Physical training associated with Enalapril but not to Losartan, results in better cardiovascular autonomic effects
Introduction
Angiotensin II is a polypeptide that plays an important role in regulating cardiovascular homeostasis through multiple actions, including those in the central nervous system (Stein et al., 1984, Reid, 1992, Fyhrquist et al., 1995, Wollert and Drexler, 1999, Ylitalo et al., 1999, Mehta and Griendling, 2007, Oparil and Schmieder, 2015, Leenen, 2014). Thus, angiotensin II plays a key role in the pathophysiology of cardiovascular disease as in hypertension, interfering with the cardiac autonomic balance (Stein et al., 1984, Reid, 1992, Fyhrquist et al., 1995, Wollert and Drexler, 1999, Ylitalo et al., 1999, Mehta and Griendling, 2007, Leenen, 2014, Oparil and Schmieder, 2015). This action is characterized by increased sympathetic influence and reduced cardiac vagal influence, resulting in important autonomic changes, such as reduction in baroreflex sensitivity (Reid, 1992, Wollert and Drexler, 1999, Ylitalo et al., 1999, Mehta and Griendling, 2007, Oparil and Schmieder, 2015).
In this context, clinical and experimental studies have shown that drugs that act by reducing the action of angiotensin II may lead to favorable adaptations in cardiovascular autonomic control when high blood pressure is present (Laflamme et al., 1997, Krum, 2001, Azevedo et al., 2003). Angiotensin converting enzyme inhibitors (ACEi) such as Enalapril and AT1 receptor blockers such as Losartan, are widely used in the clinical practice due to these effects (Gottlieb et al., 1993, Dimitrova et al., 1998, Bonner et al., 2009, Inaba et al., 2011).
The ACEi act primarily by preventing the conversion of angiotensin I to angiotensin II (Oigman and Fritsch, 1998), while AT1 receptor blockers prevent the action of angiotensin II, especially in blood vessels, contributing to the reduction of arterial pressure (AP) (Gottlieb et al., 1993, Dimitrova et al., 1998, Oigman and Fritsch, 1998, Bonner et al., 2009, Inaba et al., 2011). While, the effectiveness of these two drugs in reducing AP is well known (Rizzoni et al., 1998), their effects on the cardiovascular autonomic control have not been widely investigated (Yee and Struthers, 1998, Kaya et al., 2003). Some studies in the literature suggest that ACEi promotes broader cardiac autonomic benefits when compared to the AT1 receptor blockers (Kaya et al., 2003).
Nonetheless, other therapeutic approaches are also used in order to reduce blood pressure, improve autonomic parameters and reduce the potential cardiovascular risk associated with hypertension. Aerobic exercise training is often used as treatment for hypertension, either prior to or during pharmacological treatments. Aside from the benefits already mentioned, studies in the literature show that when performed regularly, aerobic exercises can decrease the levels of angiotensin converting enzyme (ACE) and consequently, the concentrations of angiotensin II. According to these studies, this effect of physical exercise would result in autonomic and morphofunctional adaptations that contribute safely to the improvement of cardiovascular homeostasis (Gu et al., 2014, O'Donnell et al., 2014, Wu et al., 2014).
It has also been shown that physical training, regardless of drug treatment, improves cardiac autonomic modulation of hypertensive patients (Cozza et al., 2012). Moreover, the association of physical training with AT1 receptor blockers such as Losartan, has also been studied. However, the studies show controversial results. Experimental studies have shown that the association of physical training with Losartan treatment reduces sympathetic autonomic modulation of spontaneously hypertensive rats (SHR) (Guo et al., 2008), while others have shown that the association does not promote any additional effects when compared to Losartan treatment alone (Azevedo et al., 2003).
Therefore, this study aimed to investigate whether or not treatment with Enalapril and Losartan would have different effects on the cardiovascular autonomic control in SHR. We hypothesized that the two drugs would lead to different autonomic adaptations, due to their different forms of action. In addition, we investigated whether the association of physical training with Enalapril or Losartan treatment would increase the cardiovascular autonomic effects seen with the isolated pharmacological treatments.
Section snippets
Subjects
Forty eight male SHR 18 weeks of age and weighing about 230 g, at the start of the study, were used. The rats were transferred from the Animal Facility at the Ribeirão Preto School of Medicine, University of São Paulo, to the housing colony where they were kept in a room with a strictly controlled temperature (21 ± 1 °C) and a 12:12 light:dark cycle. The rats had unrestricted access to tap water and standard rat chow (Nuvilab CR-1, Nuvital, Brazil).
All experimental protocols performed in the current
Arterial pressure
All groups started the experimental protocol with similar MAP values (Vehicle, 168 ± 4 mm Hg; Enalapril, 170 ± 2 mm Hg; Losartan, 173 ± 5 mm Hg).
The sedentary groups treated with Losartan or Enalapril for 10 weeks and the trained vehicle group showed decrease in SAP, DAP and MAP when compared to the sedentary vehicle group. In this case, the sedentary group treated with Enalapril showed the most accentuated decrease. However, the association of physical training with pharmacological treatments did not
Discussion
Pharmacological treatment with Enalapril and Losartan as well as aerobic exercise reduced the AP of SHR. However, it was the treatment with Enalapril that promoted the greatest reduction, while the combination of physical training and Enalapril or Losartan did not potentiate the reduction in AP. Autonomic evaluation through different approaches showed that the treatment with Enalapril and Losartan had similar effects on the sedentary animals. Moreover, the combination of physical training and
Conflicts of interest
None.
Acknowledgements
Grant support: “Fundação de Amparo à Pesquisa do Estado de São Paulo — FAPESP”, Process number: 2013/02880-8.
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