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Detection of endothelial dysfunction with brachial artery ultrasound scanning

AMERICAN HEART JOURNAL 2003年第6期145卷 943-951页

作者： Faulx, MD Wright, AT Hoit, BD Univ Hosp Cleveland Dept Med Div Cardiol Cleveland OH 44106 USA Case Western Reserve Univ Dept Med Cleveland OH 44106 USA

The role of the endothelium in human disease recently has become the focus of intense scientific investigation. Impaired endothelial function is associated with a number of disease states, including cardiovascular disease (CVD) and its major risk factors. Endothelial dysfunction precedes overt vascular disease by years and may itself be a potentially modifiable CVD risk factor. Although no gold standard for the measurement of endothelial function exists, the measurement of flow-mediated dilation (FMD) in the brachial artery, assessed with Doppler ultrasonography, is the most studied method and shows the most promise for clinical application. It is a well-tolerated, noninvasive, and low-risk procedure. Brachial artery FMD after transient vascular occlusion may serve as an index of nitric oxide bioavailability, and its impairment correlates with coronary arterial abnormalities. These factors, with the wide availability of vascular ultrasound scanning in clinical practice, make brachial artery FMD an attractive screening tool for endothelial dysfunction. Present limitations of this procedure include the lack of a consensus definition of normal FMD and the variability among centers in both procedural technique and image analysis. However, these limitations are likely to be overcome with increasing experience and advances in technology, and with further refinements, the measurement of brachial artery FMD will likely become the clinical technique of choice for the evaluation of endothelial disease.

关键词：血流速度/生理学肱动脉/生理学肱动脉/超声检查冠心病/血液内皮血管/生理学内皮血管/病理生理学内皮血管/超声检查血液流变学一氧化氮/代谢局部血流/生理学超声检查多普勒血管舒张/生理学人类

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No effect of an L-arginine-enriched medical food (HeartBars) on endothelial function and platelet aggregation in subjects with hypercholesterolemia

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AMERICAN HEART JOURNAL 2003年第3期145卷 E15页

作者： Abdelhamed, AI Reis, SE Sane, DC Brosnihan, KB Preli, RB Herrington, DM Wake Forest Univ Sch Med Dept Internal Med Cardiol Cardiol Sect Winston Salem NC 27157 USA Wake Forest Univ Sch Med Hypertens & Vasc Dis Ctr Winston Salem NC 27157 USA Wake Forest Univ Sch Med Dept Internal Med Winston Salem NC 27157 USA Univ Pittsburgh Cardiovasc Inst Pittsburgh PA USA

Background Providing L-arginine as a precursor for nitric oxide has been proposed to improve endothelial function in populations at high risk for cardiovascular events. We studied the effects of dietary L-arginine supplementation with HeartBars (a medical food rich in L-arginine, Cooke Pharma, Belmont, Calif) on flow-mediated dilation and markers of endothelial function in subjects with hypercholesterolemia. Methods We randomly assigned 47 subjects with hypercholesterolemia to receive one HeartBar containing 3.3 g t-arginine each, or a placebo bar, consumed twice daily for 2 weeks. Flow-mediated dilation, platelet aggregation studies, and soluble levels of endothelial and platelet adhesion molecules were obtained before and after the 2-week treatment period. Results Baseline and follow-up levels of L-arginine were 78.5 +/- 28.2 mumol/L and 80.7 +/- 26.7 mumol/L, respectively (P = .54). The HeartBar group had no improvement in flow-mediated dilation;changes in brachial artery diameter at baseline and follow-up were 5.52% +/- 3.32% and 4.96 +/- 2.39%, respectively. There were also no changes in the soluble levels of E-selectin and P-selectin by treatment group. Conclusions In our study, 2 weeks of HeartBar supplementation in subjects with hypercholesterolemia showed no favorable effects on endothelial or platelet function.

