Adaptation of Vasomotor Function of Human Coronary Arterioles to the Simultaneous Presence of Obesity and Hypertension

【摘要】  Objectives— We hypothesized that simultaneous presence of obesity and hypertension activates adaptive vascular mechanisms affecting dilations of human coronary arterioles.

Methods and Results— Agonist-induced dilations were assessed in isolated pressurized coronary arterioles from patients (n=38) who underwent cardiac surgery. Among normotensives we found that dilations to bradykinin (BK) and the NO-donor, sodium-nitroprusside (SNP) were reduced in obese subjects (BK, 10 –7 mol/L, lean:90±4%, obese:64±7%; SNP, 10 –6 mol/L, lean:89±7%, obese:76±5%). However, among hypertensives, both BK- and SNP-induced dilations were significantly enhanced in obese patients, when compared with lean individuals (BK, lean:71±7%, obese:85±3%; SNP, lean:60±6%, obese:83±2%). Correspondingly, in hypertensive patients, but not in those of normotensives, a positive correlation was found between body mass index (BMI) and BK-induced ( P =0.036, r =0.46), and also SNP-evoked ( P =0.031, r =0.44) coronary dilations. Moreover, in additional 55 hypertensive patients flow-mediated (FMD) and nitroglycerin (NTG)-induced dilations of the brachial artery were assessed. In obese hypertensive individuals, FMD- and NTG-induced dilations were greater (FMD:6.2±0.7%, NTG:17.2±0.9%), than in lean hypertensive patients (FMD:3.7±0.6%, NTG:13.6±1.1%). Correspondingly, FMD- and NTG-induced dilations were positively correlated with BMI ( P =0.020, r =0.31 and P =0.033, r =0.29, respectively).

Conclusions— These findings are the first to suggest that obesity may lead to activation of adaptive vascular mechanisms to enhance the dilator function of coronary and peripheral arterial vessels in hypertensive patients.

The present study shows enhanced dilations of coronary arterioles and brachial arteries in obese hypertensive patients, implying an important functional adaptation, such as an increased sensitivity to NO of coronary and peripheral arterial vessels, to the simultaneous presence of obesity and hypertension.

【关键词】  obesity hypertension coronary microcirculation flowmediated dilation nitrate

Introduction

Comorbidity of obesity with other diseases, such as hypertension, is very common in the Western populations. 1,2 Both obesity and hypertension are considered to be independent predictors of coronary heart disease (CHD). 3,4 Previous studies demonstrated that vasomotor dysfunction of coronary vessels is one of the early alterations associated with CHD. 5,6 In hypertension an early development of vasomotor dysfunction seems to be established by studies on experimental animals 7–10 and humans vessels, 11,12 which—in the early phase—is characterized primarily by reduced dilations of both coronary and peripherial arterial vessels. Recently, it has been shown that obese children already exhibit impaired brachial artery relaxation to hyperemic flow (flow-mediated dilation ) 13,14; and because other studies 15,16 have demonstrated a close association between coronary vasomotor function and FMD of brachial artery, it was speculated that obesity may also adversely affect coronary dilations.

There are few if any studies investigating the possible effects of hypertension and obesity on coronary microvascular vasomotor function in humans, but it seems logical to assume that simultaneous presence of hypertension and obesity adversely affects coronary arteriolar dilations, leading to disturbed regulation of blood flow hence predisposing these patients to tissue ischemia. Interestingly, early studies have postulated that any increase in body mass, such as adiposity, requires higher cardiac output, therefore at any level of systemic blood pressure vascular resistance is lower in obese than in lean patients. 17 Recent studies on animal models of obesity are favoring this assumption, in which unexpectedly preserved 18 or even enhanced 19 vasodilations have been described in coronary resistance vessels. These findings led us to raise the hypothesis that hypertension and obesity may not simply have an additive deleterious effect. Alternatively, we also hypothesized that adaptive mechanisms intrinsic to vascular wall are activated aiming to maintain or enhance the dilator function of coronary arterioles during the development of diseases. In humans with hypertension and obesity the possible alterations in the vasomotor function of coronary arterioles have not yet been elucidated. Thus, the aim of this study was to investigate the impact of hypertension and obesity on dilations of human coronary arterioles to endothelium-dependent and -independent vasoactive agents with known mechanism of action. In addition, we aimed to test further the hypothesis that alterations in the vasomotor function of coronary microvessels are mirrored in that of large peripheral conduit arteries.

