Scand J Med Sci Sports 2013: ••: ••–•• doi: 10.1111/sms.12152
© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Amlodipine reduces blood pressure during dynamic resistance exercise in hypertensive patients D. R. Souza1, R. S. Gomides1, L. A. R. Costa1, A. C. C. Queiroz1, S. Barros2, K. C. Ortega2, D. Mion Jr2, T. Tinucci1,2, C. L. M. Forjaz1 1
Exercise Hemodynamic Laboratory, School of Physical Education and Sport, University of São Paulo, São Paulo, Brazil, Hypertension Unit, General Hospital, University of São Paulo, São Paulo, Brazil Corresponding author: Cláudia L. M. Forjaz, PhD, Av. Prof. Melo Moraes, 65 – Butantã – São Paulo, Zip Code: 05508-030, SP – Brazil. Tel: +55 (11) 30913136, Fax: +55 (11) 38135921, E-mail: [email protected] 2
Accepted for publication 17 October 2013
This study investigated the effect of the dihydropyridine calcium channel antagonist, amlodipine, on blood pressure (BP) during resistance exercise performed at different intensities in hypertensives. Eleven hypertensives underwent 4 weeks of placebo and amlodipine (random double-blinded crossover design). In each phase, they performed knee extension exercise until exhaustion following three protocols: one set at 100% of 1 RM (repetition maximum), three sets at 80% of 1 RM, and three sets at 40% of 1 RM. Intraarterial BP was measured before and during exercise. Amlodipine reduced maximal systolic/ diastolic BP values achieved at all intensities (100% = 225 ± 6/141 ± 3 vs. 207 ± 6/130 ± 6 mmHg; 80% = 289 ± 8/178 ± 5 vs. 273 ± 10/169 ± 6 mmHg; 40% = 289 ± 10/
176 ± 8 vs. 271 ± 11/154 ± 6 mmHg). Amlodipine blunted the increase in diastolic BP that occurred during the second and third sets of exercise at 40% of 1RM (+75 ± 6 vs. +61 ± 5 mmHg and +78 ± 7 vs. +64 ± 5 mmHg, respectively). Amlodipine was effective in reducing the absolute values of systolic and diastolic BP during resistance exercise and in preventing the progressive increase in diastolic BP that occurs over sets of low-intensity exercise. These results suggest that systemic vascular resistance is involved in BP increase during resistance exercise, and imply that hypertensives receiving amlodipine are at lower risk of increased BP during resistance exercise than non-medicated patients.
Hypertension is considered one of the most important risk factors for the development of cardiovascular disease, and its prevalence is very high worldwide (Chobanian et al., 2003). A combination of pharmacological and non-pharmacological therapies is recommended for the treatment of hypertensive patients (Chobanian et al., 2003; Brazilian Society of Hypertension, 2010). Among the non-pharmacological approaches, aerobic training has been extensively recommended because of its hypotensive effects (Cornelissen & Smart, 2013). More recently, dynamic resistance exercise has also been recommended to hypertensives (Pescatello et al., 2004) because of its health benefits on the musculoskeletal function (Kraemer & Fry, 1995), and also on some of the cardiovascular risk factors that are usually associated to hypertension (Williams et al., 2007). In addition, a recent meta-analysis concluded that this kind of exercise may also have hypotensive effects, at least in normotensive subjects (Cornelissen & Smart, 2013). Nevertheless, during dynamic resistance exercise, blood pressure (BP) increases substantially, achieving values as high as 231/ 128 mmHg in non-medicated hypertensives (de Souza Nery et al., 2010). This may represent an important risk
for the rupture of preexisting cerebral aneurysms (Haykowsky et al., 1996; Vermeer et al., 1997; Vlak et al., 2011, 2012), which is especially important in hypertensives because they are more likely to have aneurysms than normotensives (Isaksen et al., 2002). Most hypertensive patients receive antihypertensive medication. In Brazil, approximately 76% of these patients are under drug therapy (Akashi et al., 1998), and it would be beneficial if these drugs reduce BP not only at rest, but also during physical effort (Gomides et al., 2010). There are several classes of antihypertensive drugs, and they act on different pathophysiological mechanisms to control BP (Hoffman, 2006), which implies that they may have different impacts on BP during exercise. During dynamic resistance exercise, the increase in BP is due, in part, to an increase in cardiac output. In a previous study (Gomides et al., 2010), we observed that a β1-blocker, atenolol, was able to blunt systolic BP increase during the first set of dynamic resistance exercise, but this effect was not maintained in subsequent sets. Thus, an increase in systemic vascular resistance may also be responsible for the increase in BP during dynamic resistance exercise (Seals et al., 1988),
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Souza et al. especially when exercise is prolonged for the second and third sets. Thus, an antihypertensive drug that diminishes vascular resistance may also blunt BP increase during dynamic resistance exercise. Among the many drugs that reduce systemic vascular resistance, this investigation studied the dihydropyridine calcium channel antagonist, amlodipine, which reduces systemic vascular resistance by preventing the influx of Ca+2 into vascular smooth muscle (Hoffman, 2006). We hypothesized that amlodipine reduces the maximal value and the increase in BP during dynamic resistance exercise in hypertensive subjects, especially when exercise is prolonged for the second and third sets. Materials and methods Subjects Essential hypertensive patients of both genders were studied. To guarantee the subjects’ safety, inclusion and exclusion criteria were establish to assure that only hypertensive subjects with BP levels lower than 160/105 mmHg and without any sign of comorbidities were included. For that, before the study enrollment, the volunteers were followed in the Hypertension Unit of the General Hospital, where they underwent a detailed screening. This screening procedure was conducted with the subjects receiving their normal medication, and included clinical evaluation, blood and urine analysis, target organ exams and resting and exercise ECG. These exams allowed excluding volunteers who presented secondary hypertension, target organ damage, and other cardiovascular or muscle skeletal disease that precluded exercise. In addition, subjects should not have diabetes, and should not be obese or at most have an obesity level 1. All these aspects reduce the chance that subjects had any aneurism. None of the subjects was engaged in any regular physical exercise program. This study was approved by the Ethics Committee of the General Hospital, School of Medicine, University of São Paulo. All subjects were informed about the study procedures and risks, and signed a written informed consent before study enrollment.
