Abstract P209: Androgen Receptor Antagonist, Bicalutamide, And Androgen Receptor Degradation Enhancer, Asc-j9, Decrease Blood Pressure Similarly In Male Spontaneously-hypertensive Rats.

Abstract

Background: Men are at greater risk for cardiovascular disease (CVD) than women until after menopause. For this reason, androgens have been implicated as playing a role in CVD in men. We have studied the role that androgens play in mediating the hypertension (HT) in spontaneously-hypertensive rats (SHRs), and found that blood pressure (BP) is decreased with castration and increased with testosterone supplements. In addition, we found that androgen receptor (AR) antagonists reduce BP, but blockers of the conversion of testosterone to dihydrotestosterone have no effect on BP, suggesting that testosterone alone is capable of mediating HT in male SHR. Testosterone is known to induce genomic and non-genomic effects via binding to nuclear AR or via independent mechanisms caused by membrane-bound AR. It is unclear whether or not membrane-bound AR play a role in mediating HT in male SHRs. In the present study we tested the hypothesis that only nuclear AR, not membrane-bound AR, mediate the HT in male SHR. Methods: Male SHR (aged 13 months; n = 5 - 6 rats/group) were implanted with radiotelemeters, and after 2 weeks recovery, mean arterial pressure (MAP) was measured for 4 days (baseline). Then rats were given vehicle (dimethylacetamide, DMA, 1 ml/kg, s.c.); bicalutamide (BICA, nuclear AR antagonist; 5 mg/k/d, s.c.); or Asc-j9 (AR degradation enhancer, 50 mg/kg/d, s.c.) for 8 days while measuring their MAP. Asc-j9 degrades both nuclear and membrane-bound AR. Results: Both BICA and Asc-j9 reduced MAP in male SHRs (BICA: 171 ± 2 to 151 ± 1 mmHg, p < 0.05; Asc-j9: 172 ± 3 to 148 ± 2 mmHg, p < 0.05.). DMA vehicle also reduced MAP (176 ± 5 to 161 ± 4 mmHg, p < 0.05). The decrease in the BICA and Asc-j9 groups was significantly different than the DMA group. Conclusion: In summary, AR degradation enhancer, that degrades both membrane-bound and nuclear AR, reduced MAP to similar level as nuclear AR antagonist in male SHR, suggesting that it is the nuclear AR that plays a greater role in mediating chronic BP control in male SHR. It is likely that membrane-bound AR may mediate more acute effects of androgen function independent of the BP.