高浓度曲马朵通过内皮依赖与非依赖机制诱导家兔主动脉舒张(英文)

AIM: The mechanism of tramadol-induced vasodilation was investigated using isolated rabbit thoracic aortic rings. METHODS: Aortic rings from 8 rabbits were placed in organ bath and precontracted with phenylephrine(10~(-5) mol/L) before addition of tramadol. Relaxation responses by tramadol were evaluated in the presence and absence of endothelium, indomethacin (an inhibitor of cyclooxygenase), N~G-nitro-L-arginine methyl ester (L-NAME, a specific inhibitor of nitric oxide synthase), glibenclamide (an inhibitor of ATP-sensitive potassium channels), tetraethylammonium chloride (TEA, an inhibitor of calcium-sensitive potassium channels), and naloxone (an antagonist of opioid receptors). RESULTS: Tramadol(10~(-4) mol/L and 3×10~(-4) mol/L) caused significant vasodilation in endothelium-intact and endothelium-denuded aortic rings (P<0.05). The relaxation response to tramadol was significantly greater in endothelium-intact rings than in endothelium-denuded rings. Pretreatment of aortic rings with indomethaci     

介导乙酰胆碱诱发内皮依赖性血管舒张反应受体的特性

目的　针对血管内皮细胞上是否存在M受体的疑点 ,从基因水平和信号转导机理上探讨介导乙酰胆碱 (ACh)诱发内皮依赖性血管舒张反应受体的特性。方法　以新鲜分离和传代培养的牛主动脉内皮细胞为实验材料 ,比较两种内皮细胞M1～M5受体mRNA的分布状况、ACh诱发细胞内游离钙离子浓度 ([Ca2 + ]i)、环腺苷酸 (cAMP)含量变化。①设计高选择性、特异性寡核苷酸探针 ,采用点杂交方法对内皮细胞M1～M5受体mRNA进行分析 ,并通过反转录 聚合酶链反应 (RT PCR)、DNA序列测定及同源性分析确证点杂交的实验结果 ;②以Fluo 3和Fura 2为荧光探针 ,用共聚焦和荧光光度仪测定内皮细胞 [Ca2 + ]i 变化 ;③内皮细胞cAMP含量采用12 5I放射免疫分析方法测定。结果　在新鲜分离的牛主动脉内皮细胞存在M1～M4 受体mRNA ,内皮细胞经传代培养后仅检测到M4 受体mRNA ;1和 10μmol·L- 1ACh能够引起原代培养内皮细胞 [Ca2 + ]i增加 ,最大增加量为 12和 19nmol·L- 1;ACh激活原代培养内皮细胞的钙离子信号 ,表现为单次或连续2次的钙振荡 ,具有异时性和快速耐受的特点 ;此外 ,随ACh浓度增加 ,原代培养内皮细胞cAMP含量均呈微弱增加趋势 ;ACh不引起传代培养内皮细胞[Ca2 + ]i 浓度的改变 ,但能浓度依赖地降低cAMP含量。结论　新鲜分?     

山莨菪碱对乙酰胆碱诱导的猫离体动脉内皮依赖性舒张反应的影响(英文)

目的　观察山莨菪碱对乙酰胆碱 (ACh)诱导的内皮依赖性血管舒张反应的影响。方法　采用猫离体血管功能实验 ,观察山莨菪碱对ACh诱发的内皮依赖性血管舒张反应的影响。结果　在猫肠系膜动脉、肾动脉和股动脉 ,山莨菪碱 0 .0 1～ 1 .0nmol·L-1 能够浓度依赖地抑制ACh诱导的内皮依赖的血管舒张反应。山莨菪碱抑制 1 0 μmol·L-1 ACh所诱导血管舒张的IC50 分别为 0 .2 36 ,0 .72 9和 0 .50 8nmol·L-1 ,山莨菪碱的拮抗作用符合非竞争性拮抗模式。此外 ,1 0nmol·L-1 山莨菪碱能有效拮抗ACh诱导的冠状动脉内皮依赖性舒张反应。结论　山莨菪碱能强效拮抗ACh诱发的内皮依赖性血管舒张反应 ,这种效应具有组织特异性的特点。     

