Inflammation plays an important role in the pathophysiology of cardiovascular dysfunction and neurohumoral excitation in heart failure and hypertension. Growing evidence has demonstrated significant sex differences in the inflammatory response and immune processes, with estrogen exerting an anti-inflammatory effects and testosterone potentially having pro-inflammatory influence. We previously reported that central administration of tumor necrosis factor-α (TNF-α) elicited different effects on blood pressure (BP), heart rate (HR) and renal sympathetic nerve activity (RSNA) in male and female rats. Whether the sex steroids estrogen and testosterone contribute to the observed differences in TNF-α-induced hemodynamic and sympathetic responses remains unknown. We hypothesized that estrogen protects against TNF-α-induced sympathetic excitation and pressor responses while testosterone enhances these excitatory outcomes in response to TNF-α. Female or male Sprague Dawley rats (10-12 weeks) anesthetized with ketamine plus xylazine underwent bilateral ovariectomy or castration, respectively, 2 weeks prior to study. Sham-operated (Sham) female or male animals served as controls. TNF-α (100 ng) was administered intracerebroventricularly (ICV). BP (mmHg), HR (bpm) and RSNA (% change) were recorded in urethane anesthetized rats. In ovariectomized female rats (n=6), ICV TNF-α induced significantly (*p<0.05 vs. Sham) larger increases in BP (19.3 ± 1.4* vs. 12.8 ± 1.2 ), HR (76.3 ± 4.8* vs. 51.5 ± 4.3) and RSNA (104.8 ± 6.9* vs. 72.4 ± 5.1), compared with Sham-female rats, that began within 20-30 mins and peaked at 90-120 mins after ICV injection. In castrated male rats (n=6), ICV TNF-α-elicited significantly smaller increases in BP (15.2 ± 1.3* vs. 21.8 ± 1.6), HR (57.7 ± 4.2* vs. 82.6 ± 4.1) and RSNA (72.6 ± 4.3* vs. 110.3 ± 4.7), compared with Sham-male animals. These data indicate a distinct role of sex hormones estrogen and testosterone in central inflammation-driven cardiovascular and sympathetic activation and suggest a protective effect of estrogen and a harmful effect of testosterone in the development of hypertension and heart failure.
Magnetic Resonance Imaging and Invasive Evaluation of Development of Heart Failure in Transgenic Mice With Myocardial Expression of Tumor Necrosis Factor-α
