Increased endothelin receptor B and G protein coupled kinase-2 in the mesentery of portal hypertensive rats

AIM: To elucidate the mechanisms of mesenteric vasodilation in portal hypertension (PHT), with a focus on endothelin signaling. METHODS: PHT was induced in rats by common bile duct ligation (CBDL). Portal pressure (PP) was measured directly via catheters placed in the portal vein tract. The level of endothelin-1 (ET-1) in the mesenteric circulation was determined by radioimmunoassay, and the expression of the endothelin A receptor (ETAR) and endothelin B receptor (ETBR) was assessed by immunofluorescence and Western blot. Additionally, expression of G protein coupled kinase-2 (GRK2) and β-arrestin 2, which influence endothelin receptor sensitivity, were also studied by Western blot. RESULTS: PP of CBDL rats increased significantly (11.89 ± 1.38 mmHg vs 16.34 ± 1.63 mmHg). ET-1 expression decreased in the mesenteric circulation 2 and 4 wk after CBDL. ET-1 levels in the systemic circulation of CBDL rats were increased at 2 wk and decreased at 4 wk. There was no change in ETAR expression in response to CBDL; however, increased expression of ETBR in the endothelial cells of mesenteric arterioles and capillaries was observed. In sham-operated rats, ETBR was mainly expressed in the CD31+ endothelial cells of the arterioles. With development of PHT, in addition to the endothelial cells, ETBR expression was noticeably detectable in the SMA+ smooth muscle cells of arterioles and in the CD31+ capillaries. Following CBDL, increased expression of GRK2 was also found in mesenteric tissue, though there was no change in the level of β-arrestin 2. CONCLUSION: Decreased levels of ET-1 and increased ETBR expression in the mesenteric circulation following CBDL in rats may underlie mesenteric vasodilation in individuals with PHT. Mechanistically, increased GRK2 expression may lead to desensitization of ETAR, as well as other vasoconstrictors, promoting this vasodilatory effect.     

杓型和非杓型高血压病患者动脉重构的改变

目的通过比较杓型与非杓型原发性高血压患者动脉重构的参数变化，探讨原发性高血压患者血压节律类型与动脉重构的相关性。方法选取1、2级原发性高血压患者128例，行动态血压监测，根据夜间平均动脉压下降10％以上或以下的标准分为杓型组（56例）与非杓型组（72例），应用彩色多普勒超声检测颈总动脉内膜中层厚度（IMT）、脉搏波速度测定仪同时检测颈动脉-桡动脉（C-RPWV）、颈动脉-股动脉（C-FPWV）的脉搏波速度，测定血清中内皮素1（ET-1）和一氧化氮（N0）浓度。比较两组间上述检测指标。结果非杓型组IMT较杓型组明显增厚；C-RPWV和C-FPWV在非杓型组明显高于杓型组；血清ET-1浓度在非杓型组明显高于杓型组，而NO浓度低于杓型组，两因子在两组间比较具有统计学差异。结论非杓型血压较杓型血压对动脉结构及功能的影响可能更明显。     

Hypertension and arterial stiffness: the atherosclerosis risk in communities study

Our objective was to describe the relationship of arterial stiffness and hypertension in a large, population-based sample of men and women. Hypertension-related increases in arterial stiffness may reflect the distending pressure and/or structural alterations in the artery. Included were 10,712 participants, ages 45 to 64 years, of the Atherosclerosis Risk in Communities Study, free of prevalent cardiovascular disease. Hypertension was classified as systolic or diastolic blood pressure (BP) ≥140/90 mm Hg, respectively, or the current use of antihypertensive medications. Common carotid arterial diameter change was measured using B-mode ultrasound and an electronic device that utilized radio frequency signals to track the motion of the arterial walls.Using statistical models to control for diastolic BP and pulse pressure, arterial diameter change was calculated separately in normotensive/nonmedicated and medicated hypertensives. Hypertension was associated with a smaller adjusted diameter change (ie, greater stiffness) in comparison to optimal blood pressure (BP < 120/80 mm Hg): normotensive/nonmedicated men, 0.33 versus 0.43 mm (P < 0.001); medicated men, 0.34 versus 0.42 mm (P < 0.001); normotensive/ nonmedicated women, 0.34 versus 0.40 mm (P < 0.001), and medicated women, 0.33 versus 0.40 mm (P < 0.001). The relationship between pulse pressure and diameter change (ie, the slope of pulse pressure and diameter change) did not differ between hypertensives and normotensives.These cross-sectional data suggest that hypertension is associated with carotid arterial stiffness; however, these differences in the calculated stiffness appear to be the effect of distending pressure rather than structural changes in the carotid artery.     

