Captopril improves impaired endothelium-dependent vasodilation in hypertensive patients.

Animal studies suggest that some angiotensin converting enzyme inhibitors augment endothelium-dependent vasorelaxation. We aimed to determine if captopril augments endothelium-dependent vasodilation in middle-aged hypertensive patients. By using strain-gauge plethysmography, forearm vasodilation evoked with intra-arterial acetylcholine (4, 8, 16, and 24 micrograms/min) or nitroprusside (0.2, 0.4, 0.8, and 1.2 micrograms/min) was examined before and after captopril administration (25 mg per os). Before captopril, forearm vasodilation with acetylcholine was less in hypertensive patients (n = 12) than in age-matched (n = 7) or young (n = 7) normotensive subjects, but forearm vasodilation with nitroprusside did not differ among the three groups. Captopril improved forearm vasodilation in hypertensive patients (n = 7) with acetylcholine but nitroprusside did not. In contrast, nifedipine (10 mg per os) did not alter forearm vasodilation with acetylcholine or nitroprusside in hypertensive patients (n = 5). The decreases in mean blood pressure caused by captopril and nifedipine in hypertensive subjects were comparable. Captopril did not alter forearm vasodilation with acetylcholine or nitroprusside in young normotensive subjects (n = 7). These results suggest that captopril in hypertensive patients may acutely improve impaired endothelium-dependent forearm vasodilation that does not result from reduction in blood pressure per se.     

四氢喋呤对高胆固醇血症兔内皮舒张功能的影响

目的　研究四氢喋呤 (tetrahydrobiopterin ,BH4)对于胆固醇喂养兔的血管内皮舒张功能的影响。方法　 2 4只新西兰兔随机分为三组 :A组进食普通饲料 ,B、C组进食高脂饲料。C组在指标观测前 2h耳缘静脉注射BH410mg/kg ,5周后三组动物取胸主动脉进行离体血管条实验 ,分别测定血管条对乙酰胆碱 (Ach)、三磷酸腺苷 (ATP)、硝普钠 (SNG)的累积浓度舒张反应。结果　B组血管条对Ach、ATP的最大舒张反应能力较A组明显降低 (分别为Bmax =4 65± 1 63比Amax =13 87±2 62 ,Bmax =4 2 7± 1 41比Amax =12 0 3± 2 55,P <0 0 1) ;C组对Ach、ATP的最大舒张反应能力较B组明显改善 (分别为Cmax =9 0 6± 2 14比Bmax =4 65± 1 63 ,Cmax =10 87± 1 89比Bmax= 4 2 7± 1 41,P <0 0 1) ;而三组血管条对硝普钠的最大舒张功能无明显改变 (Amax =7 2 0± 2 3 0 ,Bmax =6 77± 1 86,Cmax =6 2 3± 2 13 ,P >0 0 5)。结论　高胆固醇血症时内皮依赖性舒张功能受损 ,四氢喋呤能改善高胆固醇血症时内皮依赖性舒张功能 ,而对非内皮依赖性舒张功能无影响     

Tetrahydrobiopterin improves aging-related impairment of endothelium-dependent vasodilation through increase in nitric oxide production

Deficiency of tetrahydrobiopterin (BH4), an essential cofactor for nitric oxide (NO) synthase, decreases NO production and increases reactive oxygen species. The purpose of this study was to elucidate the effects of aging on endothelial function and to determine whether the degree of BH4 deficiency is related to aging and oxidative stress. We evaluated forearm blood flow (FBF) responses to acetylcholine (ACh), an endothelium-dependent vasodilator, and isosorbide dinitrate (ISDN), an endothelium-independent vasodilator, before and after co-infusion of BH4 (500 mg/min) in 37 healthy men (mean age, 41+/-18 yr; range, 19-81 yr). FBF was measured using strain-gauge plethysmograph. Urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) and serum malondialdehyde-modified low-density lipoprotein (MDA-LDL) were measured as indices of oxidative stress. Both ACh and ISDN increased the FBF in a dose-dependent manner in all subjects. Co-infusion of BH4 resulted in a significant increase in ACh-induced vasodilation (from 22.3+/-6.7 to 30.1+/-7.5 mL/min/100 mL tissue, P<0.05). Aging was found to be significantly correlated with ACh-induced vasodilation (r=-0.47, P=0.006), urinary 8-OHdG (r=0.38, P=0.02), serum MDA-LDL (r=0.36, P=0.02), and the change in ACh-induced vasodilation after co-infusion of BH4 (r=0.45, P=0.007). The FBF response to ISDN did not correlate with any parameters. Infusion of N(G)-monomethyl-L-arginine, an NO synthase inhibitor, abolished the BH4-induced enhancement of forearm vasorelaxation evoked by ACh. The increase in FBF after ISDN was not altered by BH4. These findings suggest that a deficiency of BH4 may be involved in the pathogenesis of disturbances in endothelium-dependent vasodilation related to aging through decrease in NO production and increase in oxidative stress.     

