Characteristics of flow-mediated brachial artery vasodilation in human subjects

In an effort to determine whether arterial conductance vessels dilate in response to increased blood flow stimuli, brachial artery area (cm2) and diameter (cm) were derived by simultaneous measurement of forearm blood flow (ml/min.100 ml) and brachial artery blood flow velocity (cm/sec) following the release of arterial occlusion. Measurements were made at rest and at the time of maximal flow after the release of graded periods of forearm arterial occlusion (20 seconds to 10 minutes). These studies showed a graded large vessel dilation following occlusions of up to 1 minute (baseline diameter, 0.33 +/- 0.01; after 1 minute occlusion, 0.45 +/- 0.02 cm; p less than 0.05) after which time diameter plateaued (after 10 minutes of occlusion, 0.48 +/- 0.02 cm). In addition, the time course of diameter and flow changes after 3 minutes of arterial occlusion were examined. Flow was maximal at 5 seconds but diameter was maximal at 15-30 seconds after release. Furthermore, the half time for the return of diameter to baseline was longer than that for blood flow. We also measured the diameter after forearm heating (42 degrees C) and noted a substantial increase in diameter (before heating, 0.32 +/- 0.01; after heating, 0.39 +/- 0.02 cm; p less than 0.05). Finally, we applied pressure to the venous side of arteriovenous fistulae in five hemodialysis patients. This maneuver was associated with large reductions in forearm blood flow (baseline flow, 63.3 +/- 10.6; venous compression flow, 36.0 +/- 4.4 ml/min.100 ml; p less than 0.05) and a decrease in brachial artery size (baseline diameter, 0.63 +/- 0.07; venous compression diameter, 0.58 +/- 0.06 cm; p less than 0.05). We conclude that 1) the human brachial artery size changes in response to changes in blood flow, and 2) the maximal dilation occurs after maximal flow is noted. Although alternate explanations are possible for each of our observations, our results are most consistent with a flow-mediated, localized vasodilating process.     

Vector U loop in normal and hypertensive subjects

The U loops of vectorcardiograms (VCG) were recorded in 100 normal subjects and 123 subjects with hypertension, using a direct-writing vectorcardiograph with memory function. These U loops were examined qualitatively and quantitatively. Subjects with hypertension were classified into four groups on the basis of electrocardiographic findings, and the correlation between findings on the U loop and the severity of hypertension was studied. The U loop of normal subjects was directed similarly to the T loop, showing either an arc or semilunar shape in the horizontal plane. In hypertensive subjects the U loop tended to be displaced anteroinferiorly and to the right with an increase in severity of hypertension. In these subjects the U loop was of slightly greater amplitude than in normal subjects, and was long and slender in shape. Anterior and rightward displacement of the U loop was also observed in hypertensive cases who showed no abnormality in the T wave of standard lead ECGs or in the T loop of the VCG. These findings seem useful as clinical parameters of the hemodynamic state in the early stage of hypertension. Based on these results, it was hypothesized that mechanical factors, such as stretch of the ventricular muscles induced by pressure loading of the left ventricle, may contribute greatly to genesis of the U loop.     

Effect of hemodilution on endothelium-dependent vasodilation in the in vivo canine femoral artery

