Heterogenous nature of flow-mediated dilatation in human conduit arteries in vivo: relevance to endothelial dysfunction in hypercholesterolemia

Flow-mediated dilatation (FMD) of conduit arteries is dependent on an intact endothelium, although the mechanisms are not fully understood. Using high-resolution ultrasound, we examined the role of endothelial mediators in radial artery dilatation in response to transient (short period of reactive hyperemia) and sustained (prolonged period of reactive hyperemia, hand warming, or an incremental infusion of acetylcholine into the distal radial artery) hyperemia. After short episodes of reactive hyperemia, FMD was abolished by local infusion of the nitric oxide synthesis inhibitor N:(G)monomethyl-L-arginine (5.3+/-1.2% versus 0.7+/-0.7%, P:<0.001). In contrast, basal vessel diameter and dilatation after prolonged episodes of reactive hyperemia, hand warming, and distal infusion of acetylcholine were not attenuated by nitric oxide synthesis inhibition. Inhibition of cyclooxygenase or local autonomic nervous system blockade also had no effect on FMD. Patients with hypercholesterolemia exhibited reduced FMD in response to transient hyperemia, but the response to sustained hyperemia was normal. These data suggest heterogeneity of endothelial responses to blood flow that are dependent on the characteristics of the flow stimulus. Dilatation after brief episodes of hyperemia is mediated by release of nitric oxide, whereas dilatation during sustained hyperemia is unaffected by NO synthesis inhibition. Hypercholesterolemia seems to differentially affect these pathways with impairment of the nitric oxide-dependent pathway and preservation of non nitric oxide-mediated dilatation to sustained flow stimuli.     

Peripheral vascular endothelial function in essential hyperhidrosis.

BACKGROUND: Essential hyperhidrosis, a disorder of the eccrine sweat glands, is associated with sympathetic overactivity and the aim of the present study was to determine endothelium-dependent vasodilator function in patients with this condition. METHODS AND RESULTS: Using high-resolution ultrasound, the diameter of the brachial artery at rest and during reactive hyperemia (flow-mediated dilatation, %FMD endothelial-dependent stimulus to vasodilatation), as well as after sublingual administration of nitroglycerin (%NTG endothelium-independent vasodilatation) was measured in 18 subjects (mean age 27+/-5 years) with essential hyperhidrosis and 24 healthy control subjects (mean age 29+/-5 years). Baseline brachial artery diameter and FMD were comparable in both groups (BAD: 4.1+/-0.7 mm vs 4.3+/-0.5 mm (control), p = 0.8; FMD: 5.6+/-1.9% vs 6.7+/-2.2%, p=0.1). The time-averaged flow velocity during peak reactive hyperemia was similar in the 2 groups (75+/-11 cm/s vs 72+/-10 cm/s, p = 0.5), nor did NTG-induced dilatation in the patients with essential hyperhidrosis differ significantly from that in healthy control subjects (12.8+/-2.7% vs 14.0+/-3.6%, p = 0.3). CONCLUSION: These findings suggest that endothelium-dependent dilatation of large conduit arteries is preserved in essential hyperhidrosis and it seems to be a localized disorder of the eccrine sweat glands rather than a generalized disorder involving vascular endothelium.     

Correlation of endothelial function in large and small arteries in human essential hypertension

OBJECTIVES: The structure and function of blood vessels varies along the vascular tree, and alterations found in hypertension are also different. The aim of this study was to determine whether non-invasive measurement of endothelial function in conduit arteries reflects that of subcutaneous resistance arteries measured in vitro. METHODS AND RESULTS: Sixteen essential hypertensive patients (aged 50 +/- 2 years) were studied. Flow-mediated dilation (FMD) during reactive hyperemia (endothelium-dependent) and sublingual nitroglycerin (NTG)-induced dilatation (endothelium-independent) were assessed in brachial arteries by ultrasound. Structure, and acetylcholine (10(-9) to 10(-4) mol/l) and sodium nitroprusside (SNP, 10(-8) to 10(-3) mol/l)-induced vasorelaxation of resistance arteries dissected from gluteal subcutaneous biopsies were measured in vitro using a pressurized myograph. Brachial artery FMD and NTG-induced dilatation were 8.4 +/- 1.0 and 18.1 +/- 1.4%, respectively. Resistance arteries of hypertensive patients showed greater media:lumen ratio (8.6 +/- 0.4 versus 5.9 +/- 0.3% in normotensive subjects, P< 0.01), and maximal acetylcholine responses was diminished to 75 +/- 6% compared to normotensive subjects (97 +/- 2%, P< 0.01). FMD correlated with maximal acetylcholine responses (r2 = 0.57, P< 0.001). FMD did not correlate significantly with the media: lumen ratio of resistance arteries (r2 = -0.22, P= 0.07). By multivariate analysis, FMD predicted resistance artery endothelial function independently of age, sex, body mass index, blood lipid status and lumen diameter of brachial artery (beta = 0.81, P< 0.001). CONCLUSIONS: Endothelial dilatory responses are similar in large and small arteries in hypertensive patients. Abnormal FMD in the brachial artery predicts the presence of endothelial dysfunction in human resistance arteries, suggesting that impairment of endothelial function is a generalized alteration in hypertension. Ultrasound measurement of endothelial dysfunction in the brachial artery appears to be less sensitive than in-vitro measurement in resistance arteries.     