Endothelin-1 released by vascular smooth muscle cells enhances vascular responsiveness of rat mesenteric arterial bed exposed to high perfusion flow

Vasodilation of resistance vessels ensues in response to increased perfusion flow to maintain tissue perfusion. The flow-induced vasodilation is mainly dependent on nitric oxide (NO), which also regulates vascular responsiveness to vasoconstrictors. Besides NO, however, high flow increases endothelin-1 (ET-1) production from endothelial cells. It is likely, therefore, that the interaction between NO and ET-1 may play a critical role in the control of arterial vascular tone under high perfusion flow.In this study, the vascular responsiveness (VR) to high flow rate and the role of ET-1 released by vascular smooth muscle cells (VSMC) were evaluated in isolated and in vitro-perfused mesenteric arteries (MA). MA were perfused at constant (3.5 mL/min; CPF) and increased flow rate (4.5, 5.5, 6.5 mL/min; IPF). VR was evaluated by infusing norepinephrine (NE; 5 μmol/L) and potassium chloride (KCl; 80 mmol/L). Mesenteric vascular resistance (MVR), ET-1, and cGMP release were measured under different flow rates. The role of endothelium-derived ET-1 was evaluated by perfusing MA with phosphoramidon (endothelin converting enzyme inhibitor), whereas the role of other endothelium-derived vasoactive substances was excluded by measuring VR in MA without endothelium. Finally, ETA and ETB receptor antagonists were perfused in disendothelized MA. In the IPF group of intact MA, MVR dropped (P < .05) and both ET-1 and cGMP increased in the perfusate (P < .05). VR was enhanced by high flow after NE (101 ± 9 v 56 ± 12 mm Hg in CPF, P < .005) and KCl (119 ± 12 v 51 ± 10 mm Hg in CPF, P < .005) and it was unaffected by either phosphoramidon or endothelium removal. On the contrary, BQ-610 abolished the flow-dependent increase in VR. No further additive effect was achieved with BQ-788. In conclusion, in MA, high flow reduces MVR and concurrently enhances VR, likely through VSMC-derived ET-1.     

Molecular variations in the calcium-sensing receptor in relation to sodium balance and presence of hypertension in blacks and whites

Sodium (Na) excretion is to an extent tied to calcium (Ca) excretion; increases in Ca result in increased Na excretion. We hypothesized that molecular variation in the calcium-sensing receptor (CaSR), which imparts certain of the influences of extracellular Ca, might be related to differences in Na balance and blood pressure. We further hypothesized that such an influence by CaSR is more pronounced in blacks than in whites, as the hypertension in blacks appears to be more dependent on Na retention. Three common molecular variants in CaSR were studied. Two were more frequent in the whites (A986S, P < .0001, and G990R, P = .093), whereas Q1011E was more frequent in the blacks (P < .0001). Two distinctly separate groups were studied: (1) healthy schoolchildren in whom levels of the renin-aldosterone axis and blood pressure were measured, and (2) normotensive and hypertensive adults. Studies of association were made separately in the whites and the blacks. No association of any of the variants with Na balance (as estimated from renin and aldosterone levels) was observed. In the black schoolchildren, Q1011E showed a marginal association with a higher blood pressure (P = .093 for systolic and P = .025 for diastolic), a relationship that was considered to be nonsignificant after adjusting for multiple comparisons. Nor was there a significant association of the variants with presence or absence of hypertension. In summary, studies of two cohorts that included whites and blacks did not suggest that molecular variations in the CaSR influence either Na balance or blood pressure.     