哇巴因和高钾对乙酰胆碱致家兔肺动脉内皮依赖性超极化的作用

采用标准微电极技术观察了哇巴因和高钾对乙酰胆碱（ａｃｅｔｙｌｃｈｏｌｉｎｅ，Ａｃｈ）致家兔肺动脉内皮依赖性超极化的作用。结果；Ａｃｈ１０μｍｏｌ·Ｌ－１可使内皮完整的肺动脉膜电位产生明显的超极化。该作用在去除内皮或预先用阿托品阻断Ａｃｈ受体的条件下消失。哇巴因可抑制无钾／复钾所致的膜电位超极化，但不影响Ａｃｈ所致的内皮依赖性超极化。高钾则可取消Ａｃｈ的内皮依赖性超极化。提示：Ａｃｈ引起的家兔肺动脉内皮依赖性超极化可能由细胞膜上钾通道开放所致，而和Ｎａ／Ｋ泵无关。     

An investigation into variability in microvascular skin blood flow and the responses to transdermal delivery of acetylcholine at different sites in the forearm and hand

Aims Transdermal iontophoresis in combination with laser Doppler fluxmetry (LDF) are useful techniques for examining dermal microcirculatory responses to different vasodilators. Differences in skin and microcirculation structure could influence the recorded baseline flux, and the observed vasodilatation. To examine this we compared baseline flux and the response of microvascular blood flow to a single vasodilator, acetylcholine, at sites in the forearm and hand.
Methods Baseline microcirculation flow was recorded by LDF in a temperature controlled laboratory. The change in flux with iontophoresis of identical doses of acetylcholine, 150  μA for 40  s, was recorded at 12 different sites in the forearm and hand in 10 female and 3 male subjects.
Results Baseline flux patterns and the vasodilatation to identical periods of iontophoresis of acetylcholine were site dependent. Palmar sites showed a higher baseline flux, but no vasodilatation to iontophoresis of acetylcholine. In contrast the volar forearm, dorsal hand and finger sites showed lower site-dependent baseline flux, but did vasodilate.
Conclusions Patterns of baseline flux are specific to sites on the hand and forearm reflecting differences in underlying microvascular structure. The vasodilatation to transdermal delivery of acetylcholine is also site dependent, but differences in skin structure may be more important than the underlying microvasculature in determining the response.     

Effects of blockade of alpha- and beta-adrenoceptors and neuropeptide Y(1) receptors,as well as brachial plexus blockade,on endothelium-dependent vasodilation in the human forearm

1. The aim of the present study was to investigate the effects of alpha-adrenoceptor blockade (phentolamine), beta-adrenoceptor blockade (propranolol), neuropeptide Y(1) receptor blockade and neurogenic blockade (brachial plexus) on endothelium-dependent vasodilation (EDV) in the human forearm. 2. Forty-four young healthy volunteers underwent forearm blood flow (FBF) measurements, using venous occlusion plethysmography, during local intra-arterial infusions of methacholine (MCh; inducing EDV) and sodium nitroprusside (SNP; inducing endothelium-independent vasodilation (EIDV)). These measurements were undertaken at baseline and were repeated with either concomitant local intra-arterial infusion of phentolamine (n = 8), propranolol (n = 7) or saline (n = 6) in the forearm, neuropeptide Y(1) receptor blockade (n = 12) given i.v. or during axillary plexus blockade (n = 11). 3. Both alpha-adrenoceptor blockade and neurogenic blockade induced an upward shift in the dose-response curve for both EDV and EIDV. beta-Adrenoceptor blockade did not change resting FBF or EIDV, but induced a significant decrease in EDV (P = 0.015). Neuropeptide Y(1) receptor blocker induced no significant changes in resting FBF, EDV and EIDV and neither did saline. No changes in blood pressure or heart rate were induced by any of the blockades. 4. Whereas beta-adrenoceptor blockade impaired EDV, alpha-adrenoceptor blockade and neurogenic blockade caused a general vasodilation that was not endothelium dependent. Neuropeptide Y does not seem to influence blood flow in the resting forearm.     

