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1 3 Eur J Appl Physiol (2016) 116:749–757 DOI 10.1007/s00421-016-3328-8 ORIGINAL ARTICLE Low‑intensity resistance training with blood flow restriction improves vascular endothelial function and peripheral blood circulation in healthy elderly people Ryosuke Shimizu1 · Kazuki Hotta2 · Shuhei Yamamoto1,3 · Takuya Matsumoto4 · Kentaro Kamiya5 · Michitaka Kato1,6 · Nobuaki Hamazaki1,5 · Daisuke Kamekawa1 · Ayako Akiyama1 · Yumi Kamada1 · Shinya Tanaka1 · Takashi Masuda1 Received: 12 April 2015 / Accepted: 27 December 2015 / Published online: 28 January 2016 © Springer-Verlag Berlin Heidelberg 2016 The reactive hyperemia index (RHI), von Willebrand fac- tor (vWF) and transcutaneous oxygen pressure in the foot (Foot-tcPO2) were assessed before and after the 4-week resistance training period. Results Lac, NE, VEGF and GH increased sig- nificantly from 8.2 ± 3.6 mg/dL, 619.5 ± 243.7 pg/ mL, 43.3 ± 15.9 pg/mL and 0.9 ± 0.7 ng/mL to 49.2 ± 16.1 mg/dL, 960.2 ± 373.7 pg/mL, 61.6 ± 19.5 pg/ mL and 3.1 ± 1.3 ng/mL, respectively, in the BFR group (each P < 0.01). RHI and Foot-tcPO2 increased signifi- cantly from 1.8 ± 0.2 and 62.4 ± 5.3 mmHg to 2.1 ± 0.3 and 68.9 ± 5.8 mmHg, respectively, in the BFR group (each P < 0.01). VWF decreased significantly from 175.7 ± 20.3 to 156.3 ± 38.1 % in the BFR group (P < 0.05). Conclusions BFR resistance training improved vascular endothelial function and peripheral blood circulation in healthy elderly people. Keywords Peripheral circulation · Reactive hyperemia · Low-intensity exercise · Hypoxia · Muscle strength · Neurohumoral factors Abbreviations BFR Blood flow restriction eNOS Endothelial nitric oxide synthase EPI Epinephrine GH Growth hormone NE Norepinephrine NO Nitric oxide RHI Reactive hyperemia index RM Repetition maximum tcPO2 Transcutaneous oxygen pressure TM Thrombomodulin VEGF Vascular endothelial growth factor vWF von Willebrand factor Abstract Purpose The present study aimed to investigate the effects of low-intensity resistance training with blood flow restriction (BFR resistance training) on vascular endothe- lial function and peripheral blood circulation. Methods Forty healthy elderly volunteers aged 71 ± 4 years were divided into two training groups. Twenty subjects performed BFR resistance training (BFR group), and the remaining 20 performed ordinary resistance train- ing without BFR. Resistance training was performed at 20 % of each estimated one-repetition maximum for 4 weeks. We measured lactate (Lac), norepinephrine (NE), vascular endothelial growth factor (VEGF) and growth hor- mone (GH) before and after the initial resistance training. Communicated by Fabio Fischetti. * Takashi Masuda tak9999@med.kitasato-u.ac.jp 1 Department of Angiology and Cardiology, Kitasato University Graduate School of Medical Sciences, 1-15-1 Kitasato, Minami-ku, Sagamihara 252-0373, Japan 2 Department of Biomedical Sciences, College of Medicine, Florida State University, 1115 West Call Street, Tallahassee, FL 32306, USA 3 Department of Rehabilitation, Shinsyu University Hospital, 3-1-1 Asahi, Matsumoto 390-0862, Japan 4 Department of Rehabilitation, Kitasato University Kitasato Institute Hospital, 5-9-1 Shirokane, Minato-ku 108-8642, Japan 5 Department of Rehabilitation, Kitasato University Hospital, 1-15-1 Kitasato, Minami-ku, Sagamihara 252-0375, Japan 6 Department of Shizuoka Physical Therapy, Faculty of Health Science, Tokoha University, Mizuochi, 1-30 Aoi-ku, Shizuoka 420-0831, Japan 750 Eur J Appl Physiol (2016) 116:749–757 1 3 Introduction Supervised or home-based training programs are known to improve not only physical function but also quality of life in healthy elderly people (Schechtman et al. 2001). Resistance training is considered essential for maintaining their activities of daily living in these training programs, because it increases muscle strength more effectively than aerobic training (Pollock et al. 2000). Resistance training performed at a moderate to high-intensity workload has recommended to develop muscle strength in healthy adults (American College of Sports