Methods

Patients

All protocols were approved by the Ethical Committee at the University of Debrecen, Medical and Health Science Center. All patients were given written information about experimental interventions and the experimental use of human specimen. Assessment of coronary arteriolar responses was performed in patients (n=38, Table 1 ) who underwent cardiac surgery. Assessment of brachial artery relaxation was performed in a separate group of patients with documented hypertension (n=55, Table 2 ), who were recruited locally.

Table 1. Patients Underwent Cardiac Surgery

Table 2. Demography of Patients Underwent Brachial Artery Ultrasound Investigation

Isolation of Human Coronary Arterioles and Experimental Protocols

With the use of microsurgical instruments and an operating microscope, the coronary arteriole ( 1 mm in length) from the right atrial appendage were isolated and cannulated, as described previously. 20 The cannulated arteriole was connected with silicone tubing to a pressure servo control system (Living Systems Instrumentation) to set the intraluminal pressure to 80 mm Hg. Changes in arteriolar diameter were continuously recorded with a digital camera (CFW1310, Scion Corp), connected to a microscope (Nikon, Eclipse 80i). During an incubation period of 1 hour, a spontaneous myogenic tone developed in the isolated coronary arterioles in response to the intraluminal pressure of 80 mm Hg. Then, the endothelium-dependent dilator bradykinin (0.1 nmol/L to 1 µmol/L, from Sigma) and the endothelium-independent dilator, nitric oxide donor, sodium nitroprusside (SNP; 1 nmol/L to 10 µmol/L, from Sigma) were administered to the arterioles, and the peak changes in diameter were measured. Concentrations of the drugs were selected on the basis of our previous study. 20 Agonist-induced arteriolar responses were expressed as changes in arteriolar diameter as a percentage of the maximal dilation defined as the passive diameter of the vessel at 80 mm Hg intraluminal pressure in a Ca 2+ -free medium. At all drug concentrations data and correlation analyses were then performed and selected (representative) concentrations were presented.

Assessment of Brachial Artery Relaxation to Hyperemic Flow (Flow Mediated Dilation) and to Nitroglycerin

Ultrasound measurements of the brachial artery were performed according to the method described by Celermajer et al, 21 using high-resolution ultrasound (Acuson Sequoia) with a 7.5-MHz linear array transducer. Diameter measurements of the right brachial artery were taken at rest after supine rest for at least 10 minutes, after cuff deflation completing suprasystolic compression (at least 50 mm Hg above systolic pressure) of the right upper arm for 4.5 minutes, and after sublingual application of 0.4 mg of nitroglycerin. Scans were taken of the brachial artery proximal to the bifurcation of the radial and the ulnar artery by the same ultrasound operator. Lumen diameters were measured from one media-adventitia interface to the other at least 3 times at baseline, every 20 seconds after reactive hyperemia, and subsequent to the administration of nitroglycerin. The maximum flow mediated dilation (FMD)- and nitroglycerin (NTG)-induced dilation diameters were taken as the average of the 3 consecutive maximum diameter measurements. Vasodilation was then calculated as the percent change in diameter over the baseline value. 22

Statistical Analysis

Data were stored and analyzed with the NCSS statistical software. Test selection was based after evaluating the variables for normal distribution, using the Kolmogorov-Smirnov test. Testing differences of different variables between normotensive and hypertensive groups was accomplished by 2-way analysis of variance (ANOVA) followed by Tukey-Kramer multiple comparison test. One-way ANOVA followed by Tukey posthoc test was performed to compare differences in brachial artery responses, which was investigated only in hypertensive patients. Because all the obtained data in this study met the normality criteria accomplished by Kolmogorov-Smirnov test, associations between continuous variables were analyzed by the Pearson correlation test. To examine categorical variables 2-way ANOVA was performed with the categorical variable and hypertension, as the 2 factors. Those associations which were significant on univariate analysis were entered into a multiple regression model, adjusted for the significant covariates. In a linear regression analysis the slopes of regression lines were also compared between normotensive and hypertensive groups. Data are expressed as means±SEM. P <0.05 was considered statistically significant.