Effects of endothelin-1 and endothelin-1 receptor blockade on cardiac output,aortic pressure,and pulse wave velocity in humans

Endothelin-1 (ET-1) is a potent vasoconstrictor. Its effect on arterial wave reflections and central pressure augmentation is unknown. We studied whether ET-1, in plasma concentrations present in disease, increases pulse wave velocity (PWV) and augmentation index (AIx) and therefore compromises cardiac output, and whether the ET-1 receptor blocker VML-588 (previously AXV-034343 and Ro 61-1790) prevents such effects. Nine healthy men received a 2-hour infusion with ET-1 (2.5 ng x kg(-1) x min(-1)) superimposed on vehicle or VML-588 (0.05, 0.20, or 0.40 mg x kg(-1) x h(-1)) (randomized order). Arterial tonometry and pulse wave contour analysis were used to assess aortic PWV and central aortic pressures and impedance cardiography for cardiac output. ET-1 slightly increased mean arterial pressure and peripheral resistance but had no significant effect on systolic blood pressure and pulse pressure. PWV increased from 5.4+/-0.2 to 5.7+/-0.3 m/s (P<0.05), AIx from 9.9+/-3.3 to 17.2+/-3.8 (P<0.05), central systolic blood pressure by 8.7+/-1.7 mm Hg (P<0.05), and central pulse pressure by 5.1+/-1.9 mm Hg (P<0.05). This was associated with a fall in cardiac output by approximately 18% (P<0.05). VML-588 caused a slight decrease in brachial mean arterial pressure, PWV, and AIx, and prevented the effects of ET-1 on central hemodynamics without a clear dose-response effect. In summary, ET-1 in plasma concentrations as found in renal failure and heart failure accelerates PWV, causes a disproportionate increase in central aortic systolic blood pressure and pulse pressure, and decreases cardiac output. These effects can be prevented with an ET-1 receptor blocker such as VML-588. This makes it worthwhile to focus on endothelin as a target to prevent ventricular hypertrophy and to maintain cardiac function in diseases associated with high ET-1.     

Association of three polymorphisms in the gene coding for endothelin-1 with essential hypertension,overweight and smoking

OBJECTIVE:

To evaluate the association of three endothelin-1 (ET-1) gene polymorphisms with essential hypertension, as well as with two cardiovascular risk factors: body mass index (BMI) and smoking.

DESIGN:

Three gene polymorphisms and the genotype and allelic distributions were compared between normotensive healthy volunteers and patients with essential hypertension. The genetic association of the three genotypes with BMI and smoking status was calculated.

PATIENTS AND METHODS:

CA/CT dinucleotide repeat polymorphism, G(8002)A polymorphism and −3A/−4A polymorphism (−138 insertion/deletion) were examined in the gene coding for ET-1 (6p21.3) in 398 subjects: 192 normotensives (healthy volunteers) and 206 patients with essential hypertension. Normotension was verified by 24 h ambulatory blood pressure monitoring.

RESULTS:

Significant inner associations were observed between all three polymorphisms, which suggests possible complex interactions inside the gene. The only significant difference in a single gene case control study was in the lengths of allelic variants of CA/CT dinucleotide repeat polymorphism. In hypertensive patients, the alleles of G(8002)A and −3A/−4A ET-1 polymorphisms were found to be significantly associated (G with −3A and A with −4A). None of the ET-1 gene polymorphisms was associated with BMI. A highly significant increase of the −3A allele of the −3A/−4A ET-1 polymorphism was found in hypertensive men who were current smokers or had smoked at least seven cigarettes a week for at least one year at any time in their life compared with hypertensive men who had never smoked (odds ratio 1.54, 95% CI 1.03 to 2.32, P=0.009).

CONCLUSIONS:

Smoking seems to be an independent cardiovascular risk factor genetically codetermined by the ET-1 gene variant.     

The endothelin-1 receptor-mediated pathway is not involved in the endothelin-1-induced defenestration of liver sinusoidal endothelial cells.