Medicine position stand 2009). Indeed, it has been reported that more than 65 % of one-repetition maximum (1RM) is required as a workload for resistance training to increase muscle strength signifi- cantly (McDonagh and Davies 1984). However, people suf- fering from muscle and/or joint disorders often find it dif- ficult to perform even moderate-intensity training as well as high-intensity training. Recently, exercise training with blood flow restric- tion (BFR) was reported to increase muscle strength in the extremities, and was performed by compressing the stem of upper or lower extremities using a pneumatic cuff (Loenneke et al. 2012). Previous studies have showed that hypoxic stress to skeletal muscles induced by exercise training with BFR increases muscle strength through the excessive secretion of neurohumoral factors such as lactate (Lac), norepinephrine (NE), vascular endothelial growth factor (VEGF) and growth hormone (GH) (Takarada et al. 2000a ; Patterson et al. 2013). It is also known that exer- cise training with BFR, performed even at low-intensity workloads, increases muscle strength in equivalent degrees to ordinary resistance training at a high-intensity work- load (Takarada et al. 2000b). Furthermore, some studies have reported that muscle strength increases significantly in exercise training with BFR performed even for 4 weeks (Loenneke et al. 2012). Therefore, low-intensity exercise training with BFR is considered an effective means for increasing muscle strength, even for healthy elderly people (Ozaki et al. 2011). With regard to vascular endothelial function, one mecha- nism that improves the endothelial dysfunction is exercise training, which increases blood flow in skeletal muscles and enhances shear stress on vascular endothelial cells (Niebauer and Cooke 1996). Enhanced shear stress accel- erates endothelial nitric oxide synthase (eNOS) expression, resulting in the amelioration of endothelial dysfunction in vessels of skeletal muscles (Green et al. 2004). Further- more, hypoxic stress to vascular endothelial cells induced by exercise training with BFR reportedly increases eNOS expression via the activation of VEGF (Shweiki et al. 1992; Patterson et al. 2013; Ziche et al. 1997), a mediator of angiogenesis. One study found that high-intensity aero- bic exercise lowered tissue oxygen tension, which in turn upregulated VEGF mRNA expression in skeletal muscles (Breen et al. 1996). Another recent investigation demon- strated that VEGF mRNA expression was accelerated in skeletal muscles 24 h after low-intensity resistance train- ing with blood flow restriction (BFR resistance training) in healthy young subjects (Larkin et al. 2012). Further- more, Hunt et al. showed that 4-week BFR handgrip train- ing induced structural change in brachial artery indicating the enlargement of its diameter at rest (Hunt et al. 2012). Thus, low-intensity BFR resistance training is expected to serve as a useful means by which elderly people may not only increase muscle strength, but also enhance vascular endothelial function and peripheral blood circulation as well. However, it is still unknown whether or not low-inten- sity BFR resistance training alleviates vascular endothelial dysfunction and increases peripheral blood circulation, although moderate to high-intensity resistance training without BFR has been known to improve them (Vona et al. 2009). The present study aimed to clarify the effects of 4 weeks of low-intensity BFR resistance training on vascular endothelial function and peripheral blood circulation in healthy elderly people. Methods This study was approved by theEthics Committee of Kita- sato University, School of Allied Health Sciences. Written informed consent was obtained from all subjects after each received a detailed explanation of the study. Subjects Forty community-dwelling healthy elderly volunteers aged 65 years or older (33 males and 7 females) were recruited for this study between April 2011 and March 2013. None of the subjects received outpatient care for any reason, and none had experienced any cardiovascular, cerebrovascular or