Nitric oxide release is impaired in hypertensive individuals with familial history of stroke

BACKGROUND: A genetic origin of cerebrovascular accidents has long been suspected on the basis of epidemiologic evidence and familial aggregation. Nevertheless, the final phenotype is largely influenced by concomitant risk factors. We aimed to investigate whether impairment of endothelium-dependent vasodilation can be used as an informative intermediate vascular phenotype in hypertensive patients with familial history of stroke. METHODS: Fourteen hypertensive individuals, seven with familial history of stroke (FH+), seven without familial history of stroke (FH-), and six normotensive volunteers (C) were included in the study. High-resolution ultrasound and Doppler were used to measure radial artery diameter and blood flow at rest, during reactive hyperemia, and after intra-arterial infusion of N(G)-monomethyl-l-arginine (L-NMMA) to inhibit NO synthase. RESULTS: Basal blood flow and diameter were comparable in all groups. Flow-mediated dilation was impaired in FH+ (3.2% +/- 2%), compared with FH- (9.6% +/- 1%; P = . 01) and C (15.9% +/- 3%; P = . 001). The L-NMMA decreased basal flow in FH- (16.0 +/- 2 v 13.8 +/- 1 mL/min; P = . 04), and C (23.3 +/- 2 v 16.5 +/- 2 mL/min, P = .003) but did not exert any significant effect in FH+ subjects (16.4 +/- 3 v 15.8 +/- 2 mL/min, P = .77). CONCLUSIONS: These findings demonstrate that NO bioavailability is reduced in hypertensive subjects with familial history of stroke. Such a phenotype may represent an early marker of susceptibility to cerebrovascular events in this population.     

Ramipril dose-dependently increases nitric oxide availability in the radial artery of essential hypertension patients

DESIGN AND PARTICIPANTS: A double-blind, crossover, randomized study was designed to evaluate the effect of 3-month treatment with a lower versus a higher antihypertensive dosage of ramipril (5 or 10 mg/day) on nitric oxide (NO)-dependent vasodilation in 46 untreated patients with essential hypertension. Radial artery flow-mediated dilation (FMD), before and after the intra-arterial infusion of NG-monomethyl-L-arginine (L-NMMA), to block NO synthase, and the response to sublingual glyceril trinitrate (GTN, 25 microg) were measured at baseline and after the two treatment periods as a change in artery diameter (computerized system from ultrasound scans). Plasma angiotensin II and oxidative stress markers were also assessed. RESULTS: FMD was significantly (P < 0.01) lower in hypertensive patients (4.6 +/- 1.8%) than in normotensive subjects (7.1 +/- 2.6%), whereas the response to GTN was similar. L-NMMA significantly (P < 0.001) inhibited FMD in normotensive but not in hypertensive subjects. Mean 24-h ambulatory blood pressure, plasma angiotensin II and oxidative stress marker levels were similarly reduced at the end of the two treatment periods. Both dosages of ramipril significantly (P < 0.001) increased FMD (5 mg: 5.9 +/- 2.1%; 10 mg: 6.3 +/- 2.4%) without modifying the response to GTN. However, compared with baseline (11 +/- 19%), the inhibiting effect of L-NMMA on FMD (NO-dependent FMD) was significantly (P < 0.01) greater with ramipril 10 mg (49 +/- 12%) than 5 mg per day (38 +/- 15%). The improvement in FMD and NO-dependent FMD was not related to changes in plasma levels of angiotensin II or markers of oxidative stress. CONCLUSION: Treatment with ramipril at a higher dosage induced a greater improvement in NO-dependent vasodilation compared with the lower antihypertensive dosage in hypertensive patients.     