BACKGROUND/AIMS: We previously reported that endothelin (ET)-1 may be involved in the contraction of hepatic sinusoidal endothelial fenestrae (SEF). Rho has emerged as an important regulator of the actin cytoskeleton and consequently cell morphology. To clarify the role of ET receptors [endothelin A receptor (ETAR) and endothelin B receptor (ETBR)] in ET-1-induced defenestration, we studied the size of hepatic SEF under various experimental conditions. METHODS: Liver sinusoidal endothelial cells (LSECs) isolated from rat livers by collagenase perfusion were cultured and divided into four groups: control, ET-1 (10(-6) -10(-10) M)-treated, ET-1+selective ETAR antagonist (BQ610)-treated and ET-1+ETBR antagonist (BQ788)-treated groups. SEF morphology was observed by scanning electron microscopy. Protein expressions of ETAR and ETBR, Rho A and phosphorylated myosin light-chain kinase were analyzed by Western blotting. F-actin stress fiber formation was observed by confocal microscopy. Active Rho was measured by Ren's modification. Intracellular free Ca2+ concentration ([Ca2+]i) was measured by fluorescence digital imaging using fura-2 AM by Aqua cosmos. RESULTS: ET-1 induced a reduction in the number and size of SEF. ETAR antagonist pretreatment inhibited defenestration induced by low ET-1 concentrations (10(-8) -10(-10) M), whereas ETBR antagonist pretreatment did not block defenestration at low to high ET-1 concentrations (10(-6) -10(-10) M). F-actin stress fibers, Rho A levels and phosphorylated myosin light-chain kinase levels remained the same in various treatments. Active Rho was not detected in control and various treatments. ET-1 did not increase [Ca2+]i. Western blot showed prominent ETBR but scarce ETAR protein expression in LSECs. CONCLUSIONS: The present findings demonstrated that ETBR- and ETAR-induced contractile mechanisms are not involved in ET-1-induced defenestration, and that Rho is also not activated. Therefore, ET-1 induces hepatic defenestration by mechanisms other than receptor-mediated contraction.     

The effect of isosorbide dinitrate on placental blood flow and maternal blood pressure in women with pregnancy induced hypertension

The effect of isosorbide dinitrate (ISDN) on maternal and fetal circulation was assessed in 23 women with pregnancy induced hypertension (PIH). A double-blind randomized design was employed. Each woman was given a sublingual tablet of ISDN (5 mg) or placebo. Maternal blood pressure (BP) and heart rate (HR) were measured before and every 2 min after the medication or placebo, for a total of 20 min. Flow velocity waveforms in the uterine and umbilical arteries were recorded at the same time periods, using pulsed Doppler ultrasound. The ratio of peak systolic to end-diastolic flow velocity (S/D) in those vessels was calculated. After ISDN mean maternal BP fell from 103 ± 1.8 mm Hg to 90.5 ± 2.9 mm Hg at 14 min (P < .0001) and mean maternal HR increased from 97.3 ± 3.8 beats/min to 115.7 ± 3.5 beats/min at 12 min (P < .0001). The mean S/D in the umbilical artery fell from 3.07 ± 0.33 to 2.58 ± 0.23 at 8 min (P < .0007). The mean S/D in the uterine artery fell from 3.27 ± 0.6 to 2.38 ± 0.28 at 10 min (P < .0001). In seven of 12 women with an early diastolic notch in the uterine artery flow velocity waveform the notch diminished or disappeared within the first 6 min after the medication. No significant change in any of the measured parameters was observed in the placebo group. Our finding that ISDN altered maternal and fetal hemodynamics in PIH lends support to the further exploration of nitric oxide donors in the treatment and prevention of pregnancy induced hypertension.     

高血压不同部位大动脉缓冲功能不均一性的临床研究

目的：研究正常人和高血压患者不同部位动脉缓冲功能的变化。方法：对１２０例正常人和２０５例原发性高血压患者应用动脉搏波速度（Ｐｕｌｓｅ ｗａｖｅ ｖｅｌｏｃｉｔｙＰＷＶ）测定仪进行检测。颈动脉－股动脉ＰＷＶ（ＣＦＰＷＶ）、肱动脉－找动脉ＰＷＶ（ＢＲＰＷＶ）和股动脉－足背动脉ＰＷＶ（ＦＴＰＷＶ）分别为反映大动脉和中等动脉扩张性（Ｄｉｓｔｅｎｓｉｂｉｌｉｔｙ）的参数。并能敏感反映动脉缓冲功能的改变。结果：无论正常人还是高血压患者,ＣＦＰＷＶ与年龄和收缩压成正相关关系（Ｐ均小于０．００１）,而ＢＲＰＷＶ和ＦＴＰＷＶ并不随年龄和收缩压的改变而改变。结论：正常人和高血压患者不同部位动脉节段的缓冲功能发生不同的变化,大动脉扩张性降低,中等动脉无明显变化。对大动脉缓冲功能变化的早期检测和有效治疗具有重要的临床价值。     

Preferential macrovasculopathy in systemic sclerosis detected by regional pulse wave velocity from wave intensity analysis: Comparisons of local and regional arterial stiffness parameters in cases and controls

Objective

To study the extent and severity of macrovasculopathy in systemic sclerosis (SSc; scleroderma) patients by comparing both local and regional arterial stiffness parameters.