Methods After screening, the volunteers who fulfilled all the study criteria underwent 2 weeks of drug washout with placebo (lactose 40 mg, corn starch 102 mg, cellulose 5 mg and magnesium 3 mg) administered once a day, in the morning. They were instructed to measure BP at home with an automated monitor, and they were excluded from the study if their systolic/diastolic BP remained above 160/105 mmHg or below 140/90 mmHg. In addition, drug therapy was resumed if BP was above 160/105 mmHg. After the washout period, the volunteers received, in a random order and with a double-blinded crossover design, 4 weeks of placebo and amlodipine (besylate – 5 mg) administered once a day, in the morning. These therapy periods were interspersed with a 2-week period of drug washout. Similar to the first washout period, during all the study, subjects measured their BP at home with an automated device and if BP levels were maintained above 160/105 mmHg, the subject was excluded and active therapy was reassumed. In addition, during each therapy period (placebo and amlodipine), auscultatory BP was measured three times during two visits to the laboratory in the first and second weeks. The mean of these measurements was accepted as the patient’s BP level. The first and the fifth Korotkoff’s sounds were employed, respectively, to determine systolic and diastolic BP. Subjects continued in the
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study, only if their systolic/diastolic BP values remained between 140 and 160/90 and 105 mmHg. During the second and third weeks of each therapy, the subjects attended two familiarization sessions in order to learn the correct execution of the knee extension exercise. In each of these sessions, they performed 10 repetitions of the exercise with the lowest load allowed by the equipment (Physicus PHA 23, São Paulo, Brazil). In addition, in the third week, they also underwent a 1-repetitionmaximum test (RM) following Kraemer and Fry’s protocol (1995). In the fourth week of each therapy period, subjects’ forearm blood flow was measured by venous occlusion plethysmography (AI6 D.E. Hokanson, Washington, USA) for 3 min while the subjects to assess the vasodilatory efficacy of the medication (Wilkinson & Webb, 2001). Finally, during the fourth week of each therapy, the subjects participated in the study experimental session. They were instructed to arrive at the laboratory between 13:00 h and 15:00 h, and to abstain from any sporadic exercise for the previous 24 h, and from smoking for at least 3 h. They were asked to have a light meal at least 2 h before the experiment, and to avoid products containing caffeine. All subjects received the last dose of amlodipine or placebo in the morning, approximately 6 h before the experiment. After arriving at the laboratory, the subjects’ auscultatory BP was measured, and the experiment only began if systolic/diastolic BP were below 160/105 mmHg, which is considered a safe level for beginning exercise, according to the American College of Sports Medicine (2010).
Experimental session During the experimental session, intraarterial BP measurement was employed. BP was measured at the radial artery of the nondominant arm as previously described (Baron et al., 1995). Briefly, after subcutaneous administration of local unaesthetic (2% lidocaine without vasoconstrictor), a 22-G catheter (BD-Angiocath, Becton Dickinson, Franklin Lakes, NJ, USA) was inserted into the radial artery, and was maintained patent by a constant infusion of saline. All procedures were performed by a trained physician in the hospital. The catheter was connected to a transducer kit (PX-260, Edwards Life Sciences, Irvine, CA, USA) that was positioned at the level of the fourth intercostal space. The signal was amplified (KS3800, Gould Instrument Systems, Valley View, OH, USA), and acquired on a computer at a sampling frequency of 500 Hz, using a data acquisition system (WinDaq DI-720, Dataq Instruments Inc, Akron, OH, USA). After catheter insertion, the subjects moved to the knee extension machine, where they rested for 10 min. A 10-min baseline measurement was taken. The subjects then performed, in a random order, three different knee-extension exercise protocols. Each protocol was executed to fatigue, and they consisted of: (a) one set at 100% of 1 RM; (b) three sets at 80% of 1 RM with a 90-s rest interval between the sets; and (c) three sets at 40% of 1 RM with a 90-s rest interval between the sets. A resting period of at least 10 min, which was long enough to allow BP to return to baseline, was allowed between the protocols. In each protocol, beat-to-beat intraarterial BP was continuously recorded for 3 min before the exercise, during all the exercise protocol, and during 3 min of recovery period. For each subject, the protocol order remained the same in the two therapy phases (placebo and amlodipine). For each subject, beat-to-beat data collected for 1 min prior to each exercise protocol were averaged and analyzed as the preexercise value. These values were compared with the highest beat value achieved during each exercise set (S1, S2, and S3), which usually occurred at the end of each set, and with the lowest beat value obtained during each interval between sets (I1, I2, and I3), which usually occurred at the end of the interval. This kind of
Amlodipine and resistance exercise response beat-to-beat analysis during resistance exercise has already been employed in other studies (Lamotte et al., 2005; Gomides et al., 2010).
Statistical analysis Based on a minimum reduction in BP of 4 mmHg, a standard deviation of 3 mmHg for such a reduction, an alpha error of 0.05 and a power of 90%, the minimal number of subjects required for the group was 7. Data normality was checked using the Shapiro-Wilk test (Statistical Package for the Social Sciences for Windows 18.0; Lead Technologies Inc., Chicago, IL, USA). The results obtained at each exercise intensity were compared between therapies using a two-way analysis of variance for repeated measures (Statistica for Windows 5.0; Statsoft Inc., Tulsa, OK, USA), with therapy (placebo or amlodipine) and exercise stage (pre, S1, I1, S2, I2, S3, I3) as the main factors. When necessary, the Newman–Keuls posthoc test was employed. A P < 0.05 was accepted as significant. Data are presented as mean ± standard error.
Results Twenty-one patients started the study protocol, but 10 were excluded as their BP was outside the desired level, or due to problems inserting the catheter, or for personal reasons. Thus, 11 volunteers completed the study, and their characteristics are shown in Table 1. All patients had normal electrocardiographic indices and showed no proteinuria. Most had hypercholesterolemia, none had diabetes, and only one was a smoker. All volunteers were sedentary, and presented a VO2 peak below the predicted level for their characteristics. Five volunteers received placebo and six amlodipine in the first phase of the study. Weight, body mass index and heart rate were similar while subjects were receiving placebo and amlodipine. Resting systolic and diastolic BP were significantly lower and forearm blood flow was significantly greater with amlodipine than with placebo (Table 1). Amlodipine did not change maximum strength. Thus, exercise at 100%, 80%, and 40% of 1 RM was performed with 55 ± 6 and 53 ± 6 kg, 43 ± 4 and 41 ± 4 kg, Table 1. Subjects’ characteristics measured when hypertensives were receiving amlodipine and placebo therapies
N Gender (male/female) Age (years) Height (m) Weight (kg) Body mass index (kg/m2) Heart rate (bpm) Systolic BP (mmHg) Diastolic BP (mmHg) Forearm blood flow (mL/100 mL tissue/min)
Placebo
Amlodipine
11 4/7 47.0 ± 2.3 1.60 ± 0.03 72.7 ± 4.3 26.8 ± 1.6 79 ± 2 146 ± 3 92 ± 2 3.2 ± 0.5
72.6 ± 4.3 26.8 ± 1.2 80 ± 2 132 ± 3* 81 ± 2* 4.8 ± 0.6*
Values: Mean ± standard error. BP, blood pressure. *Significantly different from placebo (P < 0.05).