The vasodilation responses to increased blood flow and acetylcholine require endothelial cells. We noticed that dogs with low hematocrit had reduced endothelial cell dependent responses; infusion of whole blood often restored the responses. Therefore, experiments were designed to test the hypothesis that hemodilution attenuates endothelial cell-dependent dilation. An extracorporeal shunt was created from the femoral artery to the jugular vein in pentobarbital-anesthetized dogs. Femoral artery diameter was measured by sonomicrometry. Blood flow was controlled by a screw clamp placed distally on the shunt tubing, and flow was increased from control (10% maximum) to maximum by opening the clamp for 3 mins. Hemodilution was achieved by withdrawal of whole blood and infusion of either 1) saline, 2) physiologic salt solution (PSS, containing 2.7 mM CaCl2), 3) saline with CaCl2 (2.7 mM), or 4) PSS without CaCl2. Endothelial cell-dependent dilations were evaluated after a 50% decrease in hematocrit. Hemodilution with either PSS or saline with CaCl2 did not decrease dilation responses to increased flow or acetylcholine. However, hemodilution with saline or PSS without CaCl2 markedly attenuated endothelium-dependent dilations. Ionized plasma calcium concentration decreased with saline and PSS without CaCl2 hemodilution, but it was maintained with PSS and saline with CaCl2 hemodilution. These data suggest that a 50% decrease in hematocrit does not influence endothelium-dependent dilation if plasma calcium is maintained. Our data support in vitro results that suggest that extracellular calcium is necessary for the release of endothelium-derived relaxing factor. Furthermore, relatively small changes in ionized calcium, within the physiologic range, have large effects on endothelial cell-mediated dilator responses to flow and acetylcholine. However, relatively large changes in hematocrit have no effect on the endothelium-dependent responses.     

Endothelium-dependent vasodilation and carotid artery wall remodeling in athletes and sedentary subjects

In this study, the relationship between age, carotid artery remodeling, and endothelium-dependent vasodilation is investigated in sedentary subjects and athletes. Thirty-two young and old healthy sedentary subjects and 32 age-matched endurance athletes underwent ultrasonography of the carotid wall for measuring intima-media thickness (IMT) and corrected integrated backscatter (C-IBS), two early indicators of the atherosclerosis process. Endothelium-dependent vasodilation was assessed by intra-brachial acetylcholine (strain-gauge plethysmography), at baseline and during NO sythase inhibitor NG-monomethyl-L-arginine (L-NMMA), and the antioxidant Vitamin C. Response to sodium nitroprusside (SNP) was also evaluated. Independently of trained status, IMT and C-IBS were higher in older than in young individuals (p<0.0001), while response to acetylcholine, but not to SNP, was lower (p<0.0001). Older athletes showed lower IMT, lower C-IBS (p<0.0001), greater response to acetylcholine (p<0.0001), and greater inhibition of acetylcholine by L-NMMA (p<0.001) than older controls. Only in older sedentary individuals, Vitamin C increased response to acetylcholine (p<0.001) and restored the inhibiting effect of L-NMMA (p<0.01). In the whole population maximal acetylcholine-induced vasodilation was inversely related to IMT (r=-0.60, p<0.0001) and to C-IBS (r=-0.56, p<0.0001). In conclusion, regular physical training can attenuate the age-related impairment of endothelium-dependent vasodilation, which is related to an attenuation of the age-induced remodeling of the carotid wall.     

Does the endothelium play a role in flow-dependent constriction? A study in the isolated rabbit femoral artery

We studied the role of the endothelium in diameter changes as a function of flow of the isolated femoral artery of the rabbit (n = 15) perfused and superfused with a physiological salt solution (37 degrees C). In 10 vessels, diameters were studied before and after exposure to gossypol, an agent that impairs the endothelial function pharmacologically. In 5 of these 10 vessels we added albumin (1.5%) to the perfusion solution. The mean external diameter (+/- SEM) after equilibration for 60 min at a transmural pressure of 50 cm H2O (n = 10) was: 1,426 +/- 34 microns. Vessels were then constricted with norepinephrine (1.0-1.5 microM in the superfusion solution) to 70% of the resting diameter, acetylcholine was used to check endothelial function. All vessels constricted as flow was increased (p less than 0.001), irrespective of the impairment of the endothelial function by gossypol or the presence of albumin. It is therefore unlikely that the flow-induced constriction results from a 'wash away' effect of endothelium-derived relaxing factor (EDRF). To test whether EDRF could still play a role after gossypol, we used hemoglobin (n = 5) to bind EDRF. Flow-dependent constriction was still observed, although the mean diameter was decreased. We conclude that flow-dependent constriction is either mediated via the endothelial cells, but not via EDRF, or that the endothelial cells are not involved.     