Crumbs protein homolog 3 (CRB3) expression is associated with oestrogen and progesterone receptor positivity in breast cancer

The crumbs protein homolog 3 (CRB3) regulates the tight junction to help maintain epithelial polarity. Altered CRB3 expression was associated with carcinogenesis of epithelial cells. This study detected CRB3 expression in 192 cases of breast cancer tissues and in the Molecular Taxonomy of Breast Cancer International Consortium (Metabric) and The Cancer Genome Atlas (TCGA) datasets for association with triple negative breast cancer (TNBC) phenotypes. The in vitro experiments confirm the ex vivo data. The data showed that levels of both CRB3 mRNA and protein were associated with TNBC phenotypes, ie, 41.1% (39/95) of ER+ breast cancer was CRB3‐positive, whereas 26.9% (25/93) ER– tumour was CRB3‐positive (P = 0.046). Moreover, 47.6% (30/63) of PR+ breast cancer was CRB3‐positive vs 28.4% (33/116) PR‐ tumours positive for CRB3 (P = 0.013). In addition, 40.1% (27/66) of ER+/PR+ tumour was CRB3‐positive, but only 22.4% (19/85) of TNBC showed CRB3 expression (P = 0.048). Indeed, levels of CRB3 mRNA were higher in non‐TNBC than TNBC in both Metabric (P = 3.682e‐10) and TCGA datasets (P = 2.501e‐07). The in vitro data showed that CRB3 expression was higher in luminal (MCF7 and T47D) than in HER2 (MDA‐MB‐453 and SK‐BR‐3) and basal (MDA‐MB‐231 and BT‐549) breast cancer cell lines. More interestingly, ERα regulated expression of CRB3 protein in MCF7 and BT‐549 cells and ERα expression was associated with CRB3 expression in breast cancer tissues specimens. This study demonstrated that ERα could be a novel regulator for CRB3 expression in breast cancer.     

Improvement of bradykinin endothelium-mediated vasodilation of forearm resistance circulation by quinaprilat in patients with coronary artery disease with or without left ventricular dysfunction.

Angiotensin-converting enzyme (ACE) inhibition potentiates bradykinin and acetylcholine endothelium-mediated vasodilation. Three groups were studied. Group I (n = 10) was the reference group; group II was composed of nine patients with coronary artery disease; and group III of seven patients with coronary artery disease and left ventricular dysfunction. Forearm blood flow was measured with plethysmography. Acetylcholine and bradykinin were administered in a random order in the brachial artery at infusion rates of 40 and 80 microg/min and 10, 30, 100 pmol/min, respectively. Then quinaprilat was infused alone at the rate of 50 microg/min and then coinfused with acetylcholine and bradykinin. Five of the reference subjects were pretreated with acetylsalicylate. Acetylcholine and bradykinin increased forearm blood flow in a dose-dependent manner in the three groups. However, the vasodilator responses to both agents were significantly lower in the two groups of patients than in the reference group. Quinaprilat significantly enhanced the vasodilator response to acetylcholine only in subjects of the reference group, whereas it enhanced the vasodilator response to each dose of bradykinin, both in subjects of the reference group and in patients. Pretreatment with aspirin did not change the vasodilator responses in any group. In healthy persons, quinaprilat had no effect on its own on forearm blood flow but enhanced the response to bradykinin and even acetylcholine. In patients with coronary disease, short-term administration of quinaprilat was able to improve the impaired response to bradykinin. The response to acetylcholine, however, could not be significantly enhanced in contrast to that in healthy subjects.     

Alpha-adrenoceptor-mediated vasoconstriction is not involved in impaired functional vasodilation in the obese Zucker rat

1. Obesity/metabolic syndrome is associated with augmented a-adrenoceptor sensitivity and impaired hyperaemic responses to exercise. Thus, it is possible that this elevated a-adrenoceptor constriction contributes to the blunted hyperaemic response. 2. Male lean and obese Zucker rats were instrumented for acute measurements of blood pressure (BP) and iliac blood flow (BF). Changes in BP and BF were determined in anaesthetized animals in response to intravenous administration of increasing doses of the a(1)-adrenoceptor agonist phenylephrine (PE). Once BF and BP returned to normal, a single bolus of the a-adrenoceptor antagonist phentolamine (0.5 mg) was administered. In separate animals, the spinotrapezius muscle was exteriorized for direct in situ observation of the microcirculation in response to phentolamine and muscle contraction. 3. Administration of PE demonstrated that iliac BF is highly autoregulated in the face of increasing perfusion pressure. Iliac conductance following phentolamine was significantly greater in obese rats. Following phentolamine administration, iliac vascular conductance was significantly greater in obese rats compared with lean animals. However, a-adrenoceptor blockade did not significantly alter arteriolar diameter in the spinotrapezius muscle during muscle contraction in either lean or obese animals. 4. These results suggest a greater contribution of the a-adrenoceptors in basal hindlimb vascular tone in obese rats. Furthermore, an augmented a-adrenoceptor-mediated vasoconstriction may not contribute to the impaired functional dilation in anaesthetized obese rats.     