and 22 ± 2 and 21 ± 2 kg with placebo and amlodipine, respectively (P > 0.05). The number of repetitions to failure was also similar for both therapies at 80% (S1 = 11.3 ± 1.1 vs. 12.0 ± 1.1, S2 = 8.9 ± 0.5 vs. 9.5 ± 0.7, and S3 = 8.2 ± 0.4 vs. 8.1 ± 0.6 repetitions, P > 0.05), and 40% of 1 RM (S1 = 23.3 ± 2.2 vs. 21.5 ± 1.5, S2 = 15.8 ± 0.7 vs. 16.1 ± 1.0, and S3 = 14.2 ± 0.7 vs. 14.6 ± 0.5 repetitions, P > 0.05). BP responses to exercise Systolic BP levels and changes observed during the three exercise protocols are shown in Fig. 1. At all exercise intensities, systolic BP increased during the sets and returned to the pre-exercise level during the intervals between the sets (Fig. 1(a, c and e)). In addition, at 80% of 1RM, maximum systolic BP increased progressively from one set to the next (Fig. 1(c and d)). The absolute values of systolic BP were significantly lower with amlodipine than with placebo at all times and intensities (Fig. 1(a, c and e)). However, the increase in systolic BP during all sets and intensities was similar regardless of whether the subjects were receiving placebo or amlodipine (Fig. 1(b, d and f)). Diastolic BP levels and changes observed during the three exercise protocols are shown in Fig. 2. Diastolic BP also increased significantly during exercise sets and returned to the pre-exercise level or even fell below pre-exercise during the intervals between sets (Fig. 2(a, c and e)). During the exercises performed at 80% and 100% of 1 RM, diastolic BP absolute values were lower with amlodipine than with placebo (Fig. 2(a and c)), but diastolic BP behavior was similar regardless of whether the subjects were receiving placebo or amlodipine (Fig. 2(b and d)). Analysis of diastolic BP response to exercise at 40% of 1 RM revealed a significant interaction between the factors phase and moment. Thus, during the placebo session, diastolic BP increased during the exercise sets with the increases during the second and third sets being significantly greater than during the first set (Fig. 2(e and f)). On the other hand, in the session with amlodipine, absolute diastolic BP levels were lower than with placebo at all points, and diastolic BP did not increase from the first to the second and third sets of exercise (Fig. 2(e and f)). Therefore, at exercise at 40% of 1RM, amlodipide reduce not only the absolute diastolic BP levels, but also blunted diastolic BP increase in the second and third exercise sets. Discussion The main findings of this study were that: (a) the absolute maximal values of systolic and diastolic BP achieved during the execution of the three resistance exercise intensities were lower when the hypertensives were receiving amlodipine; and (b) the increase in
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Souza et al.
Fig. 1. Systolic blood pressure absolute values (SBP) and changes (ΔSBP = exercise SBP – pre-exercise SBP) measured pre-exercise (PRE) and during the sets of (S1, S2, and S3) and intervals between (I1, I2, and I3) the knee-extension resistance exercise performed to failure at 100% (panels a and b), 80% (panels c and d), and 40% (panels e and f) of 1 RM. Measurements were taken from hypertensive subjects receiving placebo (solid line and gray bars) and amlodipine (dotted line and black bars). * Significantly different from PRE (P < 0.05). $ Significantly different from S1 (P < 0.05). & Significantly different from S2 (P < 0.05). # Significantly different from placebo (P < 0.05). Data = mean ± standard error.
diastolic BP observed during the exercise sets at 40% of 1RM was abolished when the hypertensives were receiving amlodipine. To the best of our knowledge, this is the first study to describe the effect of a calcium channel antagonist on BP behavior during a dynamic resistance exercise in hypertensive patients. Previous studies have investigated the effect of this class of medication on isometric (Grossman et al., 1993; Malhotra et al., 2001), but not dynamic effort, and have reported a reduction in the absolute maximal BP values, but not in BP increase during exercise. In the present study, similar to the results of the isometric studies (Grossman et al., 1993; Malhotra et al., 2001), amlodipine reduced the absolute systolic and dia-
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stolic BP levels achieved during the exercise protocol regardless of exercise intensity, showing that the hypotensive effect of amlodipine observed at rest was maintained during the dynamic resistance effort. However, amlodipine did not affect systolic BP rise during exercise, but abolished diastolic BP increase at low-intensity exercise, showing that this drug was not able to mitigate or blunt the exercise-induced systolic hypertensive stimulus, but was able to abolish the low-intensity exercise-induced diastolic hypertensive effect over the exercise sets. This study did not assess the hemodynamic mechanisms responsible for BP responses during dynamic resistance exercise, but a discussion about them may
Amlodipine and resistance exercise response
Fig. 2. Diastolic blood pressure absolute values (DBP) and changes (ΔDBP = exercise DBP – pre-exercise DBP) measured preexercise (PRE) and during sets of (S1, S2, and S3) and intervals between (I1, I2, and I3) the knee-extension resistance exercise performed to failure at 100 (panels a and b), 80 (panels c and d), and 40% (panels e and f) of 1 RM. Measurements were taken from hypertensive subjects receiving placebo (solid line and gray bars) and amlodipine (dotted line and black bars). * Significantly different from PRE (P < 0.05). $ Significantly different from S1 (P < 0.05). & Significantly different from S2 (P < 0.05). # Significantly different from placebo (P < 0.05). Data = mean ± standard error.
arise from the results. BP increase during this kind of exercise has been attributed to both an increase in cardiac output and systemic vascular resistance. Cardiac output increase is mainly mediated by an increase of heart rate and myocardial contractility induced by central command stimuli and mechanoreflex (McCartney, 1999; Chrysant, 2010), while systemic vascular resistance increase is attributed to the mechanical contraction of the muscles around the vessels (Asmussen, 1981) and the exercise pressor reflex promoted by metaboreflex activation (Asmussen, 1981; Palatini, 1994; McCartney, 1999; Boushel, 2010).
