Maturitas 62 (2009) 200–204
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Exercise improves cardiovascular control in a model of dislipidemia and menopause Marcelo Velloso Heeren a , Leandro Eziquiel De Sousa b , Cristiano Mostarda b , Edson Moreira b , Henrique Machert a , Katya Vianna Rigatto c , Rogério Brandão Wichi a , M.C. Irigoyen b , Kátia De Angelis a,∗ a b c
Human Movement Laboratory, São Judas Tadeu University, Rua Taquari, 546, Sao Paulo – São Paulo 03166-000, Brazil Hypertension Unit, Heart Institute (InCor), Medical School, University of São Paulo, São Paulo – São Paulo, Brazil Department of Physiology, Fundac¸ão Faculdade Federal de Ciências Médicas de Porto Alegre, Brazil
a r t i c l e
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Article history: Received 12 July 2008 Received in revised form 16 December 2008 Accepted 18 December 2008 Keywords: Lipid profile Arterial pressure Baroreflex sensitivity Exercise training Menopause
a b s t r a c t The present study investigated the effects of exercise training on arterial pressure, baroreflex sensitivity, cardiovascular autonomic control and metabolic parameters on female LDL-receptor knockout ovariectomized mice. Mice were divided into two groups: sedentary and trained. Trained group was submitted to an exercise training protocol. Blood cholesterol was measured. Arterial pressure (AP) signals were directly recorded in conscious mice. Baroreflex sensitivity was evaluated by tachycardic and bradycardic responses to AP changes. Cardiovascular autonomic modulation was measured in frequency (FFT) and time domains. Maximal exercise capacity was increased in trained as compared to sedentary group. Blood cholesterol was diminished in trained mice (191 ± 8 mg/dL) when compared to sedentary mice (250 ± 9 mg/dL, p < 0.05). Mean AP and HR were reduced in trained group (101 ± 3 mmHg and 535 ± 14 bpm, p < 0.05) when compared with sedentary group (125 ± 3 mmHg and 600 ± 12 bpm). Exercise training induced improvement in bradycardic reflex response in trained animals (−4.24 ± 0.62 bpm/mmHg) in relation to sedentary animals (−1.49 ± 0.15 bpm/mmHg, p < 0.01); tachycardic reflex responses were similar between studied groups. Exercise training increased the variance (34 ± 8 vs. 6.6 ± 1.5 ms2 in sedentary, p < 0.005) and the high-frequency band (HF) of the pulse interval (IP) (53 ± 7% vs. 26 ± 6% in sedentary, p < 0.01). It is tempting to speculate that results of this experimental study might represent a rationale for this non-pharmacological intervention in the management of cardiovascular risk factors in dyslipidemic post-menopause women. © 2009 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Menopause has been associated with aerobic fitness impairment, decline in muscle strength and in bone mineral density; in addition, it is frequently accompanied by an increase in body weight, type 2 diabetes, osteoporotic fractures, and cardiovascular disease (CVD) [1]. After menopause, the increase in arterial pressure (AP) in women is such that the prevalence of hypertension is higher in postmenopausal women than in age-matched men [2]. In fact, postmenopausal women are 2–3 times more likely to suffer from coronary heart disease than premenopausal women [3]. The exact mechanisms of hypertension in postmenopausal woman are not well understood. However, menopause has been associated with central obesity and metabolic syndrome development [4], sympathetic overactivity [5], changes on lipid profile [6] and endothelial dysfunction [7]. In addition, it is well known that
∗ Corresponding author. Tel.: +55 11 60991909; fax: +55 11 30857887. E-mail address:
[email protected] (K. De Angelis). 0378-5122/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.maturitas.2008.12.011
estrogen deprivation has an important role in these alterations, since estrogen induces endothelial nitric oxide (NO) production, and reduces LDL oxidation in vivo and in vitro [8]. Hypercholesterolemia is an important cardiovascular risk factor. Several studies have pointed a direct relationship between total and LDL cholesterol increase and HDL cholesterol decline in post-menopausal women and endothelial dysfunction prevalence [9]. Indeed, the severity of endothelial dysfunction is related to an increased risk for an initial or a recurrent cardiovascular event [10]. Reduced baroreflex function and heart rate variability (HRV) are important mechanisms in the pathophysiology of cardiovascular disease [11]. Nowadays, the baroreflex sensitivity and the HRV have been recognized as markers of autonomic control and as predictors of cardiovascular mortality [12]. Actually, frequency-domain analysis of heart rate variability has gained popularity due to its broad applications as a functional indicator of the autonomic nervous system. Furthermore, spectral analysis provides more detailed and specific information of HRV, including data on sympathetic and parasympathetic modulation of cardiac function [13].