neuromuscular disease. None of the subjects were smok- ers, and none had any exercise habits including aerobic exercise, endurance training, resistance training, et cetera, for at least 6 months before the beginning of the study. Subject characteristics Subject age, sex, medication and orthopedic diseases his- tory were examined by interview. We then measured their weight, height, blood pressure, fasting serum glucose, total cholesterol, high-density lipoprotein cholesterol, 751Eur J Appl Physiol (2016) 116:749–757 1 3 low-density lipoprotein cholesterol and triglycerides, and calculated body mass index from their weight and height. We excluded subjects if they felt pain in the upper or lower extremities in activities of daily living. We also excluded any subjects who had received antihypertensive, hypolipi- demic or hypoglycemic medications, or if they showed sys- tolic blood pressure (SBP) ≥140 mmHg, diastolic blood pressure (DBP) ≥90 mmHg or abnormal blood examina- tion results. Study design This study employed a randomized trial design. Subjects were initially divided into BFR resistance training (BFR) and non-BFR resistance training (non-BFR) groups using a randomized block method. Study protocol The study protocol consisted of (a) measurement of base- line muscle strength, vascular endothelial function and peripheral blood circulation, (b) assessment of the acute effects of BFR resistance training, (c) conducting BFR or non-BFR resistance training for 4 weeks and (d) post-train- ing measurement of the same parameters measured at base- line. Acute effects of BFR resistance training were assessed at the initial resistance training session of the 4-week resist- ance training period. All subjects performed 15-min resist- ance training once a day, 3 days per week for 4 weeks. All measurements and resistance training were performed in a thermoneutral training room, which was maintained at 22–24 °C and 40–60 % humidity. BFR or non‑BFR resistance training In the BFR group, four types of BFR resistance training, leg extension, leg press, rowing and chest press, were per- formed each at 20 % intensity of estimated 1RM for bilat- eral extremities in a seated or semi-reclined position using resistance training machines (COP-1202, COP-1201, COP- 0104 and COP-1101, respectively, SAKAI Medical, Tokyo, Japan). First, pneumatic cuffs (10 cm width) were attached to both proximal thighs, and subjects sat on the leg exten- sion training machine. BFR was induced by inflating the cuffs to the same pressure as the subject’s femoral SBP using an inflator (Tourniquet 9000, VBM Medizintechnik GmbH, Sulz am Neckar, Germany). Subjects performed 3 sets of leg extension training with the BFR, with each set consisting of 20 repetitions of leg extensions followed by 30 s of rest. After leg extension training, they moved to the leg press training machine, wearing the cuffs which remained inflated, and rested on it for 1 min. They started leg press training using the same protocol as leg extension training. The cuffs were deflated and removed after sub- jects finished the leg press training. Next, pneumatic cuffs (7 cm width) were attached to both proximal upper arms and inflated to the same pressure as their brachial SBP. The subjects performed rowing and chest press training, also using the same protocol as the lower extremity resistance training. The cuffs were never deflated during the training except when they were transferred from lower extremities to upper ones. In the non-BFR group, subjects performed a series of resistance training without wearing cuffs. Physical activity Physical activity was assessed during the 4-week resist- ance training period using an accelerometer (Lifecorder, SUZUKEN, Nagoya, Japan). The accelerometer, worn at the waist of each subject except during bathing and sleep- ing, recorded vertical acceleration of the body. Energy expenditure was calculated using subject height, weight, sex and vertical acceleration. Physical activity was expressed in kcal/week (Kumahara et al. 2004). Acute effects of resistance training Changes in hemodynamic and neurohumoral