Finally, if Valsalva maneuver is performed during the exercise, a greater BP increase may arise (Palatini, 1994). Amlodipine is a dihydropyridine calcium channel blocker that exerts its primary action on peripheral vessels, inhibiting the calcium influx through calcium channels, which reduces intracellular calcium concentration, leading to vasodilatation (Hoffman, 2006; Opie & Gersh, 2009). Consequently, the effects of amlodipine on BP responses to exercise may imply on preventing systemic vascular resistance increase. The absence of effect of amlodipine on blunting systolic BP increase during resistance exercise suggests that
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Souza et al. an increase in systemic vascular resistance is not the underlying mechanism for systolic BP response in this type of exercise. In accordance with this theory, in a previous study (Gomides et al., 2010), we observed that atenolol, a betablocker that decreases heart rate and cardiac output (Hoffman, 2006; Opie & Gersh, 2009), was able to reduce the increase in systolic BP during resistance exercise. Taken together, our results strengthen the hypothesis that the increase in systolic BP during dynamic resistance exercise is partially due to central mechanisms that lead to an increase in cardiac output. On the other hand, when diastolic BP behavior during exercise was considered, the results differed. The use of amlodipine abolished the diastolic BP increase over the sets of the low- but not high-intensity exercise protocols. During muscle contractions above 60 to 70% of maximal force, the mechanical contraction around the vessels promotes a complete blocking of blood flow (Asmussen, 1981). In addition, at high-intensity exercise, Valsalva maneuver is obligatory (Palatini, 1994). These mechanisms increase BP and amlodipine may not act on them, which explains the absence of drug effect on BP response to high-intensity exercises. On the other hand, during low-intensity exercise, blood flow is only partially restricted by mechanical contraction (Asmussen, 1981) and an additional rise in BP may result from the increase in systemic vascular resistance due to the accumulation of metabolites, stimulating chemoreceptors and increasing sympathetic activity, which induces additional vasoconstriction at the active and inactive territories (Rowell & O’Leary, 1990). Amlodipine has been suggested to increase baseline sympathetic activity (de Champlain et al., 1999; Toal et al., 2012) and sympathetic response to stimuli (de Champlain et al., 2007; de Champlain et al., 1999). However, it also decreases postreceptor α1 receptor response (de Champlain et al., 1999), decreasing vasoconstriction to sympathetic activation. Amlodipine may blunt sympathetic induced vasoconstriction because this channel blocker may blunt the calcium influx induced by sympathetic activation. Champlain et al. (2007) reported that amlodipine increased sympathetic response to the tilt test, but this greater sympathetic activation did not result in a greater BP increase. A similar response might have occurred during the low-intensity dynamic resistance exercise. In terms of the clinical application of the present results, we showed that dynamic resistance exercise induces a huge (maximum systolic BP = 289 ± 10 and 289 ± 8 mmHg with placebo at 40 and 80% of 1 RM, respectively) and very sharp (it took approximately 20 s at 80% of 1 RM, and 40 s at 40% of 1 RM) increase in BP, which might increase the risk for the rupture of a pre-existing aneurysm (Haykowsky et al., 1996; Vermeer et al., 1997; Vlak et al., 2011, 2012). On the other hand, amlodipine reduced maximal BP (maximum systolic BP = 255 ± 10 and 273 ± 10 mmHg with
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amlodipine at 40 and 80% of 1 RM, respectively) suggesting that hypertensive patients medicated with this drug are better protected from the aforementioned risk. Thus, amlodipine helps protect the cardiovascular system of hypertensive individuals, lowering the risk of high BP not only at rest, as observed by others (Rothwell et al., 2010), but also during the execution of dynamic resistance exercise. This research has some limitations related to its experimental design. This study included men and women; of the seven women evaluated, two were postmenopausal and the others had normal menstrual cycles. There was no control of menstrual cycle phase in which the experimental sessions were conducted. While these aspects may affect the results of the study, any influence is unlikely, since BP responses to exercise and medication (Abad-Santos et al., 2005) do not seem to be affected by gender. The study included hypertensive patients without other comorbidities, which may have affected the result. The role of the common comorbidities associated with hypertension should be investigated in the future. In this study, amlodipine was administered according to current recommendations, and changes in dose, mode of administration, duration of treatment and the time between the last dose and exercise can alter the results. It is also important to note that the study results may also differ with other types of exercise protocols. An important aspect of this study is that although the use of drugs allows the development of a hypothesis about the mechanisms responsible for the increase in BP during resistance exercise, the experimental design and the techniques used in the present study were not designed specifically for this purpose. Thus, specific research on the mechanisms responsible for BP increase during dynamic resistance exercise still needs to be conducted. In conclusion, amlodipine was effective at reducing the absolute values of systolic and diastolic BP during different intensities of dynamic resistance exercise. Furthermore, it was effective at abolishing the diastolic BP increase that occurs over sets of low-intensity resistance exercise. These results suggest that systemic vascular resistance may influence the increase in diastolic BP during resistance exercise, especially when this exercise is prolonged over time. In addition, the results suggest that hypertensive patients receiving amlodipine are better protected against high systolic BP peaks during dynamic resistance exercise than unmedicated patients. Perspectives The findings from this study add and complement previous information about BP responses to resistance exercise in hypertensives (Palatini, 1994; de Souza Nery et al., 2010) and possible interaction with antihypertensive drugs (Gomides et al., 2010). In this context, this
Amlodipine and resistance exercise response study showed that not only beta-blockers (Gomides et al., 2010), but also amlodipine might reduce BP levels during resistance exercise in hypertensives. These finding suggest that other anti-hypertensive drugs might also have hypotensive effects during dynamic resistance exercise which might be investigated in the future. In addition, combining with previous studies (Gomides et al., 2010), the present results allows to suppose that cardiac output increment is mainly involved in BP increase during high-intensity and the first set of resistance exercise, and that systemic vascular resistance is more related to BP increase during low-intensity and
prolonged resistance exercise. This hypothesis might be tested with specific designs in future research. Key words: calcium channel antagonist, intraarterial blood pressure, strength exercise, hypertension.
Acknowledgement The authors want to acknowledge the volunteers who contributed to this study. We also want to thank Medley for the donation of amlodipine. This study was financial supported by FAPESP (2009/ 12572-3) and CAPES.