Results

Dilations of Isolated Coronary Arterioles

Agonist-induced vasomotor responses were investigated in coronary arterioles isolated from patients (n=38) who underwent coronary bypass or valve replacement surgery. Patient demographics are summarized in Table 1. Patients were divided into normotensive (NT, n=14) and hypertensive (HT, n=24) subpopulation on the basis of the absence or presence of documented hypertension. Hypertensive patients exhibited higher actual blood pressure readings, which however did not reach statistical significance ( Table 1 ). In the 2 groups there was no difference in the body mass index (BMI) and the prevalence of other underlying diseases, medications, as well as the age, gender, and the type of cardiac surgery ( Table 1 ).

In isolated coronary arterioles a spontaneous tone developed in response to 80 mm Hg intraluminal pressure (active diameter: NT: 92±9 µm versus HT, 88±7 µm, P =0.256 and passive diameter in Ca 2+ free solution: NT: 139±11 versus HT: 135±7, P =0.624). The endothelium-dependent vasodilator, bradykinin (0.1 nmol/L to 1 µmol/L) and the NO-donor, sodium nitroprusside (SNP, 1 nmol/L and 10 µmol/L) elicited substantial dilation in isolated coronary arterioles ( Figure 1a and 1 b). On the average, there were no significant differences between bradykinin-induced and SNP-evoked dilations of coronary arterioles isolated from normotensive and hypertensive individuals ( Figure 1a and 1 b). However, when the magnitudes of coronary dilations were segregated into lean (BMI <25) 30) patients groups a marked difference could be revealed by 2-way ANOVA between normotensive and hypertensive patients. Bradykinin-induced dilations were significantly reduced in obese-normotensive patients, when compared with lean-normotensive ( P =0.013), and interestingly also when compared with those of obese-hypertensive patients ( P =0.025, Figure 1 c). It should be noted, that ANOVA also revealed a significant interaction between hypertension and obesity ( P =0.001), thereby limiting the conclusions regarding to the independent effect of these variables on bradykinin-induced responses. Moreover, we have found that the NO donor, SNP-induced dilations were significantly reduced in lean-hypertensive individuals, when compared with lean-normotensive ( P =0.017) and importantly also when compared with those of obese-hypertensive patients ( P =0.021, Figure 1 d). In this case, ANOVA also revealed a possible interaction between hypertension and obesity indicated by the small probability value ( P =0.083). In addition to the selected agonist concentrations (bradykinin: 0.1 µmol/L; SNP: 1 µmol/L, shown in the Figure 1 and 2 ) similar results were observed to other agonist concentrations (data not shown). Collectively, these findings suggested that in obese and hypertensive patients agonist-induced dilations of coronary microvessels are even enhanced, rather than further reduced, as one would expect.

Figure 1. Bradykinin (BK; a) and sodium-nitroprusside (SNP)-induced (b) dilations of coronary arterioles of normotensive (non-HT, n=14) and hypertensive (HT, n=24) patients. BK- (0.1 µmol/L; c) and SNP-induced (1 µmol/L; d) dilations in lean and obese patients in normotensive and hypertensive subgroups (n 7). Data are mean±SEM. * P <0.05.

Figure 2. Pearson correlations between BK- (0.1 µmol/L; a) and SNP-induced (1 µmol/L; b) dilations and BMI, both in normotensive (non-HT, n=14, empty symbols) and hypertensive (HT, n=24, filled symbols) patients. Regression lines are included in the Figure that is dashed in non-HT and solid in HT groups.