Correlation between flow-mediated vasodilatation of the brachial artery and intima-media thickness in the carotid artery in men

Endothelial dysfunction has been reported to be the initial step in atherosclerosis. A noninvasive technique that uses ultrasound to measure the intima-media thickness of the carotid artery has been applied to evaluate localized atherosclerosis. This study was undertaken to elucidate whether endothelial dysfunction in the brachial artery is related to the intima-media thickness of the carotid artery. Thirty-four men with atherosclerosis (mean+/-SE age 61+/-2 years) and 33 age-matched men without clinical atherosclerosis were examined. The intima-media thickness and plaque formation of the common carotid artery were assessed by B-mode ultrasonography. We also noninvasively measured brachial artery diameter by the same ultrasound machine when the subjects were at rest, during reactive hyperemia, which causes endothelium-dependent vasodilatation, and after sublingual administration of nitroglycerin, which causes endothelium-independent vasodilatation. The atherosclerosis group had a significantly greater intima-media thickness of the common carotid artery than did the control group (1. 02+/-0.04 versus 0.91+/-0.03 mm, P<0.05). The flow-mediated diameter (FMD) increase (percent FMD=DeltaD/D x 100) in the atherosclerosis group was significantly smaller than that in the control group (2. 8+/-0.4% versus 5.1+/-0.6%, P<0.01). A significant negative correlation between the intima-media thickness of the carotid artery and percent FMD was found in all of the subjects. On multiple regression analysis, percent FMD showed a significant negative correlation with the intima-media thickness of the common carotid artery. These findings support the concept that endothelial dysfunction is significantly related to atherogenesis.     

Effects of prostaglandin E1alpha cyclodextrin [corrected] treatment on endothelial dysfunction in patients with systemic sclerosis

OBJECTIVE: Systemic sclerosis (SSc) is characterized by an altered nitric oxide (NO): endothelin I ratio and by endothelial dysfunction. AIMS: To verify the effects of prostaglandin E1 (PGE1) alpha-cyclodestrin treatment on endothelial function, quantified as flow-mediated dilation (FMD) of the radial artery. METHODS: In 16 women with SSc (age 57 +/- 2.7 years, means +/- SE) in whom a diagnosis of SSc had been made several years earlier (7.1 +/- 1.2 years), FMD was evaluated by an echotracking technique on the radial artery, using trinitroglycerin vasodilation as a non-endothelial measure of the vessel's ability to increase its diameter maximally. FMD was evaluated after 4 months washout period and after 4 months cyclic infusion of PGE1 alpha-cyclodestrin. Expired NO was measured at the same time. RESULTS: PGE1 alpha-cyclodestrin cyclic infusions did not modify systolic and diastolic blood pressure, heart rate or trinitroglycerin radial artery vasodilation. On the other hand, it induced a marked and significant increase in FMD of the radial artery, which was also accompanied by an increase in blood flow and expired NO. CONCLUSIONS: Endothelial dysfunction and reduced FMD associated with SSc are improved by cyclic treatment with PGE1 alpha-cyclodestrin. This effect occurs together with a concomitant increase in expired NO, suggesting its direct positive influence on endothelial function. It may also partly explain the clinical beneficial effect of the drug in SSc.     

Endothelial dysfunction and decreased exercise tolerance in interferon-alpha therapy in chronic hepatitis C: relation between exercise hyperemia and endothelial function