Ursodeoxycholic acid and endothelial-dependent, nitric oxide-independent vasodilatation of forearm resistance arteries in patients with coronary heart disease

AIMS: Ursodeoxycholic acid (UDCA) has cholesterol lowering and anti-inflammatory effects and bile acids are reported to exert vasodilator effects; all of these properties might be considered desirable in a drug used in the treatment of patients with coronary heart disease. We investigated a hypothesis that UDCA may dilate arteries and the mechanism of action. METHODS: We evaluated effects of a 6-week treatment with UDCA in 11 coronary heart disease patients on endothelium-dependent (acetylcholine-induced) and -independent (nitroprusside-induced) vasodilatations in forearm vasculature by strain-gauge plethysmography. Healthy individuals (n=14) served as baseline controls. RESULTS: The percentage increase by acetylcholine in the flow of the infused arm relative to the non-infused arm of coronary heart disease patients during the trial remained unaltered, but vasodilatation to NG-monomethyl-l-arginine+acetylcholine was improved by 161+/-27% with UDCA vs 83+/-22% with placebo (mean difference 91% [95% CI 35%, 147%], P=0.016). CONCLUSIONS: Six weeks' UDCA therapy improved endothelium-dependent nitric oxide-independent vasodilatation, which might maintain arterial flow in coronary heart disease patients under conditions of impaired nitric oxide production.     

Reperfusion injury in the human forearm is mild and not attenuated by short-term ischaemic preconditioning

1. Ischaemia-reperfusion (IR) injury is an important contributor to tissue damage and has been shown to be attenuated by preconditioning (PC) in some animal models. A recent report has suggested that the forearm can be used for the study of this phenomenon in humans. We aimed to reproduce and further characterize this model. 2. Healthy young adult volunteers (mean (+/-SEM) age 32+/-6 years) were studied on two occasions. During one visit, IR alone was induced by 10 min of upper arm cuff occlusion, whereas on another occasion a PC stimulus (three 3 min cuff inflations) preceded IR. Endothelial function in the ischaemic arm was assessed by measuring arterial flow-mediated dilatation (FMD) and by calculation of forearm blood flow at baseline and 15 and 60 min after IR. Systemic venous blood was sampled from the non-ischaemic arm at baseline, after PC and at 2, 15 and 30 min after IR to assess neutrophil/leucocyte (CD11b) and platelet (bound glycoprotein IIb/IIIa and fibrinogen) activation, as well as numbers of platelet-leucocyte complexes, which were determined by flow cytometry. Because of a lack of measurable effects, the IR experiment was repeated with 20 min ischaemia in six subjects. 3. Five females and eight males completed the study. Flow-mediated dilatation was significantly impaired 30 min after IR (4.1 vs 6.2% at baseline; P<0.05);however, this was not significantly attenuated by ischaemic PC (FMD reduction at 30 min compared with baseline was 2.1+/-0.5% with IR alone and 2.6+/-1.4% with IR after PC; NS). No significant effect was seen on the number of platelet-leucocyte aggregates or on white cell or platelet activation after IR alone or after IR with PC (P>0.6 for all comparisons). Similar results were obtained in six subjects studied subjected to 20 min ischaemia. 4. In conclusion, in healthy young adults, brief periods of skeletal muscle ischaemia lead to arterial endothelial dysfunction, but no significant platelet or white cell activation. Preconditioning does not attenuate this effect on the endothelium. Further experiments with longer ischaemia times and varying PC stimuli may be necessary to produce measurable effects; however, this may prove difficult in conscious human subjects.     