To elucidate and further validate the possible role of overweight and obesity affecting coronary arteriolar responses the impact of BMI on the magnitude of dilations was also investigated by the Pearson correlation test. We have found a significant positive correlation between bradykinin-induced dilations and BMI in the hypertensive group, whereas a negative correlation was found in those of normotensive patients ( Figure 2 a). Similarly, a positive correlation was observed between SNP-induced dilations of coronary arterioles and BMI in hypertensive, but not in those of normotensive subjects ( Figure 2 b). The slopes of regression lines were also compared between normotensive and hypertensive groups. Evaluating bradykinin-induced responses, significant difference was found between the slopes of the 2 regression lines ( P =0.008). Similarly, when the NO donor, SNP-induced responses were analyzed the slopes between normotensive and hypertensive groups was also found to be significantly different ( P =0.041).

Moreover, no significant associations were found in any other variables investigated on bradykinin-induced responses (age: P =0.617; gender/male: P =0.341, diabetes mellitus: P =0.496, coronary artery disease: P =0.809, high cholesterol levels: P =0.418, β-blockers: P =0.477, ACE-inhibitors: P =0.269, Nitrates: P =0.640, Diuretics: P =0.670, Lipid lowering drugs: P =0.444), and also on SNP-induced responses (age: P =0.406; gender/male: P =0.612, diabetes mellitus: P =0.147, coronary artery disease: P =0.793, high cholesterol levels: P =0.340, β-blockers: P =0.516, ACE-inhibitors: P =0.934, Nitrates: P =0.739, Diuretics: P =0.410, Lipid lowering drugs: P =0.115).

Brachial Artery Dilations to Hyperemic Flow (FMD) and Nitroglycerin (NTG)

To reveal that alterations in the vasomotor function of coronary microvessels are mirrored in that of large peripheral conduit arteries, in a separate group of patients with documented hypertension (n=55), brachial artery dilations were also assessed by high-resolution ultrasound. Patient demographics are summarized in Table 2. In the study population the mean value of FMD was 5.0±0.4%, whereas the mean value of NTG-induced dilation was 16.1±0.6%. Interestingly, when patients were divided to lean (BMI <25), overweight (BMI between 25 and 30) and obese subgroups (BMI 30), FMD- ( Figure 3 a) and NTG-induced dilations of brachial artery ( Figure 4 a) were significantly enhanced between the lean and obese subjects (FMD, lean versus obese: P =0.026, overweight versus obese: P =0.011 and NTG, lean versus obese: P =0.023). Correspondingly, Pearson correlation revealed a significant positive correlation between BMI and FMD ( Figure 3 b) and also between BMI- and NTG-induced ( Figure 4 b) brachial artery dilations. Vessel size and hyperemia were similar in lean, overweight, and obese patients, thus it can be assumed that the stimulus for FMD was similar in the groups studied. Also, images taken in lean and obese subjects were comparable in quality and resolution making feasible for the comparison of patients according to their body weight (supplemental Figure I, available online at http://atvb.ahajournals.org).

Figure 3. a, Summary data of flow-mediated dilation (FMD) of the brachial artery in lean (n=11), overweight (n=21), and obese (n=23) patients with hypertension. Data are mean±SEM. * P <0.05. b, Pearson correlation between FMD and BMI in hypertensive individuals (n=55, regression line is included in the Figure).

Figure 4. a, Summary data of nitroglycerin (NTG)-induced brachial artery dilations in lean (n=11), overweight (n=21), and obese (n=23) patients with hypertension. Data are mean±SEM. * P <0.05. b, Pearson correlation between NTG-induced dilations and BMI in hypertensive individuals (n=55, regression line is included in the Figure).

In addition to a significant positive correlation between BMI and brachial artery dilations, a significant negative correlation was found between FMD and age ( r =–0.32, P =0.021), but not between NTG-induced dilations and age ( r =–0.15, P =0.285). Thus, this variable was then used in the multiple regression analysis, as a covariate. Correlations between BMI- and FMD- and also BMI- and NTG-induced dilations, however, remained significant after adjusting for age (FMD versus BMI: P =0.047 and NTG versus BMI: P =0.007). No significant correlations were found in any other variables investigated on FMD (gender/male: P =0.196, diabetes mellitus: P =0.200, coronary artery disease: P =0.499, high cholesterol levels: P =0.611, β-blockers: P =0.428, ACE-inhibitors: P =0.317, Diuretics: P =0.230, Lipid lowering drugs: P =0.922) and also on NTG-induced brachial artery dilations (gender/male: P =0.245, diabetes mellitus: P =0.415, coronary artery disease: P =0.108, high cholesterol levels: P =0.541, β-blockers: P =0.619, ACE-inhibitors: P =0.980, Diuretics: P =0.566, Lipid lowering drugs: P =0.570).