BACKGROUND: We previously reported that reversible endothelial dysfunction is caused by interferon-alpha therapy (IFN) in patients with chronic hepatitis C. In experimental studies, limb blood flow during exercise is reported to be dependent on endothelium-derived nitric oxide. HYPOTHESIS: The purpose of this study was to confirm the effect of IFN on endothelial function and to investigate whether exercise hyperemia is dependent on endothelial function in humans. METHODS: We performed symptom-limited exercise treadmill testing and measured flow-mediated vasodilation (FMD, endothelium-dependent vasodilation) and sublingual glyceryl-trinitrate-induced dilation (GTN-D, 0.3 mg, endothelium-independent vasodilation) in the brachial artery by using high-resolution ultrasound in 10 patients with chronic active hepatitis C (age 53 +/- 11 years, 2 men, 8 women) before and immediately after administration of recombinant interferon 2b (10 million U/day) for 4 weeks. RESULTS: There were no significant abnormal findings in any patients in routine studies of 24-h ambulatory electrocardiogram monitoring, two-dimensional echocardiography, and exercise treadmill testing both before and after treatment. Leg fatigue and exhaustion were the reasons for termination of exercise treadmill testing in each patient. Pressure rate product was calculated at rest and peak exercise. Interferon-alpha therapy significantly (p<0.05) decreased FMD (6.8 +/- 3.1 vs. 1.9 +/- 2.6%), exercise treadmill testing tolerance time (437 +/- 89 vs. 395 +/- 62 s) and peak pressure rate product (283 +/- 41 vs. 241 +/- 47 mmHg x beats/min x 10(-2)), but not GTN-D (13.4 +/- 5.4 vs. 17.0 +/- 5.5%). The change of FMD due to IFN significantly and highly correlated with exercise treadmill testing tolerance time (r = 0.86, p<0.001), but not with change of peak pressure rate product, suggesting that FMD is more closely related to the condition of the peripheral circulation than is cardiac performance. CONCLUSION: These results suggest that IFN in patients with chronic hepatitis C impairs endothelial function and exercise tolerance, and that endothelial function might be at least partly involved in exercise hyperemia in humans.     

Non-invasive evaluation of endothelial function in hypertensive elderly patients

Impaired endothelium-dependent vasomotion is a diffuse disease process resulting in abnormal regulation of blood vessel tone and loss of several atheroprotective effects of the normal endothelium. The aim of the present study was to investigate the effects of aging and hypertension on endothelial function. Sixty-six geriatric subjects with ages over 60 (48 hypertensive and 18 healthy) and 40 middle-aged subjects (16 hypertensive and 24 healthy) were included in the study. Systemic vascular endothelial function was evaluated through measuring brachial arterial vasodilation, a physiologic answer to reactive hyperemia occured with increased blood flow in the vessel after transient ischemia (flow-mediated dilation, FMD%), and with carotid artery intima-media thickness (IMT) measurement, using high-resolution ultrasonography. Endothelial independent vasodilation was also measured after administration of sublingual isosorbide dinitrate (isosorbide dinitrate mediated dilation, IDNMD%). FMD% was significantly decreased in elderly and/or hypertensive (HT) patients (geriatric HT: 9.5 +/- 4.7%, geriatric non-HT: 12.7 +/- 5.5%, middle-aged HT: 12.9 +/- 4.3% and middle-aged non-HT: 18.9 +/- 8.1%) (geriatric HT versus geriatric non-HT (P = 0.02), geriatric HT versus middle-aged HT (P = 0.01), geriatric non-HT versus middle-aged non-HT (P = 0.008)). Both FMD% and IDNMD% were inversely correlated with age, baseline vessel diameter and carotid artery intima-media thickness. FMD% was also inversely correlated with diastolic blood pressure. No correlation was found between FMD% and systolic blood pressure, serum cholesterol and triglyceride levels. Endothelium dependent (EDD) and independent dilatation of large arteries decreased with aging even in the healthy elderly, and FMD further declined in HT elderly patients, indicating that age and hypertension independently impair endothelial function. Positive correlations with age and hypertension, and significant inverse correlation with FMD, makes carotid artery IMT a possible indicator of endothelial function.     

Myocardial perfusion reserve and peripheral endothelial function in patients with idiopathic dilated cardiomyopathy

The aim of this study was to assess the relation between peripheral endothelial function and myocardial perfusion reserve in patients with mild heart failure due to idiopathic dilated cardiomyopathy (IDC). Myocardial perfusion and brachial artery flow mediated dilation (FMD) were measured in 20 clinically stable patients with IDC (New York Heart Association classes I to III, ejection fraction 35 +/- 9%) and 13 apparently healthy subjects who were matched for age and lipid profile. Resting and hyperemic (dipyridamole; 0.56 mg/kg/min) perfusion were measured using oxygen-15-labeled water and positron emission tomography (PET). Perfusion reserve was calculated as the ratio of hyperemic to resting perfusion. FMD was assessed by measuring the change in brachial artery diameter in response to reactive hyperemia. Patients with IDC had lower hyperemic perfusion (1.73 +/- 0.83 vs 3.01 +/- 1.20 ml/min/g, p <0.001) and perfusion reserve (2.01 +/- 0.91 vs 3.08 +/- 1.35, p <0.01) compared with healthy subjects. Brachial artery FMD, however, was not different from that of the healthy subjects. Furthermore, neither hyperemic perfusion nor perfusion reserve was correlated with FMD in the patients with IDC, whereas the healthy subjects demonstrated a positive correlation between FMD and perfusion reserve (r = 0.57; p = 0.04). Thus, abnormal myocardial perfusion characterizes patients with IDC. Myocardial perfusion reserve and peripheral endothelial function do not parallel each other in patients with IDC.     