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© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Amlodipine reduces blood pressure during dynamic resistance exercise in hypertensive patients D. R. Souza1, R. S. Gomides1, L. A. R. Costa1, A. C. C. Queiroz1, S. Barros2, K. C. Ortega2, D. Mion Jr2, T. Tinucci1,2, C. L. M. Forjaz1 1
Exercise Hemodynamic Laboratory, School of Physical Education and Sport, University of São Paulo, São Paulo, Brazil, Hypertension Unit, General Hospital, University of São Paulo, São Paulo, Brazil Corresponding author: Cláudia L. M. Forjaz, PhD, Av. Prof. Melo Moraes, 65 – Butantã – São Paulo, Zip Code: 05508-030, SP – Brazil. Tel: +55 (11) 30913136, Fax: +55 (11) 38135921, E-mail: [email protected] 2
Accepted for publication 17 October 2013
This study investigated the effect of the dihydropyridine calcium channel antagonist, amlodipine, on blood pressure (BP) during resistance exercise performed at different intensities in hypertensives. Eleven hypertensives underwent 4 weeks of placebo and amlodipine (random double-blinded crossover design). In each phase, they performed knee extension exercise until exhaustion following three protocols: one set at 100% of 1 RM (repetition maximum), three sets at 80% of 1 RM, and three sets at 40% of 1 RM. Intraarterial BP was measured before and during exercise. Amlodipine reduced maximal systolic/ diastolic BP values achieved at all intensities (100% = 225 ± 6/141 ± 3 vs. 207 ± 6/130 ± 6 mmHg; 80% = 289 ± 8/178 ± 5 vs. 273 ± 10/169 ± 6 mmHg; 40% = 289 ± 10/
176 ± 8 vs. 271 ± 11/154 ± 6 mmHg). Amlodipine blunted the increase in diastolic BP that occurred during the second and third sets of exercise at 40% of 1RM (+75 ± 6 vs. +61 ± 5 mmHg and +78 ± 7 vs. +64 ± 5 mmHg, respectively). Amlodipine was effective in reducing the absolute values of systolic and diastolic BP during resistance exercise and in preventing the progressive increase in diastolic BP that occurs over sets of low-intensity exercise. These results suggest that systemic vascular resistance is involved in BP increase during resistance exercise, and imply that hypertensives receiving amlodipine are at lower risk of increased BP during resistance exercise than non-medicated patients.
Hypertension is considered one of the most important risk factors for the development of cardiovascular disease, and its prevalence is very high worldwide (Chobanian et al., 2003). A combination of pharmacological and non-pharmacological therapies is recommended for the treatment of hypertensive patients (Chobanian et al., 2003; Brazilian Society of Hypertension, 2010). Among the non-pharmacological approaches, aerobic training has been extensively recommended because of its hypotensive effects (Cornelissen & Smart, 2013). More recently, dynamic resistance exercise has also been recommended to hypertensives (Pescatello et al., 2004) because of its health benefits on the musculoskeletal function (Kraemer & Fry, 1995), and also on some of the cardiovascular risk factors that are usually associated to hypertension (Williams et al., 2007). In addition, a recent meta-analysis concluded that this kind of exercise may also have hypotensive effects, at least in normotensive subjects (Cornelissen & Smart, 2013). Nevertheless, during dynamic resistance exercise, blood pressure (BP) increases substantially, achieving values as high as 231/ 128 mmHg in non-medicated hypertensives (de Souza Nery et al., 2010). This may represent an important risk
for the rupture of preexisting cerebral aneurysms (Haykowsky et al., 1996; Vermeer et al., 1997; Vlak et al., 2011, 2012), which is especially important in hypertensives because they are more likely to have aneurysms than normotensives (Isaksen et al., 2002). Most hypertensive patients receive antihypertensive medication. In Brazil, approximately 76% of these patients are under drug therapy (Akashi et al., 1998), and it would be beneficial if these drugs reduce BP not only at rest, but also during physical effort (Gomides et al., 2010). There are several classes of antihypertensive drugs, and they act on different pathophysiological mechanisms to control BP (Hoffman, 2006), which implies that they may have different impacts on BP during exercise. During dynamic resistance exercise, the increase in BP is due, in part, to an increase in cardiac output. In a previous study (Gomides et al., 2010), we observed that a β1-blocker, atenolol, was able to blunt systolic BP increase during the first set of dynamic resistance exercise, but this effect was not maintained in subsequent sets. Thus, an increase in systemic vascular resistance may also be responsible for the increase in BP during dynamic resistance exercise (Seals et al., 1988),
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Souza et al. especially when exercise is prolonged for the second and third sets. Thus, an antihypertensive drug that diminishes vascular resistance may also blunt BP increase during dynamic resistance exercise. Among the many drugs that reduce systemic vascular resistance, this investigation studied the dihydropyridine calcium channel antagonist, amlodipine, which reduces systemic vascular resistance by preventing the influx of Ca+2 into vascular smooth muscle (Hoffman, 2006). We hypothesized that amlodipine reduces the maximal value and the increase in BP during dynamic resistance exercise in hypertensive subjects, especially when exercise is prolonged for the second and third sets. Materials and methods Subjects Essential hypertensive patients of both genders were studied. To guarantee the subjects’ safety, inclusion and exclusion criteria were establish to assure that only hypertensive subjects with BP levels lower than 160/105 mmHg and without any sign of comorbidities were included. For that, before the study enrollment, the volunteers were followed in the Hypertension Unit of the General Hospital, where they underwent a detailed screening. This screening procedure was conducted with the subjects receiving their normal medication, and included clinical evaluation, blood and urine analysis, target organ exams and resting and exercise ECG. These exams allowed excluding volunteers who presented secondary hypertension, target organ damage, and other cardiovascular or muscle skeletal disease that precluded exercise. In addition, subjects should not have diabetes, and should not be obese or at most have an obesity level 1. All these aspects reduce the chance that subjects had any aneurism. None of the subjects was engaged in any regular physical exercise program. This study was approved by the Ethics Committee of the General Hospital, School of Medicine, University of São Paulo. All subjects were informed about the study procedures and risks, and signed a written informed consent before study enrollment.