parameters before and after resistance training were examined to assess the acute effects of BFR resistance training in the first training day. Heart rate (HR) and electrocardiogram (ECG) were continuously monitored throughout the ini- tial resistance training using an ECG monitoring system (BSM-2401, NIHON KOHDEN, Tokyo, Japan). We meas- ured HR, SBP, DBP, plasma concentrations of Lac, epi- nephrine (EPI), NE and VEGF and serum concentration of GH before and immediately after the training. Long‑term effects of 4‑week resistance training Measurements of muscle strength, vascular endothelial function and peripheral blood circulation were assessed in the morning of the day before and the day after the 4-week resistance training period. All subjects were requested to refrain from eating and drinking (except for water) for 12 h before measurements. Muscle strength We assessed muscle strength with each type of resistance training using estimated 1RM testing, because an ordinary 1RM measurement often induces hemodynamic instabil- ity or skeletal muscle injuries in elderly subjects (de Vos et al. 2008; Pollock et al. 1991; Shaw et al. 1995). The estimated 1RM is calculated using the maximal number of 752 Eur J Appl Physiol (2016) 116:749–757 1 3 repetitions and submaximal weight. First, subjects lifted weights repeatedly as many as possible. If they were able to perform more than 10 repetitions, they repeated the same attempt using a heavier weight. When the maximum num- ber of repetitions was 10 or fewer, the weight was consid- ered a submaximal weight for the assessment of estimated 1RM. Estimated 1RM was calculated as follows (Matt 1993): Previous studies have found that estimated 1RM has excellent interrater reliability for muscle strength measure- ments (Abdul-Hameed et al. 2012). Therefore, the present study used estimated 1RM to assess muscle strength and determine the workload for resistance training. Vascular endothelial function The reactive hyperemia index (RHI) was measured in the supine position as a parameter of vascular endothelial func- tion using a finger plethysmograph (Endo-PAT2000, Itamar Medical, Caesarea, Israel). The principle of RHI has been previously described (Rozanski et al. 2001). A blood pres- sure cuff was placed on one of the upper arms with the con- tralateral arm serving as a control, while fingertip probes were placed on both index fingers to measure arterial pulse wave amplitude. After a 5-min equilibration period, the cuff was inflated to either 60 mmHg above SBP or at least 200 mmHg for 5 min. The cuff was then deflated to induce reactive hyperemia in the measured index finger, and the arterial pulse wave amplitude was recorded for 5 min. RHI was defined as the ratio of the arterial pulse wave ampli- tude measured for 1 min during reactive hyperemia to the baseline amplitude during the equilibration period (Kuvin et al. 2003). RHI was automatically expressed after it was analyzed by a computerized automated algorithm, which was built into the device. We also measured serum concentrations of von Wille- brand factor (vWF) and thrombomodulin(TM) as param- eters of vascular endothelial function and endothelial cell damage, respectively (Conway et al. 2003; Ishii et al. 1991). Peripheral blood circulation Transcutaneous oxygen pressure (tcPO2) was measured as an indicator of peripheral blood circulation in the foot (Foot-tcPO2) using a tcPO2 device (PO-850, Sumitomo Electric Hightechs, Tokyo, Japan). After having subjects rest on a bed in the supine position for 20 min, we attached a probe heated to 44.8 °C to their first intermetatarsal Estimated 1RM (kg) = submaximal weight (kg)/ (102.78− 2.78×maximal number of repetitions)/100. space on the dorsum of the right foot using the double- sided adhesive ring supplied by the manufacturer. Five min after probe attachment, tcPO2 was recorded as stable if the value fluctuated within 2 mmHg during a one-min meas- urement period. If the Foot-tcPO2 value measured after the resistance training period was higher than that of base- line, peripheral blood circulation was defined as having improved