Maximal hand blood flow in hypertensive and normal subjects

The present study examined whether patients with systemic hypertension have evidence of structural vascular changes, whether such changes can be detected in early stages of hypertension and whether they are reversible with treatment. Hypertensive and normal subjects were studied under conditions of maximal vasodilation in which flow at a given driving pressure was considered to give an index of structural changes in resistance vessels. Thirty-two subjects were separated into 4 groups: 8 with sustained hypertension, 8 with intermittent hypertension, 8 treated hypertensive subjects maintained at systolic pressures of less than 125 mm Hg with drugs for 5 years, and 8 normal subjects. Flow was measured by venous occlusion plethysmography after 10 minutes of ischemia, using a water-filled plethysmograph at 43 degrees C. Arterial blood pressure was measured by the arm cuff method. Transmural pressure, calculated as mean arterial minus external pressure, was varied by imposing varying external hydrostatic pressures. Flow at a transmural pressure of 85 mm Hg was calculated for each subject from the least-mean-square plot of transmural pressure vs flow. Mean flow for normal subjects was 41 ml/100 ml/min and differed significantly from that for sustained hypertensive patients (30 ml/100 ml/min), treated hypertensive patients (33 ml/100 ml/min), and intermittent hypertensive patients (32 ml/100 ml/min) (p less than 0.05). There was no overlap between sustained hypertensives and normal subjects, but half of the treated hypertensive patients were normal.(ABSTRACT TRUNCATED AT 250 WORDS)     

多普勒超声测定人股动脉的相关指标及其影响因素

目的应用高频彩色多普勒超声探讨正常人股动脉内-中膜厚度、血流动力学变化与血管弹性的相互关系,并分析不同年龄段、性别、血压和心率等因素对这些指标的影响,旨在确定正常人下肢动脉相关指标的正常值范围及其影响因素,为下肢动脉硬化的研究提供参考。方法对60例正常人的股动脉行二维及彩色多普勒超声检查,观察血管内-中膜厚度（IMT）,用M型测量血管收缩期及舒张期的内径（DS及Dd）,脉冲多普勒测量收缩期峰值速度（Vs）、舒张早期峰值速度（Vd）、舒张早期血流频谱积分（VTId）、血流波传递时间（TR-Vs）,M型超声记录股动脉前后壁收缩末期和舒张末期运动幅度内径、计算僵硬度β指数、扩张性和顺应性等参数。结果正常人股动脉IMT随着年龄的增大而逐渐增厚,血流峰值最大速度（Vm ax）及TR-Vs随着年龄的增大而递减,5070岁年龄段更明显,随着年龄的增大,DS和Dd、僵硬度指数增大,扩张性和顺应性降低（P<0.05）。IMT与僵硬度指数、扩张性和顺应性无明显相关性。僵硬度指数、扩张性、顺应性与脉压相关（P<0.01）,而与收缩压、舒张压无明显相关性。结论IMT、Vm ax、TR-Vs等指标可反映股动脉功能变化的特征,且TR-Vs可作为评价老年人股动脉硬化程度的常规指标,操作简单,受相关因素影响较小。     

Arterial compliance during exertion in hypertensive and normal subjects of the same age

In order to improve the reproducibility of arterial compliance measurements, normally taken at rest, we performed these measurements during exercise under stable conditions. Our aim was to determine, in both normotensive and hypertensive subjects, those parameters which condition changes in arterial compliance during exercise, and in particular age, systolic/diastolic arterial pressures and heart rate. The study involved 59 normotensive and 31 hypertensive subjects. Compliance was evaluated by measuring pulse wave velocity in the upper limbs at three levels of exercise: 50, 75 and 100 watts. Pulse wave velocity measured in different age-groups gradually increased at each exercise level, but age made no significant difference in values. Only one correlation appeared at recovery, with a significant (p less than 0.05) difference between normotensive and hypertensive subjects. As regards arterial pressures, there was only one correlation with diastolic pressure reflecting an increase in mural tension during exercise. A correlation with heart rate appeared during exercise, probably due to the vasomotor effect of a higher adrenergic tone. The diversity of vascular repercussions and haemodynamic regulation modes during exercise accounts for the variability of arterial compliance measurements taken during exercise, irrespective of age and blood pressure level. However, these measurements remain of interest for their reproducibility and their correlation with the adrenergic tone. This may be useful for the choice of an antihypertensive therapy.     