Methods After screening, the volunteers who fulfilled all the study criteria underwent 2 weeks of drug washout with placebo (lactose 40 mg, corn starch 102 mg, cellulose 5 mg and magnesium 3 mg) administered once a day, in the morning. They were instructed to measure BP at home with an automated monitor, and they were excluded from the study if their systolic/diastolic BP remained above 160/105 mmHg or below 140/90 mmHg. In addition, drug therapy was resumed if BP was above 160/105 mmHg. After the washout period, the volunteers received, in a random order and with a double-blinded crossover design, 4 weeks of placebo and amlodipine (besylate – 5 mg) administered once a day, in the morning. These therapy periods were interspersed with a 2-week period of drug washout. Similar to the first washout period, during all the study, subjects measured their BP at home with an automated device and if BP levels were maintained above 160/105 mmHg, the subject was excluded and active therapy was reassumed. In addition, during each therapy period (placebo and amlodipine), auscultatory BP was measured three times during two visits to the laboratory in the first and second weeks. The mean of these measurements was accepted as the patient’s BP level. The first and the fifth Korotkoff’s sounds were employed, respectively, to determine systolic and diastolic BP. Subjects continued in the
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study, only if their systolic/diastolic BP values remained between 140 and 160/90 and 105 mmHg. During the second and third weeks of each therapy, the subjects attended two familiarization sessions in order to learn the correct execution of the knee extension exercise. In each of these sessions, they performed 10 repetitions of the exercise with the lowest load allowed by the equipment (Physicus PHA 23, São Paulo, Brazil). In addition, in the third week, they also underwent a 1-repetitionmaximum test (RM) following Kraemer and Fry’s protocol (1995). In the fourth week of each therapy period, subjects’ forearm blood flow was measured by venous occlusion plethysmography (AI6 D.E. Hokanson, Washington, USA) for 3 min while the subjects to assess the vasodilatory efficacy of the medication (Wilkinson & Webb, 2001). Finally, during the fourth week of each therapy, the subjects participated in the study experimental session. They were instructed to arrive at the laboratory between 13:00 h and 15:00 h, and to abstain from any sporadic exercise for the previous 24 h, and from smoking for at least 3 h. They were asked to have a light meal at least 2 h before the experiment, and to avoid products containing caffeine. All subjects received the last dose of amlodipine or placebo in the morning, approximately 6 h before the experiment. After arriving at the laboratory, the subjects’ auscultatory BP was measured, and the experiment only began if systolic/diastolic BP were below 160/105 mmHg, which is considered a safe level for beginning exercise, according to the American College of Sports Medicine (2010).
Experimental session During the experimental session, intraarterial BP measurement was employed. BP was measured at the radial artery of the nondominant arm as previously described (Baron et al., 1995). Briefly, after subcutaneous administration of local unaesthetic (2% lidocaine without vasoconstrictor), a 22-G catheter (BD-Angiocath, Becton Dickinson, Franklin Lakes, NJ, USA) was inserted into the radial artery, and was maintained patent by a constant infusion of saline. All procedures were performed by a trained physician in the hospital. The catheter was connected to a transducer kit (PX-260, Edwards Life Sciences, Irvine, CA, USA) that was positioned at the level of the fourth intercostal space. The signal was amplified (KS3800, Gould Instrument Systems, Valley View, OH, USA), and acquired on a computer at a sampling frequency of 500 Hz, using a data acquisition system (WinDaq DI-720, Dataq Instruments Inc, Akron, OH, USA). After catheter insertion, the subjects moved to the knee extension machine, where they rested for 10 min. A 10-min baseline measurement was taken. The subjects then performed, in a random order, three different knee-extension exercise protocols. Each protocol was executed to fatigue, and they consisted of: (a) one set at 100% of 1 RM; (b) three sets at 80% of 1 RM with a 90-s rest interval between the sets; and (c) three sets at 40% of 1 RM with a 90-s rest interval between the sets. A resting period of at least 10 min, which was long enough to allow BP to return to baseline, was allowed between the protocols. In each protocol, beat-to-beat intraarterial BP was continuously recorded for 3 min before the exercise, during all the exercise protocol, and during 3 min of recovery period. For each subject, the protocol order remained the same in the two therapy phases (placebo and amlodipine). For each subject, beat-to-beat data collected for 1 min prior to each exercise protocol were averaged and analyzed as the preexercise value. These values were compared with the highest beat value achieved during each exercise set (S1, S2, and S3), which usually occurred at the end of each set, and with the lowest beat value obtained during each interval between sets (I1, I2, and I3), which usually occurred at the end of the interval. This kind of
Amlodipine and resistance exercise response beat-to-beat analysis during resistance exercise has already been employed in other studies (Lamotte et al., 2005; Gomides et al., 2010).
Statistical analysis Based on a minimum reduction in BP of 4 mmHg, a standard deviation of 3 mmHg for such a reduction, an alpha error of 0.05 and a power of 90%, the minimal number of subjects required for the group was 7. Data normality was checked using the Shapiro-Wilk test (Statistical Package for the Social Sciences for Windows 18.0; Lead Technologies Inc., Chicago, IL, USA). The results obtained at each exercise intensity were compared between therapies using a two-way analysis of variance for repeated measures (Statistica for Windows 5.0; Statsoft Inc., Tulsa, OK, USA), with therapy (placebo or amlodipine) and exercise stage (pre, S1, I1, S2, I2, S3, I3) as the main factors. When necessary, the Newman–Keuls posthoc test was employed. A P < 0.05 was accepted as significant. Data are presented as mean ± standard error.
Results Twenty-one patients started the study protocol, but 10 were excluded as their BP was outside the desired level, or due to problems inserting the catheter, or for personal reasons. Thus, 11 volunteers completed the study, and their characteristics are shown in Table 1. All patients had normal electrocardiographic indices and showed no proteinuria. Most had hypercholesterolemia, none had diabetes, and only one was a smoker. All volunteers were sedentary, and presented a VO2 peak below the predicted level for their characteristics. Five volunteers received placebo and six amlodipine in the first phase of the study. Weight, body mass index and heart rate were similar while subjects were receiving placebo and amlodipine. Resting systolic and diastolic BP were significantly lower and forearm blood flow was significantly greater with amlodipine than with placebo (Table 1). Amlodipine did not change maximum strength. Thus, exercise at 100%, 80%, and 40% of 1 RM was performed with 55 ± 6 and 53 ± 6 kg, 43 ± 4 and 41 ± 4 kg, Table 1. Subjects’ characteristics measured when hypertensives were receiving amlodipine and placebo therapies
N Gender (male/female) Age (years) Height (m) Weight (kg) Body mass index (kg/m2) Heart rate (bpm) Systolic BP (mmHg) Diastolic BP (mmHg) Forearm blood flow (mL/100 mL tissue/min)
Placebo
Amlodipine
11 4/7 47.0 ± 2.3 1.60 ± 0.03 72.7 ± 4.3 26.8 ± 1.6 79 ± 2 146 ± 3 92 ± 2 3.2 ± 0.5
72.6 ± 4.3 26.8 ± 1.2 80 ± 2 132 ± 3* 81 ± 2* 4.8 ± 0.6*
Values: Mean ± standard error. BP, blood pressure. *Significantly different from placebo (P < 0.05).