Discussion

The novel findings of this study are that in isolated coronary arterioles of hypertensive patients, bradykinin- and the NO donor, SNP-induced dilations were augmented in obese individuals compared with those of lean subjects. Alterations in coronary arterioles were mirrored in large peripheral arteries in that there was a positive correlation between the FMD- and NTG-induced dilations of the brachial artery and BMI among hypertensive patients. Collectively, these findings suggest an important adaptation of the dilator function of coronary microvessels and peripherial arteries to the simultaneous presence of obesity and hypertension.

Although it has been suggested that obesity increases the risk for developing coronary heart disease 3,4 the impact of obesity on coronary vasomotor function, especially in the presence of other diseases, such as hypertension, is poorly understood. There is a general agreement that in hypertension vascular dysfunction develops, which may contribute to the enhanced cardiac risk in these individuals. 11,12 Vasomotor dysfunction is primarily characterized by reduced endothelium- dependent dilations both in large conduit vessels and resistance arteries. 7–12 In subjects with hypertension a reduced brachial artery relaxation to hyperemic flow (FMD) has been demonstrated previously. 11 In obesity, an early development of vascular dysfunction has also been described. 13,23 For instance, in obese children with risk for atherosclerosis impaired FMD- and NTG-induced relaxation of brachial arteries was reported recently. 13 These observations suggested that both hypertension and obesity are associated with impaired conduit artery relaxations. Because of the close correlation between coronary arterial function and brachial artery relaxation, 15,16 we hypothesized that simultaneous presence of hypertension and obesity has detrimental effect on coronary arteriolar vasomotor function.

Thus, we studied the responses of coronary arterioles, isolated from the heart of patients who underwent cardiac surgery, to bradykinin and SNP, whose mechanism of actions are well known. In isolated coronary arterioles we have found no differences in the magnitude of bradykinin- and SNP-induced dilations between normotensives and hypertensive patients ( Figure 1 ). Because there were no major differences between the 2 groups in other investigated variables ( Table 1 ), it seemed that the presence of hypertension has no significant impact on coronary arteriolar dilations in this study population. However, when the magnitudes of coronary dilations were investigated in lean versus obese subjects, marked differences could be revealed between the normotensive and hypertensive groups. We have found that in normotensive patients, obesity was associated with reduction of agonist-induced coronary dilations (both bradykinin-induced, endothelium-dependent and also SNP-evoked, endothelium-independent). Also, we observed that in lean patients presence of hypertension was associated with impairment of coronary dilations ( Figure 1c and 1 d). These observations are in line with the large body of literature, suggesting detrimental effects of hypertension 11 and obesity 13,23 on vasomotor responses. However, the important and new finding of this study that in the simultaneous presence of hypertension and obesity, coronary arteriolar dilations to bradykinin and the NO-donor, SNP were markedly enhanced ( Figure 1c and 1 d) and also dilations were positively correlated with BMI in these hypertensive patients ( Figure 2 ). These findings may explain the lack of differences in the averaged data regarding coronary dilations between normotensive and hypertensive groups ( Figure 1a and 1 b), in which patients with various body weights were lumped together. The key impact of body weight affecting coronary dilator responses were also substantiated by the results showing no significant impact of other potential factors, such as age, gender, and existing comorbidities, and medications. It should be noted that when agonist-induced coronary arteriolar dilations were evaluated by ANOVA, a possible interaction between hypertension and obesity was also indicated. Given that, although our results suggest a potential impact of obesity on coronary arteriolar dilations in hypertensive patients, conclusion in regard to the independent effect of obesity and hypertension affecting vasomotor function has limitations.