Cytochrome P450 2C9 is involved in flow-dependent vasodilation of peripheral conduit arteries in healthy subjects and in patients with chronic heart failure

BACKGROUND: Flow-mediated dilation (FMD) of human conduit arteries is, in part, related to shear stress-induced release of endothelium-derived nitric oxide (NO). However, NO synthase inhibitors do not completely abolish this FMD-response. Recently, a cytochrome P450 (CYP) epoxygenase of the 2C family was linked to NO- and prostacyclin-independent relaxation of conduit arteries. We therefore evaluated the contribution of CYP 2C9 to FMD in humans. METHODS AND RESULTS: FMD of the radial artery was determined in 12 healthy volunteers by high-resolution ultrasound and analyzed before and after intra-arterial infusion of sulfaphenazole, a specific CYP 2C9 inhibitor, L-NMMA (NO synthase inhibitor) and co-infusion of both. Endothelium-independent vasodilation was characterized after intra-arterial infusion of SNP. FMD was reduced after sulfaphenazole (11.5+/-0.87% vs. 7.4+/-0.95%, p<0.01), after L-NMMA (6.0+/-0.71%; p<0.01), and after co-infusion 3.9+/-0.73% (p<0.05 vs. L-NMMA; p<0.01 vs. sulfaphenazole). Sulfaphenazole had no effect on endothelium-independent vasodilation. In patients with chronic heart failure, the portion of FMD blocked by sulfaphenazole was not affected. CYP 2C was detected by immunohistochemistry in radial artery samples obtained from patients undergoing coronary bypass surgery. CONCLUSIONS: FMD in human conductance arteries is reduced after inhibition of CYP 2C9, supporting the concept that CYP 2C metabolites contribute to endothelium-mediated vasodilation of peripheral conduit arteries in vivo. In patients with heart failure, the CYP-dependent FMD appears to be preserved.     

24-hour ambulatory blood pressure monitoring in normal and hypertensive subjects

24-hour ambulatory blood pressures (BP) of 172 normal subjects and 167 hypertensive patients recorded by automatic ambulatory monitoring device (A method) and standard mercury sphygmomanometer (B method) were studied. The results show: (1) 66% of normal subjects and 78% hypertensive patients have an evident circadian rhythm BP during 24-hours, BP readings during sleep and noon time are lower. (2) There is no significant difference between times at work and at home readings (P greater than 0.05), but the mean BP during sleeping time is the lowest (P less than 0.01). (3) The correlative coefficient of 24-hour average BP and casual clinic BP is low (r = 0.38-0.74). (4) The validity and accuracy of ambulatory BP monitoring by A and B methods were compared.     

Flow-mediated vasodilation of the femoral and brachial artery induced by exercise in healthy nonsmoking and smoking men.