Measurement of flow-mediated vasodilation of the brachial artery: a comparison of measurements in the seated and supine positions.

BACKGROUND: Measurement of flow-mediated vasodilation (FMD) is used to assess endothelial function in humans and according to the guidelines, subjects must remain supine during the study. However, measurement of FMD while seated would be more comfortable and convenient for patients, so the purpose of this study was to determine the effect of the patient's position on FMD results. METHODS AND RESULTS: High-resolution ultrasonography, a linear array transducer (13 MHz) and an arm-holding device were used to measure arterial diameter in response to reactive hyperemia (FMD, cuff inflated to 50 mmHg above systolic blood pressure for 5 min) and in response to sublingual nitroglycerine (NTG, 75 microg) in 31 subjects, which included those with cardiovascular diseases. There was no significant difference between basal or peak hyperemic blood flow in the seated or supine position. Basal brachial artery diameter, FMD and vascular response to NTG were similar in both positions (basal diameter: 3.8+/-0.4 vs 3.9+/-0.4 mm, FMD: 7.3+/-4.3% vs 7.2+/-4.5%, NTG: 13.1+/-5.1% vs 12.8+/-5.6%). CONCLUSIONS: The findings suggest that measurement of FMD in the seated position is as useful as measuring it in the supine position for assessing endothelial function. This flexibility of position is better for patients and physicians, and should lead to more widespread measurement of FMD.     

Assessment of peripheral vascular endothelial function in the ambulatory setting

Until now, peripheral vascular endothelial function testing has been performed in research laboratories under highly controlled conditions, thus limiting its clinical applicability. In this study, we evaluated endothelial function in two peripheral vascular beds before and during reactive hyperemia in an outpatient clinic setting. The brachial artery was imaged with a portable ultrasound device and changes in vessel diameter were expressed as percent flow-mediated dilation (%FMD). Pulse wave amplitude of the finger was detected by peripheral arterial tonometry (PAT) and PAT hyperemia was defined as the maximal plethysmographic recording compared to baseline. Sixty individuals (43 men) were enrolled with an average age 53 +/- 2 years (mean +/- SE). The 31 individuals with more than two cardiac risk factors (CRF) had lower FMD (7.0 +/- 1.1%) and PAT hyperemia (2.1 +/- 0.9) compared to the 29 individuals with 0-2 CRF (FMD 11.3 +/- 0.8%, PAT hyperemia 2.4 +/- 0.1; p < 0.05 for both). The 32 individuals with coronary artery disease (CAD) had lower FMD (6.8 +/- 1.1%) and PAT hyperemia (2.0 +/- 0.1) compared to the 28 individuals without CAD (FMD 11.5 +/- 0.8%, PAT hyperemia 2.4 +/- 0.1; p < 0.05 for both). Thus, peripheral vascular endothelial function testing in the ambulatory setting correlates with the extent of CAD risk and the presence or absence of CAD. In conclusion, these data suggest that peripheral vascular endothelial function testing is feasible in ambulatory patients, and this is an important next step in bringing this technology to clinical applicability.     

奥利司他对超重合并高血压患者内皮依赖性血管舒张功能的影响

目的观察超重合并高血压患者服用奥利司他治疗前后血压和超声肱动脉内皮依赖性血管舒张功能的变化.方法30例超重合并轻度高血压患者(超重高血压组)服用脂肪酶抑制剂--奥利司他(orlistat,商品名赛尼可 )120 mg,每日3次,共12周,服药前后诊所测量身高、体重、腰围及血压,并行肱动脉超声检查,测定血流介导的血管舒张功能.15例非超重的高血压患者作为对照组.结果超重高血压组治疗前加压反应性充血后肱动脉内径平均增加(9.6±1.7)%,流速增加(29.7±3.05)%,增加幅度低于对照组,与对照组比有显著性差异(P＜0.01).超重高血压组奥利司他治疗12周后,加压反应性充血后肱动脉内径增加达(14.2±2.0)%、流速增加达(56.7±4.14)%,血流介导的血管舒张功能较治疗前显著改善(P均＜0.01).超重高血压组患者治疗后平均减重5.3 kg,腰围减少6.3 cm,收缩压/舒张压平均下降13.3/5.7 mmHg(1 mmHg=0.133 kPa),与治疗前比有显著性差异(P均＜0.05～0.01).结论奥利司他能降低超重合并高血压患者的体重,并能改善血流介导的内皮依赖性动脉舒张功能.     