relative to the baseline condition. Blood examination All blood samples were drawn from the brachial vein. Plasma Lac, EPI and NE, VEGF and vWF were measured by enzymatic method using lactate kit (Determiner LA, Kyowa Medex Co., Tokyo, Japan), HPLC using catecho- lamine kit (CA test TOSOH, TOSHO CORPORATION, Tokyo, Japan), ELISA using human VEGF quantikine ELISA kit (DVE00, R&D systems, Minneapolis, USA) and aggregation method using vWF kit (BC von Willebrand fac- tor reagent, Sysmex, Kobe, Japan), respectively. Serum GH and TM were assayed by electro-chemiluminescence immu- noassay using human GH assay kit (Elecsys hGH, Roche Diagnostics Japan, Tokyo, Japan) and enzyme immunoas- say using human TM assay kit (TM panacela plate, Daiichi Fine Chemical Co, Toyama, Japan), respectively. Statistical analysis A Shapiro–Wilk test was used to confirm normal dis- tribution of the data. Natural log transformations were then performed to establish normality where necessary. An unpaired t test or χ2 test was used to compare differ- ences in baseline characteristics between the two groups. A 2-way repeated measures analysis of variance (ANOVA) (2 groups versus 2 measurement points) was used to analyze differences in hemodynamic or neurohumoral parameters measured before and after the initial resistance training, as well as differences in muscle strength, vascular endothelial function and peripheral blood circulation before and after the 4-week resistance training period. If an F ratio was sig- nificant, a post hoc test was performed using Bonferroni test. All values are expressed as mean ± standard deviation (SD), and a P value less than 0.05 was considered statisti- cally significant. All analyses were performed using SPSS 12.0J for Windows (SPSS Japan Inc., Tokyo). Results Subject baseline characteristics are displayed in Table 1. There were no significant differences in baseline character- istics including physical activity between the two groups. 753Eur J Appl Physiol (2016) 116:749–757 1 3 Acute effects of resistance training Table 2 displays changes in hemodynamic and neuro- humoral parameters before and after initial resistance training. There were no abnormal findings in HR and ECG during the training in all subjects. Significant inter- actions were detected in HR, DBP, Lac, NE, VEGF and GH (F = 20.7, P < 0.01; F = 45.0, P < 0.01; F = 9.6, P < 0.01; F = 14.2, P < 0.01; F = 4.5, P < 0.05 and F = 39.7, P < 0.01, respectively). HR, SBP, DBP, Lac and NE increased significantly after initial training as com- pared with before training in the two groups (P < 0.01 for all in each group). In the BFR group, VEGF and GH increased significantly after initial training relative to before training (P < 0.01 for both), although they showed no significant changes before and after initial training in the non-BFR group. HR, SBP, DBP, Lac, NE, VEGF and GH after initial training were significantly higher in the BFR group than in the non-BFR group (P < 0.01 for all). There was no significant change in EPI before and after initial training in the two groups. Long‑term effects of 4‑week resistance training RHI, vWF and TM values before and after 4-week resist- ance training are shown in Fig. 1a–c. A significant interac- tion was detected in RHI (F = 10.8, P < 0.01) (Fig. 1a). RHI was significantly higher after 4-week resistance train- ing than before training in the BFR group (P < 0.01). RHI after 4-week resistance training was significantly higher Table 1 Baseline characteristics Data are expressed as mean ± SD ns not significant, BMI body mass index, HR heart rate, SBP systolic blood pressure, DBP diastolic blood pressure, T-chol total cholesterol, HDL-C HDL cholesterol, LDL-C LDL cholesterol, TG triglyceride Non-BFR group (n = 20) BFR group (n = 20) P value Sex (male/female) 17/3 16/4 ns Age (years) 70 ± 4 72 ± 4 ns BMI (kg m−2) 22.9 ± 3.3 23.4 ± 2.5 ns HR (bpm) 72 ± 15 70 ± 12 ns SBP/DBP (mmHg) Brachial 132 ± 20/75 ± 18 134 ± 16/78 ± 15 ns Femoral 168 ± 22/115 ± 14 163 ± 17/120 ± 20 ns Glucose (mg dL−1) 88.3 ± 10.5 84.7 ± 13.9 ns T-chol (mg dL−1) 197.8 ± 26.6 198.5 ± 58.9 ns HDL-C (mg dL−1) 57.5 ± 17.1 55.7 ± 11.4 ns LDL-C (mg dL−1) 120.9 ± 17.3 124.2 ± 28.0 ns TG (mg dL−1) 123.1 ± 35.7 113.9 ± 33.0 ns Physical activity (kcal week−1) 12,180 ± 3733 13,114 ± 3252 ns Table 2 Changes in hemodynamic and neurohumoral parameters before and after initial resistance training Data are expressed as mean ± SD HR heart rate, SBP systolic blood pressure, DBP diastolic blood pressure, Lac lactate, EPI epinephrine, NE norepinephrine, VEGF vascular endothelial growth factor, GH growth hormone Interaction of * P < 0.05 and ** P < 0.01 (two groups versus two measurement points); †† P < 0.01 versus before; ‡‡ P < 0.01 versus Non-BFR group Non-BFR group (n = 20) BFR group (n = 20) Before After Before After HR (bpm)** 68.1 ± 4.4 86.8 ± 6.1†† 71.6 ± 8.1 95.8 ± 11.7††,‡‡ SBP (mmHg) 135.7 ± 7.0 175.4 ± 15.4†† 137.6 ± 13.0 190.4 ± 27.2††,‡‡ DBP (mmHg)** 80.7 ± 6.9 86.5 ± 12.3†† 74.1 ± 4.4 107.6 ± 16.3††,‡‡ Lac (mg dL−1)** 10.3 ± 5.3 34.3 ± 13.3†† 8.2 ± 3.6 49.2 ± 16.1††,‡‡ EPI (pg mL−1) 62.2 ± 31.3 57.7 ± 36.6 50.1 ± 21.8 55.7 ± 33.7 NE (pg mL−1)** 472.4 ± 136.8 662.1 ± 201.5†† 619.5 ± 243.7 960.2 ± 373.7††,‡‡ VEGF (pg mL−1)* 43.2 ± 15.8 42.3 ± 19.5 43.3 ± 15.9 61.6 ± 19.5††,‡‡ GH (ng mL−1)** 0.9 ± 0.8 0.8 ± 0.7 0.9 ± 0.7 3.1 ± 1.3††,‡‡ 754 Eur J Appl Physiol (2016) 116:749–757 1 3 in the BFR group than in the non-BFR group (P < 0.05). VWF decreased significantly after 4-week resistance training relative to that before training in the BFR group (P < 0.05) (Fig. 1b). TM showed no significant change with 4-week resistance training in the BFR group (Fig. 1c), and RHI, vWF and TM showed no significant changes in the non-BFR group. TcPO2 values before and after 4-week resistance training are shown in Fig. 2. A significant interaction was detected in tcPO2 (F = 16.8, P < 0.01). TcPO2 increased significantly after 4-week resistance training relative to before training in the BFR group (P < 0.01), while no significant change was evident in the non-BFR group. Muscle strength levels in leg extension, leg press, rowing and chest press before and after 4-week resistance training are shown in Table 3. Significant interactions were detected in leg extension, leg press and rowing (F = 5.1, P < 0.05; F = 11.7, P < 0.01; F = 5.7, P < 0.05, respectively). Esti- mated 1RM of leg extension and leg press increased sig- nificantly after 4-week resistance training relative to before in the BFR group (P < 0.01, and P < 0.01, respectively). No significant changes were observed in any estimated 1RM before and after 4-week resistance training in the non-BFR group.Fig. 1 Changes in RHI (a), vWF (b) and TM (c) before and after 4-week resistance training. Open squares BFR group, closed squares non-BFR group. Data are expressed as mean ± SD. †P < 0.05 and ††P < 0.01 versus before training; ‡P < 0.05 versus non-BFR group. RHI reactive hyperemia index, vWF von Willebrand factor, TM thrombomodulin. Before, before 4-week resistance training. After, after 4-week resistance training Fig. 2 Change in tcPO2 before and after 4-week resistance training. Open squares BFR group, closed squares non-BFR group. Data are expressed as mean ± SD. ††P < 0.01 versus before training. tcPO2, transcutaneous oxygen pressure; before, before 4-week resistance training; after, after 4-week resistance training Table 3 Changes in muscle strength before and after 4-week resistance training Data are expressed as mean ± SD 1RM one-repetition maximum Interaction of ** P < 0.01 and * P < 0.05 (two groups versus two measurement points); †† P < 0.01 versus before Non-BFR group (n = 20) BFR group (n = 20) Before After Before After Estimated 1RM (kg) Leg extension* 51.0 ± 12.8 52.8 ± 13.9 46.8 ± 11.1 55.7 ± 16.7†† Leg press** 145.1 ± 30.2 141.8 ± 33.0 138.7 ± 35.7 154.4 ± 36.8†† Rowing* 43.1 ± 10.1 46.3 ± 10.4 41.4 ± 7.6 45.2 ± 10.2 Chest press 35.1 ± 12.3 36.7 ± 12.2 34.7 ± 12.6 36.7 ± 12.1 755Eur J Appl Physiol (2016) 116:749–757 1 3 Discussion A recent study found that low-intensity BFR resistance training induced muscle hypertrophy, yielding increased muscle strength in healthy young people (Loenneke et al. 2012). The