Low body mass index is a risk factor for impaired endothelium-dependent vasodilation in humans: role of nitric oxide and oxidative stress

OBJECTIVES: The purpose of this study was to evaluate the relationship between body mass index (BMI), including low BMIs, and endothelial function. BACKGROUND: Epidemiologic study has demonstrated that not only obesity but also a low BMI may be a risk factor for cardiovascular disease. METHODS: The forearm blood flow (FBF) response to acetylcholine (ACh) and isosorbide dinitrate (ISDN) was measured in 87 healthy young men (15 low BMI, 51 normal, 14 obese, and 7 extremely obese). RESULTS: Plasma concentrations of 8-hydroxy-2'-deoxyguanosine and serum concentrations of malondialdehyde-modified low-density lipoprotein were higher in low BMI, obese, and extremely obese subjects than in normal subjects and were similar among the low BMI, obese, and extremely obese groups. The FBF response to ACh was greater in the normal group than in the other groups (p < 0.001), and was lower in the extremely obese group as compared with the other groups (p < 0.001). The ACh-stimulated vasodilation was similar between the low BMI group and the obese group. The ISDN-stimulated vasodilation was similar in all four groups. There were no significant differences in ACh-stimulated vasodilation between the four groups after the nitric oxide (NO) synthase inhibitor NG-monomethyl-L-arginine infusion. Co-infusion of vitamin C augmented the FBF response to ACh in low BMI, obese, and extremely obese groups--but not in normal BMI group. CONCLUSIONS: These findings suggest that not only obesity but also a low BMI may be a risk factor for impaired endothelium-dependent vasodilation through the increased oxidative stress, leading to the reduced bioavailability of NO.     

Tetrahydrobiopterin improves endothelium-dependent vasodilation by increasing nitric oxide activity in patients with Type II diabetes mellitus

Aims/hypothesis. Tetrahydrobiopterin is an essential cofactor of nitric oxide synthase, and its deficiency decreases nitric oxide bioactivity. Our aim was to find whether supplementation of tetrahydrobiopterin could improve endothelial dysfunction in diabetic patients.¶Methods. Forearm blood flow responses to the endothelium-dependent vasodilator acetylcholine (0.75– 3.0 μg · 100 ml^–1· min^–1) and to the endothelium-independent vasodilator sodium nitroprusside (0.1–1.0 μg · 100 ml^–1· min^–1) before and during concomitant intra-arterial infusion of tetrahydrobiopterin (500 μg/min) were measured by venous occlusion plethysmography in 12 control subjects and 23 patients with Type II (non-insulin-dependent) diabetes mellitus.¶Results. In control subjects, tetrahydrobiopterin had no effect on the dose-response curves to acetylcholine and sodium nitroprusside. In contrast, in diabetic patients, the attenuated endothelium-dependent vasodilation to acetylcholine was considerably improved by concomitant treatment with tetrahydrobiopterin, whereas the endothelium-independent vasodilation was not affected. This beneficial effect of tetrahydrobiopterin in diabetic patients could be completely blocked by N ^G-monomethyl-l-arginine.¶Conclusion/interpretation. These findings suggest the possibility that endothelial dysfunction in Type II diabetes might be related to decreased availability of tetrahydrobiopterin. [Diabetologia (2000) 43: 1435–1438]     

Tetrahydrobiopterin improves endothelium-dependent vasodilation in chronic smokers : evidence for a dysfunctional nitric oxide synthase

