In the present study we investigated the difference between sexes on cardiovascular autonomic modulation and oxidative stress in target organs after eight weeks of aerobic exercise training. The major finding of this study is that, besides both trained groups showing improvement on cardiovascular autonomic control and cardiac and renal oxidative stress when compared to the sedentary groups, the female group was more responsive to the exercise training protocol than the male group. This suggests that the sexes may respond differently to aerobic exercise training regarding cardiovascular autonomic control and oxidative stress.
The autonomic nervous system is a key regulator of cardiovascular homeostasis . There are multiple ways to measure cardiac autonomic control; in this study, we used the heart rate and arterial pressure variability, which allows us to assess the role of autonomic nervous system fluctuations in normal healthy individuals and in patients with various cardiovascular and non-cardiovascular disorders . Recent data support that estrogen provides a degree of cardiovascular protection by influence of the autonomic nervous system [5, 31]. In this sense, Kuo et al.  showed that healthy women had lower cardiac sympathetic modulation when compared to men before post menopause stage. That result is also in concordance with the lower LF band of SAP observed in the female groups in the present study. These results could explain the lower cardiovascular risk between pre-menopausal women compared to men. Additionally, the aerobic exercise training was able to improve HR variability and simpathovagal balance (LF/HF) independent of sex, which can be explained by a decrease of the LF band of PI and an increase in HF band of PI. In fact, the cardiac benefits induced by aerobic exercise training seems to be not dependent of sex, even with difference on cardiovascular autonomic modulation in sedentary condition .
Moreover, studies have shown that dynamic aerobic exercise training does not change arterial blood pressure in male  and female  normotensive rats. Indeed, in the present study, the AP values obtained did not change after aerobic exercise training in both sexes; however, the female animals showed lower vascular sympathetic modulation than males, which may explain a reduced vasoconstriction and a lower vascular resistance in females in comparison to males, especially after exercise . Interesting, we observed a positive correlation between LF band of SAP and SAP, showing that, despite similar basal values of AP between sexes and condition of training, animals with lower sympathetic vascular modulation presented reduced values of SAP. In the present study, we observed resting bradycardia in trained male and female rats compared to sedentary groups, which can be related with an important reduction in cardiac sympathovagal balance. In fact, supporting this hypothesis we obtained significant correlations involving all groups between HR and VAR-PI (r=-0.6) and LF/HF ratio (r = 0.7), demonstrating that animals with higher cardiac total variance of PI or lower cardiac sympathovagal balance showed reduced basal HR.
Previous studies also have shown that female rats run more than male rats . In the present study, 8 weeks of the aerobic exercise training induced an increase of exercise capacity, as evaluated by the response to the maximal exercise test, in both sexes. This result corroborates with previous studies in males and females Wistar  and ovarectomized rats .
Reactive oxygen species (ROS) are formed under both physiological and pathological conditions and have been implicated of a large number of diseases [8, 9]. Some studies have shown an association with a decreased sympathetic modulation and an enhanced oxidative stress central and peripherally [11, 12]. Moreover, accumulating evidences indicate a protective role of estrogen on cardiovascular disorder [22, 35]. In the present study, we observed that sedentary female rats showed less membrane lipid peroxidation in cardiac tissue as assessed by CL when compared to sedentary male rats. Indeed, estrogen seems to act centrally reducing BP, sympathoexcitation and oxidative stress . Some studies have reported an important role of sex difference in antioxidant capacity and exercise-induced reactive oxygen species production [34, 37]. On the other hand, some studies claim that sex does not affect oxidative stress parameters after exercise training . Therefore, the impact of exercise training on oxidative stress between sexes remains contradictory.
We observed that exercise training induced a decrease in both trained groups on membrane lipid peroxidation in cardiac tissue; however, only the trained female group showed a reduced membrane lipid peroxidation in renal tissue. This data reinforce results showing that the response to oxidative stress induced by exercise training is dependent of tissue . However, this response occurred probably due an increase in the antioxidant enzymes activity, such as CAT and GPx, which may be associated with a marked increase of nonenzymatic antioxidant capacity, evidenced by TRAP. In agreement with the present findings, previous data of our group showed a reduction on cardiac oxidative stress markers after aerobic exercise training in female ovariectomized  and male hypertensive rats . Glutathione redox balance (GSH/GSSG) in cardiac tissue also was improved in the trained female group in the present study. It is important to note that this nonenzymatic endogenous antioxidant has a major role against oxidative stress . Thus, the better antioxidative profile in trained females in both cardiac and renal tissues may be explained by female sex hormones, which can induce antioxidant enzyme expression by stimulating the antioxidant defense system , inhibit the formation of lipid peroxidase in some tissues  and lead to a higher mitochondrial/systemic antioxidant capacity .
It is important to remain that unfavorable changes in BP or HR variability were correlated with end organ damage in humans and rats, despite normal values of AP [44–46]. Furthermore, it well known that oxidative stress is one of the key mechanisms involved in end organ damage that can be developed during life spam . In this sense, our data provide evidence that changes in cardiovascular autonomic modulation related to sex or condition of training can impact in oxidative stress markers in target organ. We observed significant positive correlations between LF band of PI and cardiac LPO, as well as, between SAP or LF band of SAP with renal LPO. Together, these results suggest that animals with lower cardiac/vascular sympathetic modulation or SAP presented reduced levels of cardiac/renal oxidative damage.
Indeed, in this study, we showed that there are some differences in autonomic modulation and oxidative stress markers between males and females. Interestingly, female rats seem to be more responsive to a moderate intensity aerobic exercise training. When we compared the sedentary and trained groups, we observed that the TF group showed an increase of 71% in VAR-PI and 272% in cardiac and 206% in renal TRAP, as well as a reduction of 50% in cardiac GSSG, while the TM group showed an increase of 39% in VAR-PI and 131% in cardiac and 142% in renal TRAP, as well as a reduction of 18% in cardiac GSSG. Thus, the trained female animals showed greater improvement on VAR-PI (~ 1.8 times), on cardiac and renal TRAP (~ 2,1 and ~ 1.5 times, respectively) and on cardiac GSSG (~ 2.8 times) than trained male animals. Moreover, despite trained males reduced cardiac LPO to similar levels observed in trained females, only females rat reduced VAR-SAP and renal LPO and improved cardiac glutathione redox balance in response to aerobic exercise training.
In conclusion, aerobic exercise training protocol improved cardiovascular autonomic modulation and oxidative stress profile in target organs in both sexes. The favorable changes on BP and HR variability were associated with hemodynamic improvement and reduced end organ damage. The exercise training benefits were more pronounced in females than males. Therefore, findings from the current study suggest that sex was an important determinant of changes induced by aerobic exercise training. Our data reinforce that sex should be considered to understand autonomic modulation and oxidative stress-induced cardiovascular dysfunction, as well as, the effects of different approach to prevent/treat cardiovascular disease.
Perspectives and Significance
There is a higher prevalence of cardiovascular disease in men than in women, which suggests that sex-related differences in sex hormones might have a key role in the development CVD. Additionally, regular physical activity promotes numerous beneficial adaptations, as well as reduces the risk of chronic diseases. Our findings contribute to a fuller understanding of the impact of aerobic exercise training on cardiovascular autonomic control and oxidative stress between gender. In this since, we observed in an experimental model that female rats showed additional aerobic exercise training induced-cardiovascular autonomic modulation and target organs oxidative stress profile improvement than male rats. As the estimates of cardiovascular mortality in the coming years are still quite challenging, our data reinforce the need for further research on the effects of regular exercise on the mechanisms of autonomic cardiovascular control, oxidative stress and immunity between genders.