with the Friedewald equation or directly with the N-geneous assay. We assessed LDL-cholesterol values obtained by both methods to find an appropriate fasting period and to assess the influence of the energy content of the last meal. Blood samples were taken from 28 healthy volunteers who had consumed a standard meal (107 g of carbohydrate, 658 kcal) followed by a fasting period of 12 and 18 h, or a high-energy meal (190 g of carbohydrate, 1011 kcal) with a fasting period of 12 h. Prolongation of the fasting period from 12 h to 18 h decreased glucose level, but did not decrease triacylglycerol, total cholesterol, or high density lipoprotein (HDL) cholesterol. LDL-cholesterol levels measured with the N-geneous assay did not change (94.0 +/- 21.5 to 96.3 +/- 19.1 mg/dl). LDL-cholesterol levels calculated with the Friedewald equation were also similar after fasting periods of 12 h (98.5 +/- 21.4 mg/dl) and 18 h (99.7 +/- 20.2 mg/dl). The high-energy meal did not change the level of LDL-cholesterol measured with the N-geneous assay (96.1 +/- 21.2 mg/dl), or the glucose, triacylglycerol, total cholesterol, or HDL-cholesterol level, but LDL-cholesterol levels evaluated from the Friedewald equation (92.6 +/- 20.3 mg/dl) became significantly lower. A fasting time longer than 12 h is not necessary to obtain reasonable blood lipid levels. The Friedewald equation gave higher LDL-cholesterol levels than N-geneous assay in young Japanese females who had eaten a low-energy meal, and lower values when they had eaten a high-energy meal. Thus, it may be necessary to pay attention to energy of nigh meal prior to blood withdrawal.

Na+/H+ exchanger inhibitor cariporide attenuates the mitochondrial Ca2+ overload and PTP opening.

The Na(+)/H(+) exchanger (NHE) inhibitor cariporide has a cardioprotective effect in various animal models of myocardial ischemia-reperfusion. Recent studies have suggested that cariporide interacts with mitochondrial Ca(2+) overload and the mitochondrial permeability transition (MPT); however, the precise mechanisms remain unclear. Therefore, we examined whether cariporide affects mitochondrial Ca(2+) overload and MPT. Isolated adult rat ventricular myocytes were used to study the effects of cariporide on hypercontracture induced by ouabain or phenylarsine oxide (PAO). Mitochondrial Ca(2+) concentration ([Ca(2+)](m)) and the mitochondrial membrane potential (DeltaPsi(m)) were measured by loading myocytes with rhod-2 and JC-1, respectively. We also examined the effect of cariporide on the MPT using tetramethylrhodamine methyl ester (TMRM) and oxidative stress generated by laser illumination. Cariporide (1 microM) prevented ouabain-induced hypercontracture (from 40 +/- 2 to 24 +/- 2%, P < 0.05) and significantly attenuated ouabain-induced [Ca(2+)](m) overload (from 149 +/- 6 to 121 +/- 5% of the baseline value, P < 0.05) but did not affect DeltaPsi(m). These results indicate that cariporide attenuates the [Ca(2+)](m) overload without the accompanying depolarization of DeltaPsi(m). Moreover, cariporide increased the time taken to induce the MPT (from 79 +/- 11 to 137 +/- 20 s, P < 0.05) and also attenuated PAO-induced hypercontracture (from 59 +/- 3 to 50 +/- 4%, P < 0.05). Our data indicate that cariporide attenuates [Ca(2+)](m) overload and MPT. Thus these effects might potentially contribute to the mechanisms of cardioprotection afforded by NHE inhibitors.