OBJECTIVES: We sought to analyze diameter changes of conduit arteries in response to whole-body exercise and hypothesized that this response might be endothelium-dependent and, therefore, impaired in smokers. BACKGROUND: Hyperemia and coincident vasodilation are pivotal mechanisms for meeting the increased metabolic demands of active muscle tissue during physical exercise, but studies in humans are sparse. METHODS: We studied diameter and blood flow of the femoral and brachial arteries in response to a submaximal bicycle exercise test in 10 nonsmoking and 8 smoking healthy male subjects. During an exercise period of 40 min the investigated conduit arteries were periodically scanned in longitudinal sections by high-resolution ultrasound. In the same subjects flow-mediated dilation (FMD) of the brachial artery was recorded by inducing an ischemia through a forearm-occluding cuff. RESULTS: In response to exercise the diameter of the femoral artery significantly increased in both nonsmokers and smokers, with a diminished response in smokers (9.2 +/- 1.9% vs. 4.8 +/- 1.6%, p < 0.001). Flow-mediated dilation of the brachial artery induced by forearm occlusion was also reduced in smoking subjects, revealing a strong correlation between these different methods of FMD (exercise vs. forearm ischemia) (r = 0.88, p < 0.001). In contrast, blood flow increase of the femoral artery was similar in nonsmoking and smoking subjects (392 +/- 77% vs. 382 +/- 109%, p = NS). CONCLUSIONS: Conduit arteries react with a flow-mediated dilation in response to whole-body exercise. The impairment of this vasodilation observed in smokers was strongly related to a decrease of endothelium-dependent dilation induced by forearm ischemia, indicating that endothelial dysfunction represents the underlying mechanism.     

Tissue kallikrein gene polymorphisms induce no change in endothelium-dependent or independent vasodilation in hypertensive and normotensive subjects

BACKGROUND: Tissue kallikrein (TK) generates Lys-bradykinin, which is then converted to bradykinin and releases nitric oxide (NO) from endothelial cells via B2 receptors. TK gene inactivation in mice causes severe endothelial dysfunction, which is also a hallmark of human primary hypertension (PH). Healthy carriers of a loss-of-function Arg to His substitution at position 53 (R53H) of the TK gene exhibit paradoxical arterial eutrophic remodeling. We therefore investigated the impact of this and other TK gene single nucleotide polymorphisms (SNPs) on endothelium-dependent vasodilatation (EDV) and endothelium-independent vasodilatation (EIV) in PH patients and normotensive (NT) subjects. METHODS: The TK gene SNPs were genotyped blind to the phenotype by sequencing. We compared EDV and EIV vasodilatation across TK genotypes in 131 uncomplicated PH patients and 51 healthy NT subjects. EDV and EIV were assessed as the forearm blood flow response to a graded infusion of acetylcholine and sodium nitroprusside, respectively. We also evaluated the impact of the SNPs on NO-mediated EDV and on reactive oxygen species (ROS)-induced NO breakdown with the nitric oxide synthase (NOS) inhibitor N(G)-monomethyl-L-arginine or vitamin C, respectively. RESULTS: Genotypes and allele frequencies were in Hardy-Weinberg equilibrium and similar in PH and NT. EDV was lower in PH patients than in NT subjects. No TK genotype affected either EDV or EIV per se, or via interaction with gender and age. NO inhibition and scavenging of ROS showed no TK genotype effect on EDV. Similar conclusions were obtained with haplotype analysis. CONCLUSIONS: These results do not support the contention that TK gene SNPs have a major impact in determining NO-mediated responses to acetylcholine.     

Carotid artery intima-media thickness and brachial artery flow-mediated vasodilation in asymptomatic Japanese male subjects amongst apolipoprotein E phenotypes