关键词：门诊医疗精氨酸/代谢精氨酸/药理学精氨酸/治疗应用肱动脉/药物作用肱动脉/生理学内皮血管/药物作用内皮血管/生理学食品强化高胆固醇血症/膳食疗法一氧化氮/生物合成一氧化氮/治疗应用血小板聚集/药物作用血小板聚集/生理学药物前体/代谢药物前体/药理学药物前体/治疗应用局部血流/药物作用局部血流/生理学治疗结果血管舒张/药物作用血管舒张/生理学女(雌)性人类男(雄)性中年人

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Peripheral endothelium-dependent flow-mediated vasodilatation is associated with left ventricular mass in older persons with hypertension

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AMERICAN HEART JOURNAL 2002年第1期144卷 39-44页

作者： Sung, JD Ouyang, P Bacher, AC Turner, KL DeRegis, JR Hees, PS Silber, HA Shapiro, EP Stewart, KJ Johns Hopkins Univ Sch Med Baltimore MD USA

Background Increased left ventricular (LV) mass is associated with greater cardiovascular disease risk. Recent studies have also shown an association of increased LV mass with attenuated endothelium-dependent coronary flow reserve. Less is known about the association between LV mass and endothelium-dependent flow-mediated dilatation (FMID) in peripheral arteries, a noninvasive measure of endothelial function. Methods Sixty-two subjects with untreated mild hypertension, aged 55 to 75 years and otherwise healthy, were examined. Resting blood pressure was obtained by the average of 4 to 5 visits, each at least I week apart. LV mass was determined from magnetic resonance imaging and was indexed by body surface area, height and height(2.7). Body composition was assessed with dual energy x-ray absorptiometry. FMD was measured as the percent change of brachial artery diameter during reactive hyperemia by use of high-resolution ultrasound. Results Median LV mass index was 63 g/m(2) (interquartile range, 58-73). In bivariate analysis, LV mass was correlated to lean body mass (r = 0.63, P < .001), diastolic blood pressure (r = 0.35, P < .01), and FMD (r = -0.27, P < .05). In multivariate analysis, 44% of the variance in log-LV mass was explained by lean body mass. An additional 6% of the variance was explained by FMD (P < .05). For each 1% point decrease in FMID, LV mass increased by 1.1%. Conclusions In addition to the expected influences of body size, impairment of brachial artery FMD was independently related to LV mass in elderly subjects with mild hypertension who did not yet have LV hypertrophy. Whether mild hypertension is the common mechanism linking LV mass and endothelial function has yet to be determined.

关键词：方差分析人体质量指数内皮血管/生理学高血压/并发症高血压/病理生理学肥大左心室/并发症肥大左心室/病理学肥大左心室/病理生理学磁共振成像/方法局部血流血管舒张/生理学老年人女(雌)性人类男(雄)性中年人

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A novel mechanism for the beneficial vascular effects of high-density lipoprotein cholesterol:: Enhanced vasorelaxation and increased endothelial nitric oxide synthase expression

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AMERICAN HEART JOURNAL 2002年第1期144卷 165-172页

作者： Kuvin, JT Rämet, ME Patel, AR Pandian, NG Mendelsohn, ME Karas, RH Tufts Univ Sch Med New England Med Ctr Hosp Dept Med Boston MA 02111 USA Tufts Univ Sch Med New England Med Ctr Hosp Mol Cardiol Res Inst Boston MA 02111 USA

Background Low levels of high-density lipoprotein (HDL) cholesterol increase the risk of coronary artery disease (CAD), and recent clinical studies suggest that interventions in low-HDL patients are beneficial. The purpose of this study was to examine the effect of increased HDL levels on endothelium-dependent vasodilation. Methods We studied patients with CAD with a low-density lipoprotein (LDL) level of <100 mg/dL. Patients with an HDL level of greater than or equal to36 mg/dL were treated with niacin (n = 11), and patients with an HDL level of >36 mg/dL were followed as controls (n = 10). Baseline and 3-month follow-up studies of flow-mediated dilation (FMD) and blood lipid levels were obtained. Results HDL levels increased from 30.1 +/- 1.2 to 40.5 +/- 1.2 mg/dL in the niacin-treated patients (P <.001) but remained unchanged in the control patients. At baseline, FMD was impaired in both the treated (6.5% +/- 1 %) and the control (7.3% +/- 1%) patients compared with 10 healthy subjects (16% +/- 2%, P <.01). After 3 months, FMD improved in the niacin-treated patients (11.8% +/- 1 %, P =.001) but remained unchanged in the control patients (6.2% +/- 1 %). Exposure of cultured human vascular endothelial cells to HDL in vitro enhanced expression of endothelial nitric oxide synthase (eNOS), as shown by immunoblotting. Conclusions In patients with CAD and well-controlled LDL levels, elevation of HDL with niacin improves endothelial function. HDL increases eNOS protein expression in cultured vascular endothelial cells. Taken together, these observations suggest that HDL-mediated increases in eNOS expression may contribute to the observed enhancement in vasorelaxation and thus support a previously unrecognized mechanism for the beneficial cardiovascular effects of HDL.