Methods

The local arterial stiffness indices of the right common carotid artery, right brachial artery, right radial artery, right superficial femoral artery, and right posterior tibial artery were measured in 25 SSc patients and strictly matched healthy controls. The regional pulse wave velocity (PWV) of each arterial segment was also calculated from wave intensity analysis.

Results

There were no differences between the two groups in the stiffness index (β), Peterson's pressure modulus, arterial compliance, and local PWV derived from β (PWVβ) of all vessels except the right brachial artery, of which β, Peterson's pressure modulus, and PWVβ were markedly lower and arterial compliance was higher in SSc patients compared with controls (P < 0.05). The forearm (brachial–radial) and arm (carotid–radial) PWVs were significantly higher in SSc patients than in controls (mean ± SD 12.1 ± 7.1 meters/second versus 8.3 ± 3.5 meters/second and mean ± SD 7.9 ± 1.9 meters/second versus 6.9 ± 1.5 meters/second, respectively; P < 0.05), whereas the upper arm (carotid–brachial), aortic (carotid–femoral), and leg (femoral–ankle) PWVs were not different between groups. The aortic PWV was also higher in the diffuse cutaneous SSc subgroup than in controls (mean 6.2, 95% confidence interval [95% CI] 5.4–6.9 meters/second versus mean 5.1, 95% CI 4.7–5.6 meters/second; P < 0.05) after adjusting for potentially influential variables.

Conclusion

The macrovasculopathy occurs preferentially at the forearm and aorta in SSc, which can be sensitively and reliably detected by regional PWVs rather than commonly used local arterial stiffness indices.     

Plasma endothelin is increased in early essential hypertension

Local vascular generation of endothelin-1 (ET-1) may contribute to elevated peripheral resistance in hypertension. We tested the hypothesis that immunoreactive ET production in the forearm circulation is increased in early essential hypertensive subjects. Ten young, previously untreated male patients with mild essential hypertension and no signs of target organ damage were compared with matched normotensive subjects in an outpatient setting. Arterial and venous samples were obtained from indwelling catheters in the brachial artery and the medial cubital vein, respectively. Samples were collected at baseline and after induction of endothelium-dependent (acetylcholine) vasodilation. Immunoreactive ET (ET) was measured after column extraction by a sensitive radioimmunoassay employing a C-terminal ET-1 antibody with negligible cross-reaction to big-ET. Individual recovery rates were determined for each sample.Basal ET was significantly higher in hypertensive than in normotensive subjects, both in venous and arterial samples (P < .01). This difference was also present after correction for recovery (P < .01). There was no significant difference between venous and arterial ET concentrations. Local vasodilation did not change arterial or venous ET levels. In conclusion, plasma ET is increased in young, untreated, essential hypertensive subjects with no signs of target organ damage. The increased circulating immunoreactive ET may point to a role for the peptide early in the development of high blood pressure.     

The relation between blood pressure changes induced by passive leg raising and arterial stiffness

Passive leg raising (PLR) elicits cardiorespiratory changes because of intra-thoracic blood pooling. We previously found PLR to lower blood pressure (BP) in healthy subjects. To determine the effects of cardiovascular (CV) risk factors on the PLR BP lowering response, we measured brachial artery, systolic (SBP), diastolic (DBP), and pulse pressure (PP) before and 1 minute after 60° PLR, in 125 subjects (58% males, age 48 ± 18 years) with/without CV risk factors/disease. Baseline carotid-radial pulse wave velocity (PWV) and augmentation index (AI) were measured by applanation tonometry. Changes (?) in SBP and BA PP ranged from +31 to –27 and +35 to –20 mm Hg and were normally distributed. Mean BP decreases upon PLR were ΔSBP –3 ± 9 (P < .001), and ΔPP –2 ± 8 mm Hg (P = .04). On univariate analyses, ΔSBP was correlated with age (r = 0.31, P < .001), PWV (r = 0.53, P < .001), AI (r = 0.25, P < .01), hypertension (r = 0.37, P < .001), hypercholesterolemia (r = 0.25, P < .01) and renal insufficiency (r = 0.19, P = .038). ΔPP was correlated with age (r = 0.31, P < .001), PWV (r = 0.45, P < .001), AI (r = 0.23, P = .01), hypertension (r = 0.22, P = .01), hypercholesterolemia (r = 0.27, P < .001). Multivariate analysis showed PWV the only independent predictor of ΔSBP (B = 3.2, r² = 0.40, P < .001) and of ΔPP (B = 2.6, r² = 0.36, P < .001). Therefore, changes in SBP and PP induced by PLR are independently and inversely related to carotid-radial PWV.     

