Estradiol (E
2
) and testosterone (T) stimulate synthesis of nitric oxide (NO). Since the WHI study, postmenopausal women are given E
2
and/or T supplements to alleviate the symptoms of menopause. NO is a key regulator of blood pressure (BP), mediating endothelial and vascular function. Studies from our lab showed that E
2
plays little role in BP control in young female SHR; however, whether E
2
replacement with or without T would reduce BP in postmenopausal female SHR is not known. If E
2
does not reduce BP in old female SHR, it is possible that there is a defect in the NO system that prevents the vasodilatory E
2
effect mediated by NO. The hypothesis tested in this study was that E
2
/T replacement would reduce BP in old female SHR, and if not, the mechanism responsible is a deficient NO system that is incapable of upregulating in response to E
2
. After baseline (B) mean arterial pressure (MAP; telemetry), female SHR (19 mos, n=5) were implanted with 17-β E
2
(0.1 mg/pellet) and T (5mm in silastic tubes) and MAP was measured. After a transient reduction in MAP over 2-3 days (B: 175±5; E
2
+T: 161±4 mm Hg, p<0.05), MAP returned to baseline levels by day 4 (176±5 mm Hg). These data suggest that the acute vasodilatory response to E
2
/T in old female SHR was intact. On day 8 T tubes were removed, and MAP was measured for additional 16 days. Removal of T had no effect on BP (175±5 mm Hg). To evaluate NO system, rats were given: 1) 2% L-Arginine (L-Arg, 21 d); 2) 0.1% sodium nitrite (NaNO
2
, 6 d); 3) nitro-L-arginine methyl ester (L-NAME, 4mg/kg/d, 5 d). L-Arg supplement failed to change MAP (B: 175±5, L-Arg: 176±5 mm Hg, p<NS). In contrast, NaNO
2
did decrease MAP (B: 176±5, NaNO
2
: 161±3 mm Hg, p<0.05), suggesting a deficient endogenous synthesis of NO but the ability of the old female SHR to respond to an NO donor. L-NAME increased MAP (B: 176±5; L-NAME: 189±3 mm Hg, p<0.05). In total, these data suggest that the NO system in old female SHR is capable of responding appropriately to NO donors or complete blockade. However, the lack of response to L-Arg suggests a deficiency in the ability to normally synthesize NO, and thus may in part be responsible for the lack of a depressor response to E
2
, and therefore, may contribute to the elevated BP in old female SHR. Supported by NIH-R01HL66072, PO1HL51971 (JFR), 14POST18640015 (ROM).
Senescence and Cancer: Role of Nitric Oxide (NO) in SASP