present study is the first report to demonstrate that low-intensity BFR resistance training improves vascu- lar endothelial function and peripheral blood circulation, in addition to increasing muscle strength in healthy elderly people. We found that RHI increased and vWF decreased sig- nificantly after 4-week BFR resistance training. Because RHI and vWF mainly reflect nitric oxide (NO)-dependent endothelial function and endothelial cell damage in vessels, respectively, the increased RHI and decreased vWF indi- cate that low-intensity BFR resistance training improved vascular endothelial function in healthy elderly people (Nohria et al. 2006; Conway et al. 2003). Exercise train- ing at a moderate to high-intensity workload has been found to increase blood flow in skeletal muscles. Increased blood flow augments shear stress on vascular endothelial cells, resulting in improved endothelial function (Green et al. 2004). However, it is possible that BFR resistance training caused less shear stress due to low blood flow caused by cuff compression as compared with ordinary non-BFR resistance training (Takano et al. 2005). On the other hand, some have suggested that BFR resistance train- ing may elicit hypoxic stress to tissues due to the reduced oxygen supply from low blood flow (Downs et al. 2014). Hypoxic stress reportedly accelerates VEGF release from cells in the vascular endothelium and skeletal muscles (Ji et al. 2007). VEGF bound to the endothelial cell membrane then upregulates eNOS expression, leading to increases in NO production (Hood et al. 1998; Strijdom et al. 2009). We also found that a single bout of BFR resistance train- ing increased plasma concentrations of VEGF significantly relative to non-BFR resistance training. In addition, serum concentration of GH after a single bout of resistance train- ing increased approximately threefold with BFR resistance training compared to non-BFR resistance training. GH has been reported to upregulate eNOS expression in endothe- lial cells of human vessels or rat aorta (Thum et al. 2003; Wickman et al. 2002). Therefore, increased VEGF and GH from BFR resistance training are considered the main mechanisms underlying the improved vascular endothelial function. With regard to peripheral blood circulation, the pre- sent study demonstrated that Foot-tcPO2 increased signifi- cantly after 4-week BFR resistance training. Because tcPO2 reflects blood circulation in the skin microvasculature, our results suggest that BFR resistance training improved peripheral blood circulation in the foot. Long-term exer- cise training is known to improve blood circulation in peripheral tissues by enhancing vascular endothelial func- tion and angiogenesis (Stewart et al. 2002). Previous stud- ies have clarified that enhanced endothelial function aug- ments NO production from endothelial cells, resulting in increased regional blood flow (Niebauer and Cooke 1996). In addition, VEGF activated by hypoxic stress has been found to induce proliferation and migration of endothelial cells and accelerate angiogenesis in skeletal muscles and skin (Tammela et al. 2005; Detmar 2000). Therefore, we believe that 4-week BFR resistance training induced func- tional and structural changes in peripheral vessels, which in turn improved peripheral blood circulation in the foot. With regard to the acute effects of BFR resistance train- ing, the present study showed that HR, SBP, DBP, NE and Lac measured after a single bout of resistance train- ing were significantly higher in the BFR group than in the non-BFR group. Previous studies have clarified that BFR resistance training raises intracellular H+ concentrations in skeletal muscles followed by an increase in Lac, rela- tive to that observed with non-BFR training (Fujita et al. 2007; Suga et al. 2009). Increased H+ and Lac stimulate the chemosensors of skeletal muscles, which then activate the sympathetic nervous system during exercise training (Stebbins and Longhurst 1989). Therefore, we surmise that sympathetic nervous activity was more elevated during BFR resistance training than during non-BFR resistance