Reactivity of Mesenteric Arteries From Fructose Hypertensive Rats to Endothelin-1

We previously demonstrated that mesenteric arteries from hyperinsulinemic, insulin resistant fructose hypertensive (FH) rats contain a higher absolute amount of ET-1 and exhibit defective endothelium-dependent vasodilation. Furthermore, chronic ET receptor blockade with bosentan completely prevented the rise in blood pressure in these rats. The present study was undertaken to examine 1) whether the reactivity of mesenteric arteries to ET-1 is altered in FH rats, and 2) whether chronic bosentan treatment has any effect on ET-1 responsiveness and endothelium-dependent vasodilation. Male Sprague Dawley rats were divided into four groups: control (C), control bosentan-treated (CB), fructose (F) and fructose bosentan-treated (FB). Chronic oral bosentan treatment (100 mg/kg/day) was initiated in the CB and FB groups 1 week prior to initiating the fructose diet. At week 16, the F group was hyperinsulinemic and hypertensive when compared to the C group (plasma insulin: 5.8 ± 0.3 v C 3.2 ± 0.5 ng/mL, P < .001; systolic BP: 157 ± 5 v C 130 ± 4 mm Hg, P < .001). Treatment of the F group with bosentan prevented the rise in BP (FB: 133 ± 3 mm Hg; P < .001 v F). Analysis of the pressurized mesenteric resistance arterioles demonstrated that the wall thickness as expressed as percentage of internal diameter did not differ between arteries from C and F rats, when measured over a range of transmural pressures. Constrictor responses of resistance arterioles to NE were similar for C and F rats when studied at transmural pressures of either 120 mm Hg or 160 mm Hg, respectively. The maximum contractile response and the sensitivity of superior mesenteric arteries to NE did not differ between the groups, either with or without the endothelium. However, the maximum contractile response to ET-1 was depressed in the F group both with (+) and without (−) the endothelium [(+): 1.50 ± 0.11 v C 1.88 ± 0.1 g/mm³, P < .05, (−): 1.68 ± 0.11 v C 2.05 ± 0.1 g/mm³, P < .05.]. Furthermore, the endothelium intact F arteries exhibited a decreased sensitivity to ET-1 (pD₂ values F 8.36 ± 0.11 v C 8.83 ± 0.07). Chronic bosentan treatment of the F group restored the maximum tension responses of arteries to ET-1 [(+) in the FB group: 1.88 ± 0.12 g/mm³ v C, P > .05, (−): 1.95 ± 0.05 g/mm³ v C, P > .05] but had no effect on the responses of the CB group. In arteries with intact endothelium, bosentan treatment restored the sensitivity of the F arteries to ET-1 (pD₂ values FB 8.82 ± 0.05 v C, P < .05). Endothelium-dependent relaxation responses were diminished in the F group, which were unaffected by bosentan treatment. These data suggest that mesenteric arteries from FH demonstrate a specific alteration towards the reactivity to ET-1, which is restored by long-term bosentan treatment.     