Previous studies also demonstrated a close association between the vasomotor function of coronary arterioles and peripheral brachial artery dilation to hyperemic flow (FMD). 15,16 Thus, in the present study we also aimed to test the impact of simultaneous presence of obesity and hypertension on the vasomotor responses of the brachial artery. Particularly, we were interested whether the findings obtained in coronary microvessels are somewhat mirrored in those of large conductance vessels in hypertensive patients. In this study we have found that both FMD- and NTG-induced dilations of brachial artery were significantly elevated in obese hypertensive patients, when compared with lean hypertensive subjects ( Figures 3 and 4 ). Correspondingly, a positive correlation between BMI- and FMD- and also BMI- and NTG-induced brachial artery dilation in hypertensive patients was found ( Figures 3 and 4 ), similar to those of findings obtained in isolated coronary arterioles ( Figures 1 and 2 ). Correlations between BMI- and FMD- and also BMI- and NTG-induced brachial dilations remained significant even after adjusting for age, which variable was found to be negatively correlated with FMD of the brachial artery. No significant associations were found when the magnitude of FMD and NTG-induced brachial artery relaxations were compared with other variables, such as gender, comorbidities, and medications.

It should be noted that in this study there was a predominance of overweight and obese-hypertensive patients, when compared with those of lean-hypertensive individuals. This was taken into the account, when comparison of the results obtained from subgroups with different numbers was accomplished by ANOVA. Moreover, the impact of BMI, being a continuous variable, was also evaluated by Pearson correlation, to validate the key impact of overweight and obesity on vasomotor responses. Although these analyses demonstrated a positive, rather than a negative (as one would expect), association between BMI- and FMD- and also between BMI- and NTG-induced brachial artery dilations, still, the possible influence of the predominance of overweight and obese subjects cannot be entirely excluded, which may limit the final conclusions drawn by this study. Taken together, our present findings strongly suggest that in hypertensive patients overweight and obesity is in close association with enhanced/adaptive arterial dilations not only in the coronary microvessels but also in the peripheral conduit arteries.

The mechanisms responsible for the observed effect of obesity on vascular function of hypertensive patients are likely to be complex. Bradykinin-induced coronary arteriolar dilations and FMD of the brachial artery are considered being partly dependent on endothelium-derived relaxing factors, such as NO, 24 whereas SNP- and NTG-induced dilations are dependent on the responsiveness of vascular smooth muscle to NO. 25,26 Because both endothelium-dependent (NO agonist)- and -independent (NO donor)-induced coronary arteriolar and brachial artery dilations were enhanced in obese hypertensive patients, it is likely that primarily the enhanced sensitivity of vascular smooth muscle cells to NO is responsible for the observed alterations. This assumption is further supported by the findings showing potential limitations of the results obtained with the endothelium-dependent dilator, bradykinin in coronary microvessels. Nevertheless, the possible involvement of endothelial mechanisms cannot be completely excluded. Interestingly, recent studies elucidating alterations in vasomotor function in animal models of obesity also demonstrated preserved or even enhanced coronary arterial dilations, although the exact mechanisms remained obscure. 18,19 A very recent study has reported that in patients with morbid obesity, rapid weight reduction is associated with reduction of NO synthesis. 27 These investigations support our present findings that in certain conditions, obesity could activate adaptive vascular mechanisms, among others by increasing the sensitivity of vascular smooth muscle to NO, aiming to maintain/enhance vasodilatory function of arterial vessels.

At this time, however, one can only speculate regarding the physiological or clinical relevance of the present observation. The hallmark of essential hypertension is known to be an increased total peripheral resistance. 17 With the progression of hypertensive cardiovascular disease, cardiac output begins to fall, and total peripherial resistance becomes more elevated. Conversely, any increase in body mass (muscular or adipose tissue) requires a higher cardiac output and expanded intravascular volume to meet the elevated metabolic requirements. 17 An enhanced dilatory function of coronary arterioles may reflect increased coronary blood flow and metabolism caused by hyperdynamic circulation early in hypertension and obesity. Interestingly, in early studies it has been postulated that obesity may protect a given patient from the deleterious effect of hypertension by decreasing hypertensive target organ damage. 28 Furthermore, the increased NO sensitivity of coronary arterioles in obese and hypertensive individuals, revealed in the present study, might have beneficial effects regarding to the efficacy of nitrate therapy, as well as the prevalence of nitrate tolerance in this particular patient population, which has yet to be elucidated.