and 22 ± 2 and 21 ± 2 kg with placebo and amlodipine, respectively (P > 0.05). The number of repetitions to failure was also similar for both therapies at 80% (S1 = 11.3 ± 1.1 vs. 12.0 ± 1.1, S2 = 8.9 ± 0.5 vs. 9.5 ± 0.7, and S3 = 8.2 ± 0.4 vs. 8.1 ± 0.6 repetitions, P > 0.05), and 40% of 1 RM (S1 = 23.3 ± 2.2 vs. 21.5 ± 1.5, S2 = 15.8 ± 0.7 vs. 16.1 ± 1.0, and S3 = 14.2 ± 0.7 vs. 14.6 ± 0.5 repetitions, P > 0.05). BP responses to exercise Systolic BP levels and changes observed during the three exercise protocols are shown in Fig. 1. At all exercise intensities, systolic BP increased during the sets and returned to the pre-exercise level during the intervals between the sets (Fig. 1(a, c and e)). In addition, at 80% of 1RM, maximum systolic BP increased progressively from one set to the next (Fig. 1(c and d)). The absolute values of systolic BP were significantly lower with amlodipine than with placebo at all times and intensities (Fig. 1(a, c and e)). However, the increase in systolic BP during all sets and intensities was similar regardless of whether the subjects were receiving placebo or amlodipine (Fig. 1(b, d and f)). Diastolic BP levels and changes observed during the three exercise protocols are shown in Fig. 2. Diastolic BP also increased significantly during exercise sets and returned to the pre-exercise level or even fell below pre-exercise during the intervals between sets (Fig. 2(a, c and e)). During the exercises performed at 80% and 100% of 1 RM, diastolic BP absolute values were lower with amlodipine than with placebo (Fig. 2(a and c)), but diastolic BP behavior was similar regardless of whether the subjects were receiving placebo or amlodipine (Fig. 2(b and d)). Analysis of diastolic BP response to exercise at 40% of 1 RM revealed a significant interaction between the factors phase and moment. Thus, during the placebo session, diastolic BP increased during the exercise sets with the increases during the second and third sets being significantly greater than during the first set (Fig. 2(e and f)). On the other hand, in the session with amlodipine, absolute diastolic BP levels were lower than with placebo at all points, and diastolic BP did not increase from the first to the second and third sets of exercise (Fig. 2(e and f)). Therefore, at exercise at 40% of 1RM, amlodipide reduce not only the absolute diastolic BP levels, but also blunted diastolic BP increase in the second and third exercise sets. Discussion The main findings of this study were that: (a) the absolute maximal values of systolic and diastolic BP achieved during the execution of the three resistance exercise intensities were lower when the hypertensives were receiving amlodipine; and (b) the increase in
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Souza et al.
Fig. 1. Systolic blood pressure absolute values (SBP) and changes (ΔSBP = exercise SBP – pre-exercise SBP) measured pre-exercise (PRE) and during the sets of (S1, S2, and S3) and intervals between (I1, I2, and I3) the knee-extension resistance exercise performed to failure at 100% (panels a and b), 80% (panels c and d), and 40% (panels e and f) of 1 RM. Measurements were taken from hypertensive subjects receiving placebo (solid line and gray bars) and amlodipine (dotted line and black bars). * Significantly different from PRE (P < 0.05). $ Significantly different from S1 (P < 0.05). & Significantly different from S2 (P < 0.05). # Significantly different from placebo (P < 0.05). Data = mean ± standard error.
diastolic BP observed during the exercise sets at 40% of 1RM was abolished when the hypertensives were receiving amlodipine. To the best of our knowledge, this is the first study to describe the effect of a calcium channel antagonist on BP behavior during a dynamic resistance exercise in hypertensive patients. Previous studies have investigated the effect of this class of medication on isometric (Grossman et al., 1993; Malhotra et al., 2001), but not dynamic effort, and have reported a reduction in the absolute maximal BP values, but not in BP increase during exercise. In the present study, similar to the results of the isometric studies (Grossman et al., 1993; Malhotra et al., 2001), amlodipine reduced the absolute systolic and dia-
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stolic BP levels achieved during the exercise protocol regardless of exercise intensity, showing that the hypotensive effect of amlodipine observed at rest was maintained during the dynamic resistance effort. However, amlodipine did not affect systolic BP rise during exercise, but abolished diastolic BP increase at low-intensity exercise, showing that this drug was not able to mitigate or blunt the exercise-induced systolic hypertensive stimulus, but was able to abolish the low-intensity exercise-induced diastolic hypertensive effect over the exercise sets. This study did not assess the hemodynamic mechanisms responsible for BP responses during dynamic resistance exercise, but a discussion about them may
Amlodipine and resistance exercise response
Fig. 2. Diastolic blood pressure absolute values (DBP) and changes (ΔDBP = exercise DBP – pre-exercise DBP) measured preexercise (PRE) and during sets of (S1, S2, and S3) and intervals between (I1, I2, and I3) the knee-extension resistance exercise performed to failure at 100 (panels a and b), 80 (panels c and d), and 40% (panels e and f) of 1 RM. Measurements were taken from hypertensive subjects receiving placebo (solid line and gray bars) and amlodipine (dotted line and black bars). * Significantly different from PRE (P < 0.05). $ Significantly different from S1 (P < 0.05). & Significantly different from S2 (P < 0.05). # Significantly different from placebo (P < 0.05). Data = mean ± standard error.
arise from the results. BP increase during this kind of exercise has been attributed to both an increase in cardiac output and systemic vascular resistance. Cardiac output increase is mainly mediated by an increase of heart rate and myocardial contractility induced by central command stimuli and mechanoreflex (McCartney, 1999; Chrysant, 2010), while systemic vascular resistance increase is attributed to the mechanical contraction of the muscles around the vessels (Asmussen, 1981) and the exercise pressor reflex promoted by metaboreflex activation (Asmussen, 1981; Palatini, 1994; McCartney, 1999; Boushel, 2010).