M.V. Heeren et al. / Maturitas 62 (2009) 200–204
Some risk factors have high prevalence among American women in the 20–74-year age groups. In this group, more than 1/3 have hypertension, more than 1/4 are hypercholesterolemic, and more than 1/4 present excessive weight and are sedentary [14]. In addition, the prevalence of these dysfunctions is markedly increased in post-menopausal women. In this aspect, exercise training has been recognized as a nonpharmacological treatment for cardiovascular disease. A recent systematic review of randomized, controlled trials reported benefits of exercise on body weight, bone constitution, muscle strength and endurance, flexibility, oxygen consumption, blood pressure, and metabolic control in women after menopause [15]. A previous study performed by our laboratory has demonstrated that exercise training induces reduction in oxidative stress, which is associated with an AP reduction and with an increase in baroreflex sensitivity (BRS) in ovariectomized rats [16]. Thus, the aim of the present study was to investigate the influence of exercise training on cardiovascular, metabolic and autonomic adjustments in female LDL-receptor knockout mice submitted to ovarian hormones deprivation, an experimental model of menopause, and dyslipidemia. 2. Methods Experiments were performed on female virgin LDL-receptor Knockout mice (20–25 g) from the Animal Care Facility of the São Judas University (São Paulo, Brazil). These animals were provided by Jackson’s Laboratory, USA. The mice received standard laboratory chow and water ad libitum. They were housed in individual cages in a temperature-controlled room (22 ◦ C) with a 12-h dark/light cycle. All mice were treated similarly in terms of daily manipulation. All surgical procedures and protocols used were approved by the Experimental Animal Use Committee of the Sao Judas University and were conducted in accordance with National Institute of Health (NIH) Guide for the Care and Use of Laboratory Animals. Mice were randomly assigned to sedentary (S, n = 8) or trained (T, n = 8) groups. 2.1. Ovariectomy 1 wk before beginning the exercise training protocol, at 9 months of age, animals were anesthetized (ketamine–xylazine 80:40 mg/kg ip), and a small abdominal incision was made. The ovaries were than located, and a silk thread was tightly tied around the oviduct, including the ovarian blood vessels. The oviduct was sectioned and the ovary removed. The skin and muscle wall were then sutured with silk thread. After surgery, the animals received an injection of antibiotics (40 000 U/kg penicillin G procaine IM) [17]. 2.2. Exercise protocols Exercise training was performed on a motor treadmill at lowmoderate intensity (∼50–70% maximal running speed) for 1 h a day, 5 days/wk for 4 wk, with a gradual increase in speed from 0.3 to 1.2 km/h. All animals were adapted to the procedure (10 min/day; 0.3 km/h) for 1 wk before beginning the exercise training protocol. After the adaptation, the sedentary group was exposed to exercise only during the maximum treadmill test. However, they were placed on the stationary treadmill three times a week to provide a similar environment [18]. Sedentary and trained mice were submitted to a maximal treadmill test as described in detail in a previous publication [19,20]. The tests were made at the beginning of the experiment and in the 2nd and 4th weeks of the training protocol. The purpose was to determine aerobic capacity and exercise training intensity [18].
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2.3. Cardiovascular measurements After the last training session, mice were anesthetized (ketamine–xylazine 80:40 mg/kg ip) and a polyethylene-tipped Tygon cannulas (4 cm of PE-08 connected to 2 cm of PE-50, Clay Adams) filled with heparinized saline were inserted into the carotid artery and jugular vein for direct measurements of arterial pressure and drug administration, respectively. The free ends of the cannulas were tunneled subcutaneously and exteriorized at the top of the skull. Two days after the catheter placement, hemodynamic measurements were made in conscious, freely moving mice. The arterial cannula was connected to a transducer (Blood Pressure XDCR, Kent© Scientific), and blood pressure signals were recorded for a 20-min period using a microcomputer equipped with an analog-to-digital converter (CODAS, 4-kHz sampling frequency, Dataq Instruments). The recorded data were analyzed on a beat-tobeat basis to quantify changes in AP and heart rate (HR) [18]. Baroreflex sensitivity was evaluated by a mean index relating the tachycardic or the bradycardic responses for mean AP changes (∼30–40 mmHg) [18] induced by increasing doses of sodium nitroprusside (100–250 ng/kg body wt iv) and phenylephrine (80–250 ng/kg body wt iv) injections, respectively. Data were expressed as beats per minute (bpm) per mmHg. Maximal volume per injection was