Taken together, the present study is the first to show a close association between obesity and the magnitude of dilations of coronary microvessels and peripheral conduit arteries of hypertensive patients. Obesity seems to activate intrinsic vascular mechanisms, such as increased NO sensitivity, implying an important functional adaptation of arterial vessels in the coronary and peripheral circulation to the simultaneous presence of obesity and hypertension.

Acknowledgments

Sources of Funding

This work is supported by grants of F-048837 from the Hungarian National Science Research Fund (OTKA), NKFP 1A/008/04, ETT-454-2006, ETT-449/2006, ETT-634/2006, and American Heart Association Northeast Affiliate, 0555897T and 0735540T. Zsolt Bagi holds a Bolyai Fellowship.

Disclosures

None.

【参考文献】
  Flegal KM, Carroll MD, Ogden CL, Johnson CL. Prevalence and trends in obesity among US adults, 1999–2000. JAMA. 2002; 288: 1723–1727.

Davy KP, Hall JE. Obesity and hypertension: two epidemics or one? Am J Physiol Regul Integr Comp Physiol. 2004; 286: R803–R813.

Poirier P, Giles TD, Bray GA, Hong Y, Stern JS, Pi-Sunyer FX, Eckel RH. Obesity and cardiovascular disease: pathophysiology, evaluation, and effect of weight loss. Arterioscler Thromb Vasc Biol. 2006; 26: 968–976.

Haffner S, Taegtmeyer H. Epidemic obesity and the metabolic syndrome. Circulation. 2003; 108: 1541–1545.

Ludmer PL, Selwyn AP, Shook TL, Wayne RR, Mudge GH, Alexander RW, Ganz P. Paradoxical vasoconstriction induced by acetylcholine in atherosclerotic coronary arteries. N Engl J Med. 1986; 315: 1046–1051.

Zeiher AM, Drexler H, Wollschlager H, Just H. Endothelial dysfunction of the coronary microvasculature is associated with coronary blood flow regulation in patients with early atherosclerosis. Circulation. 1991; 84: 1984–1992.

Huang A, Koller A. Both nitric oxide and prostaglandin-mediated responses are impaired in skeletal muscle arterioles of hypertensive rats. J Hypertens. 1996; 14: 887–895.

Huang A, Sun D, Smith CJ, Connetta JA, Shesely EG, Koller A, Kaley G. In eNOS knockout mice skeletal muscle arteriolar dilation to acetylcholine is mediated by EDHF. Am J Physiol Heart Circ Physiol. 2000; 278: H762–H768.

Koller A. Signaling pathways of mechanotransduction in arteriolar endothelium and smooth muscle cells in hypertension. Microcirculation. 2002; 9: 277–294.

Ungvari Z, Csiszar A, Kaminski PM, Wolin MS, Koller A. Chronic high pressure-induced arterial oxidative stress: involvement of protein kinase C-dependent NAD(P)H oxidase and local renin-angiotensin system. Am J Pathol. 2004; 165: 219–226.

Ceravolo R, Maio R, Pujia A, Sciacqua A, Ventura G, Costa MC, Sesti G, Perticone F. Pulse pressure and endothelial dysfunction in never-treated hypertensive patients. J Am Coll Cardiol. 2003; 41: 1753–1758.

Palombo C, Kozakova M, Magagna A, Bigalli G, Morizzo C, Ghiadoni L, Virdis A, Emdin M, Taddei S, L?Abbate A, Salvetti A. Early impairment of coronary flow reserve and increase in minimum coronary resistance in borderline hypertensive patients. J Hypertens. 2000; 18: 453–459.

Jarvisalo MJ, Lehtimaki T, Raitakari OT. Determinants of arterial nitrate-mediated dilatation in children: role of oxidized low-density lipoprotein, endothelial function, and carotid intima-media thickness. Circulation. 2004; 109: 2885–2889.

