Blood Pressure, Sex, and Female Sex Hormones Influence Renal Inner Medullary Nitric Oxide Synthase Activity and Expression in Spontaneously Hypertensive Rats

Background-—We previously reported that sexually mature female spontaneously hypertensive rats (SHRs) have greater nitric oxide (NO) synthase (NOS) enzymatic activity in the renal inner medulla (IM), compared to age-matched males. However, the mechanisms responsible for this sexual dimorphism are unknown. The current study tested the hypothesis that sex differences in renal IM NOS activity and NOS1 expression in adult SHRs develop with sexual maturation and increases in blood pressure (BP) in a female sex hormone-dependent manner. Methods and Results-—Renal IM were isolated from sexually immature 5-week-old and sexually mature 13-week-old male and female SHRs. Whereas NOS activity and NOS1 expression were comparable in 5- and 13-week-old male SHRs and 5-week-old female SHRs, 13-week-old females had greater NOS activity and NOS1 expression, compared to 5-week-old female SHRs and age-matched males. NOS3 expression was greater in 5-week-old than 13-week-old SHRs regardless of sex. Treatment with antihypertensive therapy (hydrochlorothiazide and reserpine) from 6 to 12 weeks of age to attenuate age-related increases in BP abolished the sex difference in NOS activity and NOS1 expression between sexually mature SHR males and females. To assess the role of female sex hormones in age-related increases in NOS, additional females were ovariectomized (OVX), and NOS activity was studied 8 weeks post-OVX. OVX decreased NOS activity and NOS1 expression. Conclusions-—The sex difference in renal IM NOS in SHR is mediated by a sex hormone- and BP-dependent increase in NOS1 expression and NOS activity exclusively in females. ( J Am Heart Assoc. 2015;4:e001738 doi: 10.1161/JAHA.114.001738