BACKGROUND: Epidemiological studies suggest that apolipoprotein E (apoE) polymorphism influences plasma lipoprotein levels and the development of cardiovascular disease. OBJECTIVE: To clarify the role of apoE polymorphism as a risk factor for early atherosclerosis. DESIGN: Using a high-resolution ultrasound method, we investigated the association between apoE phenotypes, carotid intima-media thickness (CCA-IMT), and flow-mediated dilation in the brachial artery (brachial-FMD) in 96 healthy asymptomatic Japanese men (mean +/- SD age, 50 +/- 8 years). RESULTS: Serum cholesterol and LDL-cholesterol levels in subjects with E3E4 were highest and those with E2E3 were lowest (P < 0.05 and P < 0.05, respectively). The CCA-IMT in E3E4 subjects (0.76 +/- 0.17 mm) was greater than that in E2E3 and E3E3 (0.61 +/- 0.15 and 0.64 +/- 0.14 mm, respectively; P < 0.01). In contrast, there was no difference between brachial-FMD and apoE phenotypes (P=0.15). By univariate analysis, CCA-IMT was positively correlated with age (r=0.51, P < 0.01), LDL-chol/HDL-chol ratio (r=0.37, P < 0.01), triglycerides (r=0.23, P < 0.05), and negatively correlated with HDL-cholesterol (r=-0.31, P < 0.01). An association between CCA-IMT and the presence of E4 allele was also found (P < 0.05). Logistic regression analysis revealed that the presence of E4 allele was a higher risk for increased IMT (relative risk of 4.4, 95% CI 1.5-12.5), even after adjustment for age, LDL-cholesterol, blood pressure and other known risk factors. A negative correlation between brachial-FMD and CCA-IMT was also found in all subjects (r=-0.21, P < 0.05), being most apparent in the E3E4 subjects (r=-0.53, P < 0.02). CONCLUSION: ApoE4 phenotype was independently associated with an increased risk of carotid atherosclerosis and elevated LDL-cholesterol levels in asymptomatic middle-aged Japanese men.     

Humoral effects of metoclopramide and domperidone in normal subjects and in hypertensive patients

To evaluate whether, in humans, metoclopramide (MCP), a DA2 antagonist which readily crosses the brain-blood barrier, can stimulate plasma aldosterone (ALD) through hypophyseal-adrenal axis activation in addition to its direct adrenal antidopaminergic activity, we have investigated the effects of MCP and domperidone (DMP), a specific antagonist of peripheral DA2 receptors, on plasma ALD, adrenocorticotropin (ACTH), cortisol and prolactin (PRL) in 15 subjects. Ten controls and 5 uncomplicated essential hypertensive patients, in whom the dopaminergic tone is hypothesized to be reduced, received, according to a single-blind randomized procedure, MCP (10 mg iv) or DMP (10 mg iv) and, after an interval of at least 1 week, the reverse treatment. MCP and DMP similarly increased PRL (p less than 0.001), while only MCP significantly increased plasma ALD (p less than 0.01), ACTH (p less than 0.02) and cortisol (p less than 0.02) both in normotensives and in hypertensives, without any difference between them. These data confirm that, in spite of similar DA2 antagonistic potency of the two drugs, only MCP is able to increase plasma ALD. Since MCP significantly increased also ACTH levels we cannot exclude an involvement of this hormone on MCP-induced ALD release. Finally, the similar PRL and ALD response in normotensives and hypertensives does not support the hypothesis of a reduced dopaminergic system activity in essential hypertensives.     

Endothelium determines flow-dependent dilation of the epicardial coronary artery in dogs

The mechanisms of epicardial coronary artery dilation after reactive hyperemia were studied in instrumented conscious dogs. A pair of ultrasonic crystals, an electromagnetic flow probe and a cuff occluder were placed on the left circumflex coronary artery in 12 mongrel dogs under sterile conditions. Reactive hyperemia after 20 s of coronary occlusion dilated the epicardial coronary artery by 120 +/- 14 micron (3.8 +/- 0.6%, p less than 0.01) from 3.167 +/- 0.345 mm. This reactive dilation was abolished by flow-limiting coronary stenosis. However, vasodilation after nitroglycerin was 168 +/- 26 micron (5.1 +/- 0.5%) and 162 +/- 27 micron (4.9 +/- 0.6%), respectively, before and after flow limitation. After removal of the endothelium by a balloon catheter, dilation of the epicardial coronary artery after reactive hyperemia was markedly attenuated to 7 +/- 4 micron (p less than 0.01 versus before denudation), despite the presence of a similar degree of reactive hyperemia. The extent of coronary dilation after nitroglycerin was unchanged before and after de-endothelialization. Thus, the endothelium contributed to reactive dilation but not to the nitroglycerin-induced dilation. The negative feedback control of coronary diameter to changes in flow velocity may relate to the regulation of coronary artery tone.