Finally, if Valsalva maneuver is performed during the exercise, a greater BP increase may arise (Palatini, 1994). Amlodipine is a dihydropyridine calcium channel blocker that exerts its primary action on peripheral vessels, inhibiting the calcium influx through calcium channels, which reduces intracellular calcium concentration, leading to vasodilatation (Hoffman, 2006; Opie & Gersh, 2009). Consequently, the effects of amlodipine on BP responses to exercise may imply on preventing systemic vascular resistance increase. The absence of effect of amlodipine on blunting systolic BP increase during resistance exercise suggests that
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Souza et al. an increase in systemic vascular resistance is not the underlying mechanism for systolic BP response in this type of exercise. In accordance with this theory, in a previous study (Gomides et al., 2010), we observed that atenolol, a betablocker that decreases heart rate and cardiac output (Hoffman, 2006; Opie & Gersh, 2009), was able to reduce the increase in systolic BP during resistance exercise. Taken together, our results strengthen the hypothesis that the increase in systolic BP during dynamic resistance exercise is partially due to central mechanisms that lead to an increase in cardiac output. On the other hand, when diastolic BP behavior during exercise was considered, the results differed. The use of amlodipine abolished the diastolic BP increase over the sets of the low- but not high-intensity exercise protocols. During muscle contractions above 60 to 70% of maximal force, the mechanical contraction around the vessels promotes a complete blocking of blood flow (Asmussen, 1981). In addition, at high-intensity exercise, Valsalva maneuver is obligatory (Palatini, 1994). These mechanisms increase BP and amlodipine may not act on them, which explains the absence of drug effect on BP response to high-intensity exercises. On the other hand, during low-intensity exercise, blood flow is only partially restricted by mechanical contraction (Asmussen, 1981) and an additional rise in BP may result from the increase in systemic vascular resistance due to the accumulation of metabolites, stimulating chemoreceptors and increasing sympathetic activity, which induces additional vasoconstriction at the active and inactive territories (Rowell & O’Leary, 1990). Amlodipine has been suggested to increase baseline sympathetic activity (de Champlain et al., 1999; Toal et al., 2012) and sympathetic response to stimuli (de Champlain et al., 2007; de Champlain et al., 1999). However, it also decreases postreceptor α1 receptor response (de Champlain et al., 1999), decreasing vasoconstriction to sympathetic activation. Amlodipine may blunt sympathetic induced vasoconstriction because this channel blocker may blunt the calcium influx induced by sympathetic activation. Champlain et al. (2007) reported that amlodipine increased sympathetic response to the tilt test, but this greater sympathetic activation did not result in a greater BP increase. A similar response might have occurred during the low-intensity dynamic resistance exercise. In terms of the clinical application of the present results, we showed that dynamic resistance exercise induces a huge (maximum systolic BP = 289 ± 10 and 289 ± 8 mmHg with placebo at 40 and 80% of 1 RM, respectively) and very sharp (it took approximately 20 s at 80% of 1 RM, and 40 s at 40% of 1 RM) increase in BP, which might increase the risk for the rupture of a pre-existing aneurysm (Haykowsky et al., 1996; Vermeer et al., 1997; Vlak et al., 2011, 2012). On the other hand, amlodipine reduced maximal BP (maximum systolic BP = 255 ± 10 and 273 ± 10 mmHg with
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amlodipine at 40 and 80% of 1 RM, respectively) suggesting that hypertensive patients medicated with this drug are better protected from the aforementioned risk. Thus, amlodipine helps protect the cardiovascular system of hypertensive individuals, lowering the risk of high BP not only at rest, as observed by others (Rothwell et al., 2010), but also during the execution of dynamic resistance exercise. This research has some limitations related to its experimental design. This study included men and women; of the seven women evaluated, two were postmenopausal and the others had normal menstrual cycles. There was no control of menstrual cycle phase in which the experimental sessions were conducted. While these aspects may affect the results of the study, any influence is unlikely, since BP responses to exercise and medication (Abad-Santos et al., 2005) do not seem to be affected by gender. The study included hypertensive patients without other comorbidities, which may have affected the result. The role of the common comorbidities associated with hypertension should be investigated in the future. In this study, amlodipine was administered according to current recommendations, and changes in dose, mode of administration, duration of treatment and the time between the last dose and exercise can alter the results. It is also important to note that the study results may also differ with other types of exercise protocols. An important aspect of this study is that although the use of drugs allows the development of a hypothesis about the mechanisms responsible for the increase in BP during resistance exercise, the experimental design and the techniques used in the present study were not designed specifically for this purpose. Thus, specific research on the mechanisms responsible for BP increase during dynamic resistance exercise still needs to be conducted. In conclusion, amlodipine was effective at reducing the absolute values of systolic and diastolic BP during different intensities of dynamic resistance exercise. Furthermore, it was effective at abolishing the diastolic BP increase that occurs over sets of low-intensity resistance exercise. These results suggest that systemic vascular resistance may influence the increase in diastolic BP during resistance exercise, especially when this exercise is prolonged over time. In addition, the results suggest that hypertensive patients receiving amlodipine are better protected against high systolic BP peaks during dynamic resistance exercise than unmedicated patients. Perspectives The findings from this study add and complement previous information about BP responses to resistance exercise in hypertensives (Palatini, 1994; de Souza Nery et al., 2010) and possible interaction with antihypertensive drugs (Gomides et al., 2010). In this context, this
Amlodipine and resistance exercise response study showed that not only beta-blockers (Gomides et al., 2010), but also amlodipine might reduce BP levels during resistance exercise in hypertensives. These finding suggest that other anti-hypertensive drugs might also have hypotensive effects during dynamic resistance exercise which might be investigated in the future. In addition, combining with previous studies (Gomides et al., 2010), the present results allows to suppose that cardiac output increment is mainly involved in BP increase during high-intensity and the first set of resistance exercise, and that systemic vascular resistance is more related to BP increase during low-intensity and
prolonged resistance exercise. This hypothesis might be tested with specific designs in future research. Key words: calcium channel antagonist, intraarterial blood pressure, strength exercise, hypertension.
Acknowledgement The authors want to acknowledge the volunteers who contributed to this study. We also want to thank Medley for the donation of amlodipine. This study was financial supported by FAPESP (2009/ 12572-3) and CAPES.
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