Oral L-arginine and vitamins E and C improve endothelial function in women with type 2 diabetes

Endothelial dilator function is impaired in people with type 2 diabetes mellitus (T2DM). Prior research indicates that this can be improved with intravenous administration of ascorbate or L-arginine, but whether these agents have this effect when administered by the clinically practical oral route is unknown. To investigate this question, 10 premenopausal women with T2DM and 10 healthy, premenopausal, non-diabetic women received, in random sequence, a 1-week administration of oral L-arginine (9 g daily) or vitamins E (1800 mg) and C (1000 mg) with an intervening 1-week washout period. Flow-mediated brachial artery dilation (FMD) was measured by ultrasonography and forearm blood flow was measured by plethysmography before and following blood pressure cuff-induced forearm ischemia before and after each week of treatment. At baseline, the women with T2DM had lesser FMD responses (0.028 +/- 0.006 cm vs 0.056 +/- 0.008 cm, p < 0.05). Post-ischemic forearm hyperemia was reduced at baseline in T2DM compared with controls (16.4 +/- 1.8 vs 26.0 +/- 1.4 ml 100 ml(-1) min(-1), p < 0.05). Administration of L-arginine caused a 50 +/- 12% increase in FMD in T2DM (p < 0.05) and raised post-ischemic forearm blood flow by 29 +/- 8% (p < 0.05). No significant changes were seen in controls. Administration of vitamins E and C in women with T2DM produced an increase in the brachial artery diameter response of 79 +/- 15% (p < 0.05), but did not significantly increase the hyperemic blood flow response (p = NS). No significant changes in the responses of controls from pre to post vitamin administration were observed. We concluded that administration of two types of oral agents improved measures of endothelial function in people with T2DM.     

Cutaneous microvascular effects of mid-term hormone replacement therapy in healthy postmenopausal women: a prospective placebo controlled trial

OBJECTIVE: To study the mid-term effects of Hormone Replacement Therapy (HRT) on cutaneous microcirculatory blood flow and reactivity in healthy postmenopausal women. DESIGN: In a double-blind placebo controlled randomized study, 16 healthy postmenopausal women received either placebo or HRT (micronized estradiol: 1 mg/day, day 1-28, promegestrone: 0.25 mg/day, day 14-28). This regimen was completed 6 times. Cutaneous microcirculatory blood flow was recorded by laser-Doppler velocimetry on the foot dorsum, in the supine and then dependent positions, and after post-ischemic hyperemia. RESULTS: At day 0, the two groups were similar and none of the following data differed significantly between treated and placebo group: (supine flux: 11.8 +/- 1.8 u vs. 13.2 +/- 3.9, venoarteriolar reflex: 5.6 +/- 1.3 vs. 6 +/- 3.3, and post-ischemic hyperemia: 35.2 +/- 3.9 vs.48.3+/-11). At the end of the study (day 26-28 of 6th cycle), the supine flux was 9.8 +/- 2.1 in the HRT group vs.12.9 +/- 6 in the placebo group (NS), the venoarteriolar reflex, 1.2 +/- 2 vs. 7+/-1.7 (p=0.04), and post ischemic hyperemia, 31.8 +/- 5.4 vs. 39.5 +/- 4.6 (NS). Intragroup values did not change significantly for any of the microcirculatory parameters measured, which remained stable throughout the 6 months of the study. Intergroup values for these parameters did not change either, except for the venoarteriolar reflex, which was lower at the end of the study in the HRT (EP period, cycle 6 day 26-28) than placebo group (p=0.04). CONCLUSIONS: HRT does not impair the resting supine cutaneous microcirculation blood flow or post-ischemic hyperemia.     