Conditions associated with impaired nitric oxide (NO) activity and accelerated atherosclerosis have been shown to be associated with a reduced bioavailability of tetrahydrobiopterin (BH4). We therefore hypothesized that BH4 supplementation may improve endothelial dysfunction of chronic smokers. Forearm blood flow (FBF) responses to the endothelium-dependent vasodilators acetylcholine (ACh; 0.75, 1.5, and 3.0 microg/100 mL tissue/min) or serotonin (5-HT; 0.7, 2.1, and 6.3 ng/100 mL tissue/min), to the inhibitor of endothelial nitric oxide synthase (NOS) N(G)-monomethyl-L-arginine (L-NMMA; 2, 4, and 8 micromol/min), and to the endothelium-independent vasodilator sodium nitroprusside (SNP; 0.1, 0.3, and 1.0 microg/100 mL tissue/min) were measured by venous occlusion plethysmography in controls and chronic smokers. Drugs were infused into the brachial artery, and FBF was measured before and during concomitant intra-arterial infusion of BH4, tetrahydroneopterin (NH4; another reduced pteridine), or the antioxidant vitamin C (6 and 18 mg/min). In control subjects, BH4 had no effect on FBF in response to ACh, 5-HT, and SNP. In contrast, in chronic smokers, the attenuated FBF responses to ACh and 5-HT were markedly improved by concomitant administration of BH4, whereas the vasodilator responses to SNP were not affected. L-NMMA-induced vasoconstriction was significantly reduced in smokers compared with controls, suggesting impaired basal NO bioactivity. BH4 improved L-NMMA responses in smokers while having no effect on L-NMMA responses in controls. Pretreatment with vitamin C abolished BH4 effects on ACh-dependent vasodilation. In vitro, NH4 scavenged superoxide created by the xanthine/xanthine oxidase reaction equipotent like BH4 but failed to modify ACh-induced changes in FBF in chronic smokers in vivo. These data support the concept that in addition to the free radical burden of cigarette smoke, a dysfunctional NOS III due to BH4 depletion may contribute at least in part to endothelial dysfunction in chronic smokers.     

血管回声跟踪技术对高脂血症患者动脉弹性与血管内皮舒张功能关系的研究

目的:探讨高脂血症患者动脉弹性与血管内皮舒张功能的关系。方法:应用E-Tracking技术测量35例高脂血症患者与30例正常健康组颈动脉硬化参数,包括压力应变弹性系数(Ep)、硬化度(β)和顺应性(AC),同时采用高分辨率血管超声法检测受试者肱动脉血流介导的内皮依赖性血管舒张功能(FMD);并进行相关分析。结果:高脂血症组血流介导的肱动脉舒张功能明显低于正常组(10.15±3.98)与(16.35±2.42),P<0.05;高脂血症组Ep、β与正常对照组相比明显增高(136.27±21.11)与(112.67±29.43),P<0.01,(10.20±1.25)与(9.09±1.98),P<0.01。但高脂血症组的AC明显低于正常对照组(0.58±0.14)与(0.75±0.18),P<0.05。FMD和Ep、β负相关(r=-0.562,P<0.01;r=-0.415,P<0.01),与AC呈正相关(r=0.527P<0.01)。结论:高脂血症患者肱动脉内皮依赖性血管舒张功能受损和动脉弹性降低,且2者之间有相关性,提示E-tracking技术和FMD一样能够判断动脉功能异常,具有简便、快速、无创性及测量结果精确的优点。     

Nitroglycerin-induced coronary vasodilation is not enhanced in patients with impaired endothelium-dependent dilation

Objectives. This study was designed to determine whether enhanced sensitivity to exogenous nitrovasodilators is present in the coronary arteries of patients with impaired endothelium-dependent dilation.Background. Animal studies have demonstrated that the dilator response to exogenous nitrovasodilators is exaggerated in the setting of endothelial dysfunction (diminished nitric oxide activity). Whether such relative hyperresponsiveness to exogenous nitrates occurs and is important in humans is unknown.Methods. We assessed coronary vasomotion in 110 patients (mean [±SD] age 56 ± 10 years) by serial intracoronary infusions of acetylcholine (10⁻⁸ to 10⁻⁶ mol/liter) to test endogenous nitric oxide and nitroglycerin (40 μg) to test responses to exogenous nitrovasodilators.Results. The vasomotor response to 10⁻⁶ mol/liter of acetylcholine differed between patients with (n = 95) and those without (n = 15) normal endothelial dysfunction (−21 ± 14% vs. 12 ± 8% respectively, p < 0.001). However, neither the dilator response to nitroglycerin (21 ± 14% vs. 18 ± 13%) nor the baseline diameter differed between those with endothelial dysfunction and normal function, respectively. There was no correlation between the magnitude of the dilator response to nitroglycerin and acetylcholine. The response to nitroglycerin was decreased with increasing age (r = −0.21, p = 0.03) but was not related to any other demographic factors or to the angiographic appearance of the vessel.Conclusions. The coronary vasodilator response to nitroglycerin is not significantly enhanced in patients with impaired endothelium-dependent dilation but decreases with increasing age. This finding provides indirect evidence that basal coronary tone is not increased in patients with endothelial dysfunction and that supersensitivity to exogenous nitrates is not clinically important in humans.     