Kapiotis S, Holzer G, Schaller G, Haumer M, Widhalm H, Weghuber D, Jilma B, Roggla G, Wolzt M, Widhalm K, Wagner OF. A proinflammatory state is detectable in obese children and is accompanied by functional and morphological vascular changes. Arterioscler Thromb Vasc Biol. 2006; 26: 2541–2546.

Anderson TJ, Uehata A, Gerhard MD, Meredith IT, Knab S, Delagrange D, Lieberman EH, Ganz P, Creager MA, Yeung AC, Selwyn AP. Close relation of endothelial function in the human coronary and peripheral circulations. J Am Coll Cardiol. 1995; 26: 1235–1241.

Takase B, Uehata A, Akima T, Nagai T, Nishioka T, Hamabe A, Satomura K, Ohsuzu F, Kurita A. Endothelium-dependent flow-mediated vasodilation in coronary and brachial arteries in suspected coronary artery disease. Am J Cardiol. 1998; 82: 1535–1539.

Lavie CJ, Messerli FH. Cardiovascular adaptation to obesity and hypertension. Chest. 1986; 90: 275–279.

Henderson KK, Turk JR, Rush JW, Laughlin MH. Endothelial function in coronary arterioles from pigs with early-stage coronary disease induced by high-fat, high-cholesterol diet: effect of exercise. J Appl Physiol. 2004; 97: 1159–1168.

Prakash R, Mintz JD, Stepp DW. Impact of obesity on coronary microvascular function in the Zucker rat. Microcirculation. 2006; 13: 389–396.

Szerafin T, Erdei N, Fulop T, Pasztor ET, Edes I, Koller A, Bagi Z. Increased cyclooxygenase-2 expression and prostaglandin-mediated dilation in coronary arterioles of patients with diabetes mellitus. Circ Res. 2006; 99: e12–e17.

Celermajer DS, Sorensen KE, Gooch VM, Spiegelhalter DJ, Miller OI, Sullivan ID, Lloyd JK, Deanfield JE. Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet. 1992; 340: 1111–1115.

Kovacs I, Toth J, Tarjan J, Koller A. Correlation of flow mediated dilation with inflammatory markers in patients with impaired cardiac function. Beneficial effects of inhibition of ACE. Eur J Heart Fail. 2006; 8: 451–459.

Hashimoto M, Akishita M, Eto M, Kozaki K, Ako J, Sugimoto N, Yoshizumi M, Toba K, Ouchi Y. The impairment of flow-mediated vasodilatation in obese men with visceral fat accumulation. Int J Obes Relat Metab Disord. 1998; 22: 477–484.

Zhang X, Scicli GA, Xu X, Nasjletti A, Hintze TH. Role of Endothelial Kinins in Control of Coronary Nitric Oxide Production. Hypertension. 1997; 30: 1105–1111.

Kuga MD, Mohri MD, Egashira MD, Hirakawa MD, Tagawa MD, Shimokawa MD, Takeshita MD. Bradykinin-Induced Vasodilation of Human Coronary Arteries In Vivo: Role of Nitric Oxide and Angiotensin-Converting Enzyme. J Am Coll Cardiol. 1997; 30: 108–112.

Lind L, Hall J, Larsson A, Annuk M, Fellstrom B, Lithell H. Evaluation of endothelium-dependent vasodilation in the human peripheral circulation. Clin Physiol. 2000; 20: 440–448.

Lin LY, Lee WJ, Shen HN, Yang WS, Pai NH, Su TC, Liau CS. Nitric oxide production is paradoxically decreased after weight reduction surgery in morbid obesity patients. Atherosclerosis. 2007; 190: 436–442.

Barrett-Connor E, Khaw KT. Is hypertension more benign when associated with obesity? Circulation. 1985; 72: 53–60.

作者单位：Institute of Cardiology (T.F., N.E., T.S., I.E., Z.B.), University of Debrecen, Hungary; the 2nd Department of Medicine and Center of Cardiology (E.J., T.F.), University of Szeged, Hungary; and the Department of Physiology (A.K., Z.B.), New York Medical College, Valhalla, NY.