药物新靶标非神经性乙酰胆碱系统的分布特征与功能

非神经性乙酰胆碱系统(non—neuronal acetvl—choline system，NNAs)广泛存在于各种非神经支配的组织或器官中。非神经性ACh，以自分泌或旁分泌方式，通过相应的受体参与细胞基本功能的调节，如基因表达、增生、分化、细胞骨架的组成、细胞间接触、细胞运动、迁移、液体的分泌与重吸收以及细胞的营养等功能，也对细胞因子的释放和系统急性炎症等方面具有重要调节作用。非神经性胆碱系统具有的广泛的生物学功能提示，非神经胆碱系统功能异常在一些疾病如炎症、动脉粥样硬化、局部及系统感染以及肿瘤等中具有重要的作用。因此，NNAs已成为药物研究的新靶标。     

Endothelial function in mesenteric resistance arteries from the genetically hypertensive rat

1. Endothelial function in mesenteric resistance arteries (MRA) from male 12-week-old New Zealand genetically hypertensive (GH) rats and their normotensive control strain (N) was compared in vessels mounted on a wire myograph and by the production of intracellular cGMP. In parallel experiments, MRA from the spontaneously hypertensive (SHR) rat strain, in which there is an endothelial defect, and from GH rats, in which an endothelial defect was induced by chronic nitric oxide synthase (NOS) inhibition with Nomega-nitro-L-arginine methyl ester (L-NAME), were studied. 2. Contractile responses to potassium (124 mmol/L) depolarization and to NA (10(-8) to 10(-4) mol/L) were similar in GH and N rats; however, in SHR, enhanced contractile responses were found (P < 0.05). The endothelium-dependent relaxation induced by acetylcholine (ACh; 10(-9) to 10(-4) mol/L) and endothelium- independent relaxation induced by sodium nitroprusside (SNP; 10(-9) to 10(-4) mol/L) were identical in preparations from GH and N. A significantly attenuated (P < 0.01) vasodilator response to ACh was observed in preparations from SHR. 3. Levels of intracellular cGMP were similar in untreated small mesenteric arterial trees from GH, N and SHR rats. Acetylcholine (10-5 mol/L) significantly (P < 0.001) increased the cGMP content in both GH and N rats. A non-significant increase occurred in cGMP content in preparations from SHR. 4. In GH rats given L-NAME (10 mg/kg per day for up to 5 weeks), an attenuated (P < 0.01) endothelium-dependent relaxation to ACh and an enhanced (P < 0.01) endothelium- independent relaxation to SNP were observed. Lower basal cGMP levels were found in preparations from L-NAME-treated GH rats and ACh (10-5 mol/L) failed to significantly elevate the cGMP content in these preparations. 5. These experiments failed to show evidence of reduced endothelial function in GH rats, although an endothelial defect in SHR rats and after NOS inhibition in GH rats could be demonstrated.     

Vitamin D deficiency is associated with dyslipidemia: a cross-sectional study in 3788 subjects

Background: Previously we reported on severe vitamin D deficiency in a large-scale cohort in the Tangshan area in northern China. However, whether vitamin D deficiency is associated with cardiovascular risk factors has not been systematically examined in the cohort.

Objective: We aimed to determine the correlation between serum vitamin D status and lipid levels in circulation via an observational study.

Methods: Serum 25-hydroxyvitamin D (25[OH]D) was measured. Based on the measurement subjects were classified into quintiles. Dyslipidemia was defined as having one of the following: elevated serum total cholesterol, LDL cholesterol, triglycerides or decreased HDL cholesterol, under lipid-control treatment.

Results: The study was conducted in a total of 3788 adults in northern China during their routine health examinations. When the highest quintile of the 25(OH)D level was set as reference, the risk of having dyslipidemia increased progressively across the highest to the lowest 25(OH)D with ORs of 1 (reference), 1.232 (95% CI, 1.005–1.509), 1.235 (95% CI, 1.007–1.513), 1.403 (95% CI, 1.143–1.735) and 1.494 (95% CI, 1.217–1.833), respectively (P_trend < .0001) after adjustment for age. This trend was unchanged after further adjustment for several potential confounders. In linear regression analysis, we found an inverse significant correlation between 25(OH)D and triglycerides (β coefficient = ?0.077, p?<?.05) and LDL cholesterol (β coefficient = ?0.245, p < .05), and positive correlation with HDL cholesterol (β coefficient = 0.038, p = .018).