Carvedilol improves endothelium-dependent dilatation in patients with coronary artery disease

OBJECTIVE: Flow-mediated, endothelium-dependent dilatation (FMD) of the coronary and peripheral circulation is impaired by increased oxidative stress in patients with coronary artery disease (CAD). Carvedilol is a novel beta-blocker that also shows an antioxidant effect in vitro. However, the effect of carvedilol on endothelial dysfunction associated with established coronary atherosclerosis has not been examined in the clinical setting. METHODS: We studied 29 patients with CAD, including 17 with recent myocardial infarction and 12 with stable effort angina pectoris. Nineteen patients received carvedilol (10 with infarction and 9 with angina), and 10 were treated with placebo (7 with infarction and 3 with angina). We also studied 13 age- and sex-matched control subjects. Brachial FMD during reactive hyperemia and nitroglycerin-induced, endothelium-independent dilatation were assessed by high-resolution ultrasound. RESULTS: FMD was smaller in patients with CAD compared with controls, although nitroglycerin-induced dilatation was similar. Carvedilol significantly improved FMD after long-term treatment (5. 1% +/- 0.4% at baseline to 7.8% +/- 0.3% after 4 months; P <.01) but not after short-term treatment (5.1% +/- 0.4% at baseline to 5.0% +/- 0.7% after 2 hours). Placebo therapy had no effect on endothelial dysfunction. Neither carvedilol nor placebo had an effect on nitroglycerin-induced dilatation after short- and long-term treatment. Long-term carvedilol therapy also significantly decreased the plasma level of thiobarbituric acid-reactive substances compared with placebo (carvedilol, 5.8 +/- 0.4 nmol/mL to 4.6 +/- 0.3 nmol/mL, P <.01; placebo, 5.9 +/- 0.4 nmol/mL to 5.8 +/- 0.4 nmol/mL, P = not significant). CONCLUSION: These findings suggest that the improvement of endothelial function by carvedilol may be caused by its antioxidant activity.     

Octreotide ameliorates the increase in collateral blood flow during postprandial hyperemia in portal hypertensive rats

BACKGROUND/AIMS: The aims of this study were to examine, in a conscious rat model of portal hypertension, the effect of postprandial splanchnic hyperemia on collateral blood flow and to determine whether octreotide has an effect on postprandial collateral flow changes. METHODS: In rats with portal vein ligation, pulsed-Doppler flowmeters were implanted chronically around the splenorenal venous shunt (SRS), which is the main spontaneous collateral vessel in the portal hypertensive rat and around the superior mesenteric artery (SMA). Changes in flow after a standard liquid meal gavage and after the administration of octreotide were examined in the rat under unanesthetized and unrestricted conditions. RESULTS: SRS flow increased significantly after gavage with a standard liquid meal (10.6+/-2.9%) compared to orogastric intubation alone (-6.5+/-2.1%) (P<0.01). Similar flow changes were observed in the SMA after liquid meal gavage. The subcutaneous administration of octreotide at a dose of 400 g/kg reduces basal SRS flow (-19.5+/-2.3%) and significantly attenuated the change in SRS flow after liquid meal gavage (-8.1+/-2.9%) compared to animals that received placebo (3.6+/-4.1% and 27.8+/-7.6%, respectively) (P<0.05). CONCLUSION: These results demonstrate that, in an experimental model of prehepatic portal hypertension, postprandial splanchnic hyperemia results in an increase in collateral flow that can be ameliorated with the use of octreotide.     

Impaired endothelial function in hypertensive elderly patients evaluated by high resolution ultrasonography.

BACKGROUND: Multiple investigations both in experimental models and in middle-aged patients with essential hypertension have demonstrated impaired endothelium-dependent vasodilation. OBJECTIVE: To determine whether hypertension exerts an additional negative effect on endothelial function of large arteries in hypertensive elderly patients who may already be affected by endothelial dysfunction due to aging. PATIENTS AND METHODS: Thirteen elderly patients with hypertension (69 9 years of age [mean SD]) were compared with 13 matched healthy elderly subjects (72 6 years of age). High resolution vascular ultrasound was used to measure brachial artery responses to reactive hyperemia (with increased flow causing endothelium-dependent dilation) and to sublingual nitroglycerine (causing endothelium-independent dilation). RESULTS: Flow-mediated diameter (FMD) was significantly impaired in the hypertensive elderly group (6.7 3.3% versus 13.3 3.8% in the control group, P<0.05). No significant difference could be found in nitroglycerine-induced dilation between the elderly control group (12.1 4.9%) and the hypertensive elderly (10.2 6.8%). On simple linear analysis, FMD was inversely correlated with age (r=-0.60, P=0. 03) in the healthy elderly group. FMD in the hypertensive elderly was inversely related to age (r=-0.41, P=0.04) and mean blood pressure (r=-0.67, P=0.01). CONCLUSIONS: This study showed decreased FMD with aging even in the healthy elderly, with a further decline in hypertensive elderly compared with healthy elderly subjects. This impairment of FMD in the hypertensive elderly group was related to age and mean blood pressure, indicating that aging and hypertension may impair endothelial function in the brachial artery of elderly patients with hypertension.     