Effects of hypertension, diabetes mellitus, and hypercholesterolemia on endothelin type B receptor-mediated nitric oxide release from rat kidney

BACKGROUND: Although endothelin-1 is a potent vasoconstrictor peptide, stimulation of endothelin type B receptor (ETBR) causes bidirectional changes in vascular tone, ie, vasodilation and vasoconstriction. Roles of ETBR in pathological conditions are largely unknown. METHODS AND RESULTS: We studied the effect of BQ-3020, a highly selective ETBR agonist, on renal vascular resistance and nitric oxide (NO) release in the isolated, perfused kidney of rats with hypertension, diabetes mellitus, and hypercholesterolemia. Immunohistochemistry of endothelial NO synthase and ETBR was also examined. Infusion of BQ-3020 at concentrations of 相似文献   

Ultrasonic assessment of liver stiffness and carotid artery elasticity in patients with chronic viral hepatitis

Background

This study investigated the relationship between liver stiffness and carotid artery elasticity in patients with chronic viral hepatitis. We used an acoustic radiation force impulse (ARFI) technique to measure stiffness, and a radio frequency (RF) vascular quantitative ultrasound technique to measure changes in common carotid artery elasticity and vascular function.

Methods

Two-hundred seventeen patients with chronic viral hepatitis caused by either hepatitis B virus (HBV) or hepatitis C virus (HCV) were enrolled. We divided the patients into two groups, one comprising 147 patients with chronic hepatitis B (CHB) (98 men and 49 women, average age 46.5?±?12.2?years) and another comprising 70 patients with chronic hepatitis C (CHC) (47 men and 23 women, average age 47.6?±?12.1?years). Additionally, 64 healthy age- and sex-matched participants (43 men and 21 women, average age 47.8?±?5.1?years) were selected as the control group. The ARFI technique was used to measure liver stiffness and the RF ultrasound technique was used to measure carotid artery elasticity parameters including intima-media thickness (IMT), pulse wave velocity (PWV), arterial wall dilation coefficient (DC), compliance coefficient (CC), sclerosis indices α and β, and augmentation index (Aix). Clinical indicators, liver stiffness, and carotid artery elasticity parameters were observed and compared between the different age groups to investigate the correlation between carotid artery elasticity parameters and liver stiffness.

Results

The ARFI values for the CHB and CHC groups were significantly higher than those for the control group (1.84?±?0.52 vs. 1.04?±?0.11?m/s; 1.86?±?0.37 vs. 1.04?±?0.11?m/s, respectively; P?<?0.001). When compared to the control group, both CHB and CHC groups showed an IMT of the same order, but had significantly higher elasticity parameters, such as α and β, as well as lower DC and CC values (P?<?0.001). The PWV of the CHC group was significantly higher than that of the control group (7.98?±?1.42 vs. 6.09?±?0.90?m/s, P?<?0.001). In the CHB group, all parameters including ARFI, IMT, PWV, DC, CC, α and β, were significantly different between the two age groups (P?<?0.05). Within the CHC group, all parameters including IMT, PWV, DC, α and β, were significantly different between the two age groups (P?<?0.05), except for ARFI, wherein the difference was not statistically significant. The correlation analysis and stepwise multiple linear regression analysis indicated that for patients with CHB, age was an independent predictor of common carotid artery IMT (R²?=?0.468, F?=?54.635, and P?<?0.001). For patients with CHC, age and blood sugar were independent predictors of common carotid artery IMT (R²?=?0.465, F?=?29.118, and P?<?0.001).

Conclusion

Although based on ARFI and RF ultrasound, the carotid artery IMT in patients with CHB and CHC was not significantly higher than that in the control group, their functional elasticity parameters had already changed. This finding serves as a useful reference for the clinical diagnosis of vascular diseases in patients with viral hepatitis.

Trial registration

ClinicalTrials: ChiCTR1800015859 25/04/2018.

     

Uric acid is an independent predictor of arterial stiffness in hypertensive patients

Increased arterial stiffness is an important marker for target organ damage in essential hypertension. Both serum uric acid (UA) and C-reactive protein (CRP) were reported to be associated with target organ damage. However, the influences of UA and CRP on large arterial stiffness were not well elucidated. This study included 200 essential hypertension patients (64 women) whose age was between 20 and 50 years old (mean age 41 ± 8 years). None of the patients had diabetes mellitus or overt end-organ damage. Arterial stiffness was assessed by pulse-wave velocity (PWV) measured by tonometry from carotid to radial artery. Serum UA, high-sensitivity CRP (hsCRP), glucose, insulin, and lipid profiles were measured at the same time in each patient. PWV levels were significantly correlated with mean blood pressure (r = 0.245, P < 0.001), diastolic blood pressure (r = 0.323, P < 0.001), high-density lipoprotein (r = −0.169, P = 0.016), and UA (r = 0.234, P = 0.001), but not age, body mass index, blood sugar, insulin, low-density lipoprotein, triglyceride, and hsCRP. Pulsewave velocity levels were significantly higher in males (8.9 ± 1.2 vs 8.2 ± 1.2 m/s, P < 0.001) and smokers (9.3 ± 1.1 vs 8.5 ± 1.2 m/s, P < 0.001). Uric acid was significantly correlated with hsCRP (r = 0.294, P < 0.001). After multivariate analysis controlling for all possible confounding factors, UA (odds ratio 1.28, 95% confidence interval 1.02–1.61, P = 0.032) was still independently associated with increased PWV. In conclusion, UA but not hsCRP was independently associated with increased PWV in essential hypertension. Although UA was correlated with hsCRP, the association between UA and PWV was not through the effect of enhanced inflammation.     