Conclusion: Vitamin D deficiency is found to be associated with dyslipidemia in a cohort of 3788 subjects. Specifically, serum 25(OH)D is inversely correlated with LDL cholesterol and triglycerides levels, and positively correlated with HDL cholesterol level.     

Developmental changes in endothelium-dependent vasodilation and the influence of superoxide anions in perinatal rabbit pulmonary arteries

1. ACh-induced vasodilation was investigated in pulmonary arteries from 8 and 2 day pre-term foetal, neonatal (0–12 h and 4 day old) and adult rabbits. The effects of superoxide anion generation [with hypoxanthine (HX, 0.1 mM)/xanthine oxidase (XO, 15 mu ml⁻¹)], endogenous superoxide dismutase (SOD) inhibition [with the Cu-Zn SOD inhibitor triethylenetetramine (TETA, 1 mM)], endogenous superoxide anion scavenging [by superoxide dismutase (SOD, 50 u ml⁻¹)] and inhibition of endothelial nitric oxide synthase (eNOS) [with, N^ω-nitro-L-arginine methylester (L-NAME, 0.1 mM)], on basal and ACh-induced NO activity were studied by examining phenylephrine-induced contraction and ACh-induced vasodilation respectively.
2. L-NAME and endothelium removal abolished all ACh-induced vasodilation and 1 μM sodium nitroprusside fully dilated all vessels. ACh-induced vasodilation was absent in the 8 day pre-term foetus and 0–12 h neonate but present at all other ages. L-NAME itself contracted 2 day pre-term foetal vessels. At 0–12 h, SOD, but not the phosphodiesterase 5 inhibitor zaprinast (1 μM), uncovered ACh-induced vasodilation. At this age SOD reduced phenylephrine-induced contraction which was not influenced by TETA, L-NAME or HX/XO, and L-NAME itself did not cause contraction. This suggests both ACh-induced and basal NO activity are compromise in these vessels by endogenous superoxide anion production and deficiencies in endogenous SOD activity.
3. In 4 day vessels, but not adult vessels, L-NAME, TETA and HX/XO augmented contractions to phenylephrine, and L-NAME itself induced vasoconstriction, suggesting that basal NO and SOD activities were present by 4 days but were not evident in the adult. ACh-induced NO activity, and the influence of endogenous SOD on this, were present in the adult (and 4 day) vessels as superoxide generation with HX/XO significantly reduced ACh-induced vasodilation and this effect was inhibited by SOD and augmented by TETA.
4. Increased oxygen tensions >500 mmHg attenuated ACh-induced vasodilation in the foetal but not neonatal rabbits. Raising the oxygen tension from ∼20 to ∼120 mmHg revealed ACh-induced vasodilation in the 8 day pre-term vessels.
5. In summary, superoxide anion accumulation combined with deficiencies in SOD activity may transiently compromise basal and ACh-induced NO activity at birth. Experimental oxygen tensions markedly influence ACh-induced vasodilation in foetal rabbit pulmonary arteries.

     

Analysis of the effects of oestrogen receptor alpha (ERalpha)- and ERbeta-selective ligands given in combination to ovariectomized rats

BACKGROUND AND PURPOSE: Studies with oestrogen receptoralpha (ERalpha)- and ERbeta-selective compounds have already shown that the effects of 17beta-estradiol (E2) on body weight, movement drive and bone-protection are mediated via ERalpha. This study was based on the hypothesis that activation of ERbeta may antagonize ERalpha-mediated effects and designed to investigate potential effects of ERalpha/ERbeta heterodimers. EXPERIMENTAL APPROACH: Ovariectomized (OVX) female Wistar rats were treated with combinations of the ERalpha-specific agonist 16alpha-LE2 (ALPHA; 1 and 10 microg kg(-1) d(-1)), the ERbeta-specific agonist 8beta-VE2 (BETA; 100 microg kg(-1) d(-1)), the phytoestrogen, genistein (10 mg kg(-1) d(-1)) and with the anti-oestrogen compound, ICI 182,780 (3 mg kg(-1) d(-1)) for three weeks. The combined effects of the substances on body weight increase, tibial bone mineral density (BMD) and the influence on running wheel activity (RWA) were investigated. KEY RESULTS: OVX-induced body weight increase was reduced by co-administration of genistein and BETA. Co-application of BETA or genistein with ALPHA had no effect on ALPHA-mediated bone-protection. The RWA of OVX animals was significantly reduced by treatment with genistein but stimulated by application of ALPHA. The stimulatory effect of ALPHA on RWA could be antagonized by co-treatment with the pure antioestrogen ICI 182,780 but also by co-administration of genistein or BETA. CONCLUSIONS AND IMPLICATIONS: Our results indicate that activation of ERbeta may modulate ERalpha-mediated physiological effects in vivo. The observation that substances with selective affinity for ERbeta are able to antagonize distinct physiological functions, like RWA, may be of great relevance to the pharmaceutical use of such drugs.     