The antihypertensive effects of doxazosin on the arterial system: changes in peripheral vascular resistance and wall tension

Background: Hypertension is characterized by structural and functional abnormalities that affect the entire cardiovascular system, including the large arteries. The antihypertensive efficacy of doxazosin, a selective alpha(1) antagonist, and its effects on the arterial system were investigated. Method: In our double-blind, randomized, placebo-controlled study including 30 hypertensive patients (doxazosin group: nine males, 11 females; mean age 45+/-12 years; placebo group: four males, six females; mean age 47+/-9 years), the systolic, diastolic and mean blood pressure (BP), heart rate, diameter and area of the brachial artery, peak systolic velocity, end-diastolic velocity, pulsatility index (PI), resistance index (RI), S/D (systolic velocity/diastolic velocity), flow volume, local resistance, and wall tension were recorded before and 4 h after the administration of 2 mg doxazosin or placebo. The two groups were statistically compared. Results: In the doxazosin group, systolic, diastolic and mean pressures decreased significantly (P<0.001), while heart rate remained unchanged. Local resistance (P<0.001), RI (P<0.05), PI (P<0.05), and wall tension (P<0.001) all decreased significantly, while flow volume increased significantly (P<0.05). However, no significant changes were observed in arterial diameter, surface area, peak systolic velocity, end-diastolic velocity or S/D ratio. The placebo group did not show a significant difference in any of the parameters listed above. Conclusion: The antihypertensive effect of doxazosin is accompanied by a reduction in brachial arterial wall tension that occurs without any change in arterial diameter. The lack of change in the diameter of the artery leads us to suggest different effects on other vasomotor determinants.     

Effects of low-dose aspirin on blood pressure and endothelial function of treated hypertensive hypercholesterolaemic subjects

The main objective of this study was to assess whether aspirin 100 mg QD can improve blood pressure (BP) control and endothelial function in subjects with arterial hypertension (AH) and hypercholesterolaemia. In total, 21 patients of both sexes (52.1+/-11.5 years) with treated AH and hypercholesterolaemia on antihypertensive and statin therapy were included in the treatment group. In the control group, 20 matched patients of both sexes (51.3+/-12.7 years), but without statin therapy, were recruited. Treatment group subjects received aspirin (100 mg QD) for a duration of 12 weeks at randomization (Treatment phase-1), followed by single blind matching placebo for 12 weeks (Placebo phase) and then again received aspirin (100 mg QD) for an additional 12 weeks (Treatment phase-2). The control group participated in Treatment phase-1, but did not continue Placebo phase and Treatment phase-2. At randomization and at the end of each study phase, mean 24-h systolic BP (SBP) and diastolic BP (DBP) were assessed by 24-h ambulatory blood pressure monitoring (ABPM) and endothelium-dependent (flow mediated, FMD) and -independent (nitroglycerin induced, NTG) vasodilatations of brachial artery were measured using high-resolution ultrasound. In Treatment phase-1, reduction of SBP and DBP (DeltaSBP 5.7+/-2.6 mmHg, P=0.008; DeltaDBP 3.8+/-1.7 mmHg, P=0.014) and improvement of FMD (4.1+/-0.6%, P=0.019), in Placebo phase an elevation of SBP and DBP (DeltaSBP -6.2+/-2.9 mmHg, P=0.002; DeltaDBP -4.2+/-1.9 mmHg, P=0.031) and worsening of FMD (-3.8+/-0.9%, P=0.027), and in Treatment phase-2 reduction of SBP and DBP (DeltaSBP 4.9+/-2.3 mmHg, P=0.005; DeltaDBP 4.1+/-1.3 mmHg, P=0.024) and improvement of FMD (4.5+/-1.3%, P=0.009) were observed in the treatment Group but not in the control group. Addition of low-dose aspirin to antihypertensive medications and statins in hypertensive and hypercholesterolaemic subjects can reduce both SBP and DBP by improvement of endothelial function.