Cytochrome c oxidase regulates endogenous nitric oxide availability in respiring cells: a possible explanation for hypoxic vasodilation

One of the many routes proposed for the cellular inactivation of endogenous nitric oxide (NO) is by the cytochrome c oxidase of the mitochondrial respiratory chain. We have studied this possibility in human embryonic kidney cells engineered to generate controlled amounts of NO. We have used visible light spectroscopy to monitor continuously the redox state of cytochrome c oxidase in an oxygen-tight chamber, at the same time as which we measure cell respiration and the concentrations of oxygen and NO. Pharmacological manipulation of cytochrome c oxidase indicates that this enzyme, when it is in turnover and in its oxidized state, inactivates physiological amounts of NO, thus regulating its intra- and extracellular concentrations. This inactivation is prevented by blocking the enzyme with inhibitors, including NO. Furthermore, when cells generating low concentrations of NO respire toward hypoxia, the redox state of cytochrome c oxidase changes from oxidized to reduced, leading to a decrease in NO inactivation. The resultant increase in NO concentration could explain hypoxic vasodilation.     

Exercise training increases basal nitric oxide production from the forearm in hypercholesterolemic patients

The objective of this study was to investigate the effects of cycle training on basal nitric oxide (NO) production and endothelium-dependent dilator capacity in hypercholesterolemic patients in whom acetylcholine responsiveness is impaired. Nine sedentary hypercholesterolemic volunteers (total plasma cholesterol >6.0 mmol/L; 2 female) aged 44+/-3 years (mean+/-SEM) participated in the study. Subjects remained sedentary for 4 weeks and performed 4 weeks of home-based cycle training (3 x 30 minutes/week at 65% maximum oxygen consumption [VO(2)max]) in a randomized order. Arteriovenous nitrate/nitrite (NO(x)) gradient was assessed and plethysmography was used to measure the forearm blood flow responses to arterial infusions of acetylcholine, sodium nitroprusside, and N(G)mono methyl L-arginine. Training increased VO(2)max from 30.4+/-1.9 to 34.3+/-1.4 mL x kg(-1) x min(-1) (P=0.01). Intrabrachial diastolic blood pressure was reduced from 70+/-3 to 68+/-3 mm Hg (P=0.02) with training, whereas systolic pressure did not change. Plasma triglycerides and total, LDL, and HDL cholesterol were not different between interventions. In the sedentary state, there was a positive forearm arteriovenous difference in plasma NO(x) indicating net extraction (6.8+/-4.0 nmol x 100 mL(-1) x min(-1)), whereas in the trained state this difference was negative, indicating net production (-5.8+/-5.8 nmol x 100 mL(-1) x min(-1); P=0.03). N(G)mono methyl L-arginine, at a dose of 4 micromol/min, caused a greater vasoconstriction after training (79.6+/-3.4% versus 69.9+/-6.8%; P=0.05). Acetylcholine and sodium nitroprusside induced dose-dependent elevations in forearm blood flow that were unaffected by training. These data suggest that basal release of endothelium-derived NO is increased with 4 weeks of home based training in hypercholesterolemic patients, independently of lipid profile modification. This may contribute to the cardiovascular protective effects of exercise training, including reduced blood pressure.     