Hypothesis: Multiple factors are associated with the lack of any beneficial effects of oestrogen‐replacement therapy in the late postmenopausal stage

1. Epidemiological and clinical studies suggest that women may obtain cognitive benefits from oestrogen‐replacement therapy (ERT) during menopause transition rather than in the post‐menopausal stages. However, the underlying mechanisms remain to be determined. 2. We propose that long‐term oestrogen deficiency may result in abnormal distribution and localization of brain oestrogen receptors, brain mitochondrial dysfunction, septohippocampal cholinergic degeneration and reactive gliosis. These multiple pathogenic factors may account for the lack of any beneficial effects of ERT in post‐menopausal women with or without Alzheimer’s disease.     

Antihypertensive treatment is associated with improved left ventricular geometry: the Rotterdam Study

PURPOSE: Left ventricular hypertrophy (LVH) increases the risk of cardiovascular disease. We evaluated the association between antihypertensive therapy and echocardiographically determined LVH. METHODS AND RESULTS: The Rotterdam Study is a population-based prospective cohort study among 7983 participants aged 55 years or over. Echocardiography was performed in 2823 participants. The study population consisted of 740 participants with grade 1 hypertension or antihypertensive monotherapy, without heart failure. Of these, 646 had an adequate echocardiogram for analysis of relative wall thickness (RWT) and 642 for left ventricular mass index. Participants were followed from 1 January 1991 until the date of echocardiography, between September 1992 and June 1993. Outcome measures were defined as being in the highest gender-specific quintile of left ventricular mass index and as having a RWT higher than 0.43. A Cox regression model with duration of use of antihypertensives defined as time-dependent covariates was used for data-analysis. Antihypertensive treatment lowered the risk of increased left ventricular mass index (RR 0.6, 95%CI 0.4-0.9). ACE-inhibitors, diuretics and beta-blockers all showed a risk reduction. Use of antihypertensives was also associated, although non-significantly, with a decrease of high RWT (RR 0.8, 95%CI 0.6-1.0). ACE-inhibitors, beta-blockers and calcium antagonists showed similar risk reductions, while diuretics seemed to increase the risk, possibly by reducing left ventricular end diastolic diameter. CONCLUSIONS: The use of antihypertensive drugs is associated with a decreased risk of echocardiographically determined LVH in a population-based setting.     

Daily administration of the TP receptor antagonist terutroban improved endothelial function in high-cardiovascular-risk patients with atherosclerosis

AIMS

The specific TP receptor antagonist terutroban improves endothelial function after a single dose in patients with coronary artery disease. Our aim was to evaluate the effects and dose dependency of repeated-dose terutroban on endothelial function and platelet aggregation in high-cardiovascular-risk patients with carotid atherosclerosis.

METHODS

We randomly allocated 48 patients taking 300 mg aspirin per day to placebo or to one of three terutroban dosages (2.5, 5 or 10 mg) for 15 days in a double-blind study. Flow-mediated vasodilatation was evaluated before and 2 h after the first oral dose on day 0 and 2 h after the last oral dose on day 14.

RESULTS

On day 0 and day 14, all three terutroban dosages improved flow-mediated vasodilatation and abolished platelet aggregation induced by the TP receptor agonist U46619, without changing the aggregation response to ADP or collagen.

CONCLUSION

Terutroban, by chronically improving endothelium-dependent vasodilatation and inhibiting platelet aggregation, may prove useful for preventing cardiovascular events in high-risk patients.