Sex-dependent development of enhanced sympathoexcitation in sedentary versus physically active rats.

KEY POINTS: The rostral ventrolateral medulla (RVLM) may contribute to sex-based differences in cardiovascular disease (CVD) based on overactivation of the sympathetic nervous system observed in sedentary male rats; however, the added influence of the reproductive cycle in females is currently unknown. To our knowledge this is the first study to demonstrate greater increases in sympathetic nerve activity in response to direct activation of the RVLM in female versus male rats prior to the onset of the reproductive cycle, which persisted after the onset of the reproductive cycle. Lower resting blood pressures in females also suggest peripheral adaptations contribute to sex-based differences in CVD. Sedentary versus physically active conditions appear to promote higher resting sympathetic outflow independent of age and sex. Our results demonstrate the importance of examining sedentary conditions in the context of sex differences and the reproductive cycle in contributing to sympathetic overactivity associated with cardiovascular disease. ABSTRACT: Female reproductive hormones are considered cardioprotective based on higher risks of cardiovascular disease (CVD) in post- versus pre-menopausal women. Similarly, based on epidemiological studies, a sedentary lifestyle is also a major risk factor for CVD. The mechanisms by which sedentary conditions contribute to CVD, and their influences in the presence and absence of female reproductive hormones are unknown. We hypothesized that sexually immature male and female rats would have similar centrally mediated regulation of blood pressure, but upon sexual maturation, female rats would have lower resting blood pressure and centrally-mediated sympathoexcitation compared to age-matched males. We also predicted resting sympathetic activity would increase upon exposure to sedentary versus active conditions (voluntary wheel running) in males but not in females. We recorded splanchnic sympathetic nerve activity (SSNA) and blood pressure in 4-, 8- and 16-week-old male and female rats under Inactin anaesthesia before and during microinjections of glutamate (1-100 mM) into the rostral ventrolateral medulla (RVLM). Four-week-old female rats had lower resting blood pressure and greater sympathoexcitation following activation of the RVLM, as did 8- and 16-week-old female rats, independent of age or activity condition. Sedentary animals had higher baseline SSNA compared to active animals, independent of sex or age. Our results reveal a complex influence of the interactions between the female reproductive cycle and sedentary conditions. They also demonstrate the importance of examining sedentary conditions in the context of sex- and female reproductive cycle-dependent incidences of cardiovascular disease.