关键词：降血脂药/治疗应用病例对照研究胆固醇 HDL/血液胆固醇 LDL/血液内皮血管/酶学内皮血管/生理学尼克酸/治疗应用一氧化氮合酶/代谢一氧化氮合酶Ⅲ型血管舒张/生理学血管舒张药/治疗应用女(雌)性人类男(雄)性中年人

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Effect of cigar smoking on endothelium-dependent brachial artery dilation in healthy young adults

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AMERICAN HEART JOURNAL 2002年第1期143卷 83-86页

作者： Santo-Tomas, M Lopez-Jimenez, F Machado, H Aldrich, HR Lamas, GA Lieberman, EH Mt Sinai Med Ctr Div Cardiol Miami Beach FL 33140 USA

Background Cigar smoking has become a quickly growing trend among teenagers, women, and young adults. The objective was to explore whether cigar smoking affects flow-mediated vasodilation in healthy, non-smoking young adults. Methods This was a prospective randomized trial with open design. It was performed in a cardiology teaching program in a private community hospital that serves as a major referral center within the greater Miami area. Apparently healthy, non-smoking young adult cardiology trainees and staff between the ages of 20 and 45 years were randomly assigned to a cigar smoking group (n = 15) or a control group (n = 14). The main outcome measures were the difference in percent diameter increase in the brachial artery after reactive hyperemia and sublingual nitroglycerin between members of the cigar smoking and control groups at baseline, measured after cigar smoking, and at 5 hours. Results Twenty-nine participants were randomized. Percent diameter increase in the brachial artery was measured with the use of high-resolution ultrasonography. Baseline percent diameter increase after reactive hyperemia and sublingual nitroglycerin was similar in both groups (6.2% vs 6.7%, P = .4 and 22% vs 23%, P = .5, respectively). We observed a 2.5% increase in brachial artery diameter with hyperemia after cigar smoking compared with a 9.4% increase in the control group, P = .045. Values after nitroglycerin were similar between groups, P = .2. Between-group analysis showed no significant difference in percent dilation after reactive hyperemia at 5 hours, P = .4, but a significant difference was seen after sublingual nitroglycerin, P = .02. Conclusions These data are compatible with the possibility that cigar smoking may have an acute effect on endothelium-dependent, flow-mediated brachial artery dilation and do not support the possibility of an immediate effect on enclothelium-independent vasodilation. Taken together, these results suggest that cigars are not an innocuous

关键词：方差分析肱动脉/药物作用肱动脉/病理生理学内皮血管/药物作用内皮血管/病理生理学硝酸甘油/药理学吸烟/病理生理学血管舒张/药物作用血管舒张/生理学血管舒张药/药理学成年人女(雌)性人类男(雄)性

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Comparative study of ACE-inhibition, angiotensin II antagonism, and calcium channel blockade on flow-mediated vasodilation in patients with coronary disease (BANFF study)

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JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY 2000年第1期35卷 60-66页

作者： Anderson, TJ Elstein, E Haber, H Charbonneau, F Univ Calgary Dept Med Div Cardiovasc Calgary AB Canada McGill Univ Montreal PQ Canada Parke Davis & Co Ann Arbor MI USA