Effect of antioxidant vitamins on low density lipoprotein oxidation and impaired endothelium-dependent vasodilation in patients with hypercholesterolemia

Objectives. The aims of this study were to determine whether antioxidant vitamins could reduce the susceptibility of low density lipoprotein (LDL) to oxidation and improve endothelium-dependent vasodilator responsiveness in patients with hypercholesterolemia.Background. Animals and humans with hypercholesterolemia have exhibited impaired endothelium-dependent vasodilation. In vitro studies suggest that oxidatively modified LDL can impair nitric oxide production.Methods. Forearm blood flow was measured with strain gauge plethysmography and brachial artery drug infusions in 19 patients, aged 52 ± 9 years, with hypercholesterolemia (mean ± SD total cholesterol 283 ± 22 mg/dl, LDL 197 ± 31 mg/dl) and in 14 subjects, aged 48 ± 8 years, with normal cholesterol levels (total cholesterol 169 ± 20 mg/dl, LDL 102 ± 25 mg/dl). Acetylcholine (7.5, 15 and 30 μg/min) was utilized as an endothelium-dependent vasodilator, and sodium nitroprusside (0.8, 1.6 and 3.2 μg/min) was used to test endothelium-independent vasodilation. Oxidative susceptibility of LDL was measured by a spectrophotometric assay of conjugated diene production after the addition of copper chloride. Hypercholesterolemic patients then received daily antioxidant vitamin supplements (beta-carotene [30 mg], ascorbic acid [vitamin C] [1,000 mg], vitamin E [800 IU]) for 1 month, with repeat measurement of both forearm blood flow responsiveness to the same agonists and LDL oxidizability.Results. The maximal flow in response to acetylcholine was impaired in patients compared with that in normal subjects (9.8 ± 7.8 vs. 15.9 ± 8.1 ml/min per 100 ml, p = 0.03), with similar maximal flow responses to sodium nitroprusside (9.5 ± 4.2 vs. 9.0 ± 2.8 ml/min per 100 ml, p = 0.72). After 1 month of vitamin therapy, the onset of LDL oxidation was prolonged over baseline measurements by 71 ± 67%, and the maximal rate of oxidation was decreased by 26 ± 25% (both p < 0.001). However, the maximal forearm blood flow response to acetylcholine remained unchanged from baseline values (maximal flow after acetylcholine 9.0 ± 6.2 vs. 9.8 ± 7.8 ml/min per 100 ml, p = 0.57). This study had 80% power (alpha = 0.05) to exclude a 45% increase over baseline value in acetylcholine-stimulated flow during vitamin therapy.Conclusions. Although 1 month of administration of antioxidant vitamin supplements in hypercholesterolemic patients reduced the susceptibility of LDL to oxidation, impairment in endothelial function remained unaltered. The use of nonvitamin antioxidants or concomitant reduction in LDL levels, as well as more sensitive techniques for measuring vascular responsiveness, may be required to show a beneficial effect on endothelial vasodilator function.     

冠心病患者血管内皮功能障碍及动脉弹性与冠状动脉Gensini评分的关系

目的:探讨冠心病患者血管内皮功能障碍及动脉弹性与冠状动脉造影Gensini评分的关系.方法:采用高分辨率血管超声法检测冠心病患者(76例)与正常对照组(30例)肱动脉血流介导的内皮依赖性血管舒张功能(FMD);应用动脉弹性功能检测仪测定受试者的大动脉弹性指数(C1)和小动脉弹性指数(C2);对冠心病患者进行冠状动脉造影,并通过Gensini评分系统对冠心病患者冠状动脉病变进行评分.结果:冠心病组血流介导的FMD明显低于对照组[(6.94±4.21)%∶(11.10±4.36)%,P<0.05];冠心病组与对照组的C1差异无统计学意义[(117.0±38.1)∶(121.1±38.2)ml/mmHg(1 mmHg=0.133 kPa),P>0.05],但冠心病组的C2明显低于对照组[(516.0±2640)∶(626.0±236.0)ml/mmHg,P<0.05],冠心病患者FMD及C2均与冠状动脉造影Gensini评分呈负相关(r=-0.380,P<0.01及r=-0 329,P<0.01).结论:C2和FMD似可作为评价冠状动脉病变程度的新指标.     

Effects of different levels of exercise volume on endothelium-dependent vasodilation: roles of nitric oxide synthase and heme oxygenase