Relation between renal function within the normal range and central and peripheral arterial stiffness in hypertension

Chronic kidney disease is accompanied by increased large-artery stiffness, but the relation between glomerular filtration rate within the reference range and central or peripheral arterial stiffness has been understudied. The link between renal function and arterial stiffness was assessed in 305 patients with never-treated essential hypertension (men: 58%; age: 48+/-11 years, blood pressure: 151/95+/-20/11 mm Hg), free from overt cardiovascular disease and with serum creatinine values <1.4 mg/dL (men) and <1.2 mg/dL (women), who underwent noninvasive aortic and upper-limb pulse wave velocity (PWV) determination. Aortic PWV was strongly related to age (r=0.55; P<0.001), whereas upper-limb PWV had a weaker nonlinear relation with age (beta=1.392; P<0.001 for age; beta=-1.312; P<0.001 for age squared) and a weak relation with aortic PWV (r=0.22; P<0.001). Glomerular filtration rate (GFR), estimated according to the Mayo clinic equation for healthy subjects, was inversely correlated with large-artery stiffness, as assessed by aortic PWV (r=-0.34; P<0.001), and with peripheral artery stiffness, as assessed by upper-limb PWV (r=-0.25; P<0.001). In a multivariate linear regression, aortic PWV was independently predicted by age (beta=0.48; P<0.001), mean arterial pressure (beta=0.14; P=0.013), and GFR (beta=-0.13, P=0.029). Upper-limb PWV was predicted by GFR (beta=-0.24; P<0.001) and mean arterial pressure (beta=0.20; P<0.001). We conclude that, in hypertensive patients with normal renal function, an inverse relationship exists between GFR and stiffness of both central elastic and peripheral muscular arteries. These relations are in part independent from the effect of several confounders, including age, sex, and blood pressure values.     

Central Aortic Stiffness in Patients With Nonischemic Dilated Cardiomyopathy: Relationship With Neurohumoral Activation

BackgroundIncreased aortic stiffness has been found in heart failure (HF), but the underlying mechanisms remain to be elucidated. The aim of the present study was to examine the association between aortic stiffness and neurohumoral activation in patients with nonischemic dilated cardiomyopathy (NIDC).Methods and ResultsWe examined 101 patients with NIDC, New York Heart Association Class II-III, LVEF 33.3 ± 11.6%, and 33 controls. All subjects underwent blood sampling for plasma concentrations of renin, aldosterone, C-reactive protein (CRP), and brain natriuretic peptide (BNP). We evaluated the pulse wave velocity (PWV) of the proximal aorta in the region of the aortic arch with a new echo application. Patients showed increased PWV (P < .001), and increased plasma levels of log-renin (P < .001), log-aldosterone (P = .01), CRP (P = .01), and log-BNP (P = .01) compared with controls. PWV was correlated with log-BNP (r = 0.63, P < .001) and log-aldosterone (r = 0.34, P < .001) levels, with LV end-diastolic (r = 0.27, P = .01) and end-systolic (r = 0.33, P = 0.003) volumes, and the PW-tissue Doppler imaging systolic wave (r = –0.27, P = .006) and the E/e′ ratio (r = 0.45, P < .001). Linear regression analysis showed that log-BNP levels were independently associated with PWV.ConclusionsIn patients with HF from NIDC, there is evidence of increased aortic stiffness that is correlated with LV shape and function. Although aldosterone levels seem to influence the aortic PWV, BNP levels are the best independent predictor of increased PWV.