OBJECTIVES To determine the effect of angiotensin-converting enzyme (ACE) inhibition on brachial flow-mediated vasodilation. BACKGROUND Quinapril, an ACE inhibitor with high affinity, has been shown to improve coronary endothelial dysfunction in patients with coronary artery disease. The effectiveness of different vasoactive agents to improve human endothelial function is unknown. METHODS High resolution ultrasound was used to assess endothelium-dependent brachial artery flow-mediated vasodilation (FMD) in patients with coronary disease. We studied 80 patients (mean age 58 +/- 0.9 years) in a partial-block, cross-over design trial. Patients were randomized to one of four different drug sequences to receive quinapril 20 mg, enalapril 10 mg, losartan 50 mg or amlodipine 5 mg daily. Each patient received three drugs with a two-week washout period between treatments. The primary end point was the absolute difference in FMD after eight weeks of each study drug compared with their respective baselines analyzed in a blinded fashion. RESULTS There was mild impairment of FMD at baseline (7.3 +/- 0.6%). The change in FMD from baseline was significant only for quinapril (1.8 +/- 1%, p < 0.02). No change was seen with losartan (0.8 +/- 1.1%, p = 0.57), amlodipine (0.3 +/- 0.9%, p = 0.97) or enalapril (-0.2 +/- 0.8%, p = 0.84). No significant change in nitroglycerin-induced dilation occurred with drug therapy. The improvement in quinapril response was not seen in those with the DD ACE genotype (0.5 +/- 2.1%) but was seen in those with the ID and II genotype (3.3 +/- 1.2 and 3.2 +/- 1.9%, respectively, p = 0.03). CONCLUSION Only quinapril was associated with significant improvement in FMD, and this response is related to the presence of the insertion allele of the ACE genotype. (C) 1999 by the American College of Cardiology.

关键词：氨氯地平/投药和剂量氨氯地平/副作用血管紧张素Ⅱ/投药和剂量血管紧张素Ⅱ/生理学血管紧张素转换酶抑制药/投药和剂量血管紧张素转换酶抑制药/副作用血流速度/药物作用血流速度/生理学钙通道阻滞药/投药和剂量钙通道阻滞药/副作用冠状动脉循环/药物作用冠状动脉循环/生理学冠心病/药物疗法冠心病/病理生理学药物疗法联合依那普利/投药和剂量依那普利/副作用内皮血管/药物作用内皮血管/病理生理学异喹啉类/投药和剂量异喹啉类/副作用洛沙坦/投药和剂量洛沙坦/副作用四氢异喹啉类血管舒张/药物作用血管舒张/生理学老年人女(雌)性人类男(雄)性中年人

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Vitamin E supplementation improves endothelial function in type I diabetes mellitus: A randomized, placebo-controlled study

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JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY 2000年第1期36卷 94-102页

作者： Skyrme-Jones, RAP O'Brien, RC Berry, KL Meredith, IT Monash Med Ctr Ctr Heart & Chest Res Melbourne Vic Australia Monash Med Ctr Dept Med Melbourne Vic Australia Monash Univ Ctr Heart & Chest Res Melbourne Vic 3168 Australia Monash Univ Dept Med Melbourne Vic 3168 Australia

OBJECTIVE We sought to determine, in a double-blind, placebo-controlled, randomized study, whether vitamin E supplementation (1,000 IU for three months) would improve impaired conduit and resistance vessel endothelial vasodilator function (EVF) and systemic arterial compliance (SAC) in type I diabetes mellitus (DM). BACKGROUND Oxidative stress is thought to be important in the pathogenesis of impaired EVF. Consistent with this hypothesis, we have recently shown that impaired EVF is related to low density lipoprotein (LDL) vitamin E content (VEC) in young subjects with type 1 DM. METHODS We assessed EVF in the brachial artery (using noninvasive ultrasound, flow-mediated vasodilation [FMD];n = 41) and in the forearm resistance vessels (by flow responses to intrabrachial acetylcholine [ACh];n = 21) and measured SAC (simultaneous aortic blood flow and carotid pressure measurements;n = 41) before and after active or placebo therapy. RESULTS The LDL VEC was increased by 127% after supplementation, resulting in a significant reduction in the oxidative susceptibility of LDL. There was no time-dependent change in FMD or in the response to ACh or SAC in the placebo group. A significant improvement in FMD (2.6 +/- 0.6% to 7.0 +/- 0.7%, p < 0.005) and the dose response to ACh (p < 0.05) were observed in those randomized to vitamin E therapy. Systemic arterial compliance was not affected by vitamin E (0.41 +/- 0.03 vs. 0.49 +/- 0.06 arbitrary compliance units, p = NS). The change in FMD was related to the change in LDL VEC (r = 0.42, p < 0.05) and the change in the oxidative susceptibility of LDL (r = 0.64, p < 0.0001). CONCLUSION Short-term daily oral supplementation with vitamin E improves EVF in both the conduit and resistance vessels of young subjects with type I DM. (J Am Cell Cardiol 2000;36:44-102) (C) 2000 by the American College of Cardiology.