training, because NE was significantly higher after train- ing in the BFR group. This appears to be the main reason why HR and BP were elevated more following BFR resist- ance training. However, a previous study showed that low- intensity BFR resistance training induced fewer changes in intracellular H+ and metabolites in skeletal muscles rela- tive to those induced by ordinary high-intensity resistance training (Suga et al. 2009). Because BP and HR depend on these metabolic changes during exercise training, from the perspective of preventing hemodynamic instability in elderly people while exercising, low-intensity BFR resist- ance training may be safer to perform than high-intensity resistance training (Victor et al. 1988). With regard to muscle strength, the present study showed that estimated 1RM in leg extension and leg press increased significantly after 4-week resistance training in the BFR group. However, their estimated 1RM was not significantly different from that of the non-BFR group. A recent report demonstrated that low-intensity BFR resist- ance training effectively developed muscle hypertrophy and strength, while no effects were observed in ordinary low- intensity resistance training (Loenneke et al. 2012). In addi- tion, acidemia induced by high-intensity exercise training was found to augment GH secretion, also leading to mus- cle hypertrophy (Gordon et al. 1994; Sutton et al. 1976; De Palo et al. 2001). The present study clearly demonstrated that low-intensity BFR resistance training significantly 756 Eur J Appl Physiol (2016) 116:749–757 1 3 increased serum GH concentrations compared to non-BFR resistance training. Furthermore, acidemia accelerates neuromuscular adaptation resulting in increased muscle strength (Moritani et al. 1992). Therefore, the increase in muscle strength observed in the BFR group may have been derived from muscle hypertrophy or accelerated neuromus- cular adaptation induced by these metabolic and neurohor- monal changes. There are some limitations to the present study. Eighty-three percent of thestudy subjects were male in the present study. The ratio of males to females might have affected the improvement of vascular endothe- lial function, peripheral blood circulation and muscle strength in the present study. Therefore, further inves- tigation is necessary to assess whether sex difference affects the improvement of them after the BFR resist- ance training. We considered that hypoxic stress to skel- etal muscles during BFR resistance training was one of underlying mechanisms to improve vascular endothelial function and peripheral blood circulation. We should investigate the effect of BFR without resistance train- ing on them, because shear stress caused by reperfusion after BFR resistance training has been known to improve the endothelial dysfunction (Green et al. 2004). We sug- gested that the 4-week BFR resistance training upregu- lated eNOS expression resulting in the improvement of vascular endothelial function. However, we did not assess the eNOS expression in vascular endothelial cells in the present study. Therefore, further studies are needed to clarify whether the BFR resistance training upregulates eNOS expression using biopsied sample obtained from trained skeletal muscles (Miyauchi et al. 2003). We also suggested that the BFR resistance training improved peripheral blood circulation through the enhancement of vascular endothelial function and angiogenesis. However, we did not evaluate whether angiogenesis occurred in skeletal muscles. Therefore, it is necessary to clarify that the BFR resistance training increases capillary density in trained skeletal muscles (Hoier et al. 2012). Furthermore, we suggested that the BFR resistance training induced skeletal muscle hypertrophy resulting in the increase of muscle strength. Because we did not confirm the skeletal muscle hypertrophy in the present study, we should clar- ify whether the BFR resistance training increases skeletal muscle volume by using magnetic resonance imaging in future studies (Abe et al. 2006). 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