The objective of this study was to examine the effects of moderate and high levels of exercise volume on endothelium-dependent vasodilation and associated changes in vascular endothelial/inducible nitric oxide synthase (eNOS and iNOS) and heme oxygenase (HO). Male Sprague-Dawley rats were assigned to sedentary control, acute (2 weeks), or chronic (6 weeks) treadmill running at moderate intensity (50% maximal aerobic velocity) with different durations of exercise episodes: 2 h/d (endurance training, moderate volume) and 3 h/d (intense training, high volume). Endothelium-dependent vascular function was examined in isolated thoracic aorta. Co-localization and contents of aortic eNOS/iNOS and HO-1/HO-2 were determined with immunofluorescence and Western blotting. Compared with sedentary controls, rats subjected to acute and chronic endurance training showed enhanced endothelium-dependent relaxation (p<0.01). Whereas acetylcholine-induced dilation was inhibited completely by NOS inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME) in sedentary controls, the dilation in the training groups was only partly blocked by L-NAME (inhibition was 98+/-3%, 79+/-6%, and 77+/-5% in sedentary control, acute, and chronic training groups, respectively, p<0.01). The remnant dilation in the training groups was further inhibited by HO inhibitor protoporphyrin IX zinc, with concomitant elevation in aortic eNOS as well as HO-1 and HO-2. In contrast to endurance exercise, high-volume intense training resulted in mild hypertension with significant impairment in endothelium-dependent vasodilation and profuse increases in aortic iNOS and eNOS (p<0.01). In conclusion, endothelium-dependent vasodilation is improved by endurance exercise but impaired by chronic intense training. Elevations of vascular eNOS and HO-1/HO-2 may contribute to enhanced vasodilation, which can be offset by intense training and elevation in vascular iNOS.     

Pioglitazone improves endothelium-dependent vasodilation in hypertensive patients with impaired glucose tolerance in part through a decrease in oxidative stress

Background

The aim of this study was to determine pioglitazone treatment restores endothelial function in hypertensive patients with impaired glucose tolerance (IGT).

Methods and results

We evaluated the effects of pioglitazone treatment for 12 weeks on forearm blood flow (FBF) responses to acetylcholine and sodium nitroprusside in 34 hypertensive patients with IGT who were randomly divided into a pioglitazone group (n = 17) and an amlodipine monotherapy group (n = 17) and in 34 healthy subjects. Pioglitazone, but not amlodipine, increased the FBF response to acetylcholine and decreased urinary excretion of 8-hydroxy-2′-deoxyguanosine. Pioglitazone did not alter sodium nitroprusside-stimulated vasodilation. N^G-monomethyl-l-arginine abolished the augmentation of FBF response to acetylcholine after pioglitazone treatment. The increase in maximal FBF response to acetylcholine correlated with the decrease in urinary excretion of 8-hydroxy-2′-deoxyguanosine.

Conclusion

Pioglitazone improved endothelial function in hypertensive patients with IGT through an increase in nitric oxide bioavailability by, in part, a decrease in oxidative stress.     

Effect of obesity on endothelium-dependent, nitric oxide-mediated vasodilation in normotensive individuals and patients with essential hypertension.

The purpose of this study was to determine the interdependent and independent effects of hypertension and obesity on endothelial function in humans. We evaluated the forearm blood flow (FBF) response to acetylcholine, an endothelium-dependent vasodilator, and isosorbide dinitrate (ISDN), an endothelium-independent vasodilator, in 16 lean and 12 obese normotensive individuals and the 18 lean and 15 obese hypertensive patients with no history of smoking, hypercholesterolemia, diabetes mellitus, or renal dysfunction. The FBF was measured using a mercury-filled Silastic strain-gauge plethysmograph. The systolic and diastolic blood pressures (BP) and forearm vascular resistance were significantly greater in hypertensive patients than in the normotensive individuals. Insulin resistance, determined by a homeostatic model assessment (HOMA), was significantly greater in the obese group than in the lean group (3.59 +/- 1.68 v 1.91 +/- 1.12, P < .01). There was no significant difference in the HOMA index between normotensive and hypertensive subjects regardless of weight. The response of FBF to acetylcholine was greatest in lean normotensive individuals and least in obese hypertensive patients (40.5 +/- 8.5 and 10.4 +/- 2.8 mL/min/100 mL of tissue, P < .001 v other groups). The FBF response was similar in obese normotensive individuals and lean hypertensive patients (24.1 +/- 7.9 and 19.3 +/- 3.2 mL/min/100 mL of tissue). The vasodilatory effect of ISDN was similar in all four groups. Multiple regression analysis revealed that the maximal FBF response to acetylcholine correlated independently with age (P = .043), obesity (P = .012), HOMA index (P = .002), and mean BP (P < .001). These findings suggest that obesity and hypertension are independently involved in abnormal endothelium-dependent vasodilation by attenuated nitric oxide production.