关键词：投药口服血流速度/药物作用血压肱动脉/诊断显像肱动脉/药物作用肱动脉/代谢顺应性/药物作用糖尿病 1型/血液糖尿病 1型/药物疗法糖尿病 1型/病理生理学营养保健品双盲法内皮血管/药物作用内皮血管/代谢内皮血管/病理生理学脂蛋白类 LDL/血液氧化性应激/药物作用体积描记术治疗结果超声检查血管阻力/药物作用血管阻力/生理学血管舒张/药物作用血管舒张/生理学维生素E/投药和剂量成年人女(雌)性人类男(雄)性

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Role of nitric oxide in the pathogenesis of chronic pulmonary hypertension

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PHYSIOLOGICAL REVIEWS 2000年第4期80卷 1337-1372页

作者： Hampl, V Herget, J Charles Univ Prague Sch Med 2 Dept Physiol Prague 15000 5 Motol Czech Republic

Chronic pulmonary hypertension is a serious complication of a number of chronic lung and heart diseases. In addition to vasoconstriction, its pathogenesis includes injury to the peripheral pulmonary arteries leading to their structural remodeling. Increased pulmonary vascular synthesis of an endogenous vasodilator, nitric oxide (NO), opposes excessive increases of intravascular pressure during acute pulmonary vasoconstriction and chronic pulmonary hypertension, although evidence for reduced NO activity in pulmonary hypertension has also been presented. NO can modulate the degree of vascular injury and subsequent fibroproduction, which both underlie the development of chronic pulmonary hypertension. On one hand, NO can interrupt vascular wall injury by oxygen radicals produced in increased amounts in pulmonary hypertension. NO can also inhibit pulmonary vascular smooth muscle and fibroblast proliferative response to the injury. On the other hand, NO may combine with oxygen radicals to yield peroxynitrite and other related, highly reactive compounds. The oxidants formed in this manner may exert cytotoxic and collagenolytic effects and, therefore, promote the process of reparative vascular remodeling. The balance between the protective and adverse effects of NO is determined by the relative amounts of NO and reactive oxygen species. We speculate that this balance may be shifted toward more severe injury especially during exacerbations of chronic diseases associated with pulmonary hypertension. Targeting these adverse effects of NO-derived radicals on vascular structure represents a potential novel therapeutic approach to pulmonary hypertension in chronic lung diseases.

关键词：慢性病内皮血管/药物作用内皮血管/代谢酶抑制剂/药理学自由基/代谢自由基/药理学高血压肺性/病因学高血压肺性/代谢肺/血液供给肺/药物作用肺/胚胎学一氧化氮/代谢一氧化氮/药理学一氧化氮合酶/拮抗剂和抑制剂一氧化氮合酶/代谢一氧化氮合酶Ⅱ型一氧化氮合酶Ⅲ型肺循环/药物作用肺循环/生理学血管阻力/药物作用血管阻力/生理学血管收缩/药物作用血管收缩/生理学血管舒张/药物作用血管舒张/生理学成年人动物人类婴儿新生

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Pharmacological examination of the neurokinin-1 receptor mediating relaxation of human intralobar pulmonary artery

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 2000年第1期292卷 319-325页

作者： Pedersen, KE Buckner, CK Meeker, SN Undem, BJ Johns Hopkins Univ Sch Med Johns Hopkins Asthma & Allergy Ctr Baltimore MD 21224 USA Univ Oklahoma Coll Pharm Oklahoma City OK USA

The effect of selective tachykinin receptor agonists and antagonists on human isolated intralobar pulmonary arterial rings was investigated. Neither Substance P (SP) nor neurokinin A (NKA) contracted the arteries. Both of these agonists, however, were potent and efficacious at relaxing the arteries that were precontracted with phenylephrine. The negative log (M) EC50 values for SP and NKA were 9.0 and 8.3, respectively. The neurokinin (NK)-3 selective agonist, senktide-analog, and the NK-2 receptor selective agonist, [beta-Ala(8)]NKA(4-10), caused neither contractions nor relaxations of the arteries, whereas the NK-1 receptor agonist Ac-[Arg6, Sar9, Met(O2)11] SP( 6-11) (ASM-SP) relaxed the tissue with a potency similar to SP. The relaxations to SP, NKA, and ASM-SP were competitively antagonized by the selective NK-1 receptor antagonist CP 99994, with a pK(b) in the nanomolar range. Antagonism of the ASM-SP-induced relaxations was also noted with FK 888, RP 67580, and L 732,138, although these antagonists were much less potent than CP 99994 in this regard. Another NK-1 receptor selective antagonist, SR 140333, caused an insurmountable antagonism of the SP-induced relaxations. The NK-1 receptor-mediated relaxations could be blocked by removing the endothelium, or by a combination of N- nitro-L-arginine and indomethacin. Measurement of prostanoid generation revealed that in endothelial-intact but not endothelial-denuded tissue, ASM-SP caused a selective increase in the production of 6-keto-PGF1 alpha, the stable metabolite of prostacyclin. The results indicate that stimulation of NK-1 receptors leads to relaxation of human intralobar pulmonary arteries, which is mediated largely by nitric oxide and prostacyclin released from the endothelium of these vessels.

关键词：剂量效应关系药物药物相互作用内皮血管/生理学依前列醇/生理学依前列醇/分泌肺/生理学神经激肽A/药理学一氧化氮/生理学肽碎片/药理学苯福林/药理学肺动脉/生理学受体神经激肽1/生理学受体速激肽/激动剂受体速激肽/拮抗剂和抑制剂 P物质/类似物和衍生物 P物质/药理学血管收缩/药物作用血管舒张/生理学青少年成年人女(雌)性人类男(雄)性中年人

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Attenuated coronary flow reserve and vascular remodeling in patients with hypertension and left ventricular hypertrophy

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JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY 2000年第6期35卷 1654-1660页

作者： Hamasaki, S Al Suwaidi, J Higano, ST Miyauchi, K Holmes, DR Lerman, A Mayo Clin & Mayo Fdn Ctr Coronary Physiol & Imaging Div Cardiovasc Dis Dept Internal Med Rochester MN 55905 USA

OBJECTIVES The purpose of this study was to evaluate the association between hypertension and left ventricular hypertrophy (LVH) with both coronary vascular remodeling and endothelial function. BACKGROUND The association between endothelial and nonendothelial coronary flow reserve with vascular remodeling in patients with hypertension and LVI-I is still unclear. METHODS One hundred and eleven patients with normal or mildly diseased coronary arteries at angiography underwent intravascular ultrasound examination of the left anterior descending coronary artery. Patients were divided into three groups: group I: n = 13, hypertensive patients with LVH;group 2: n 30, hypertensive patients without LVH;group 3: n 68, normotensive patients. Vessel and lumen area and atherosclerotic plaque area were evaluated. Vascular reactivity was examined using intracoronary adenosine and acetylcholine. RESULTS Vessel area in group 1 (with LVH) was significantly (p < 0.01) greater than that in group 2 (without LVH), whereas, vessel area in both groups 1 and 3 was similar (12.8 +/- 0.8 mm(2), 10.7 +/- 0.4 mm(2) and 11.5 +/- 0.3 mm(2)). Coronary blood flow at baseline for patients in group 1 (with LVH) was significantly greater than it was for patients in groups 2 and 3 (81.1 +/- 9.9 ml/min, 56.5 +/- 6.2 ml/min and 48.1 +/- 3.2 ml/min, both p < 0.05). In comparison with groups 2 and 3, the response to both acetylcholine and adenosine was significantly impaired in patients with LVH. CONCLUSIONS The current study demonstrates that hypertension with LVH is associated with both coronary vascular remodeling and attenuated endothelial and nonendothelial coronary flow reserve. (C) 2000 by the American College of Cardiology.

关键词：乙酰胆碱腺苷冠状血管造影术冠状动脉疾病/诊断冠状动脉疾病/病理生理学冠状动脉循环/生理学冠状血管/病理生理学腔内超声检查内皮血管/病理生理学高血压/诊断高血压/病理生理学肥大左心室/诊断肥大左心室/病理生理学前瞻性研究血管舒张/生理学心室功能左/生理学女(雌)性人类男(雄)性中年人

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