Inhibition of nuclear factor-κB activation improves non-nitric oxide-mediated cutaneous microvascular function in reproductive-aged healthy women

The transcriptional regulator nuclear factor-kappa B (NF-kappa B) is a mediator of endothelial dysfunction. Inhibiting NF-kappa B with salsalate is used to investigate inflammatory mechanisms contributing to accelerated cardiovascular disease risk. However, in the absence of disease, inhibition of NF-kappa B can impact redox mechanisms, resulting in paradoxically decreased endothelial function. This study aimed to measure microvascular endothelial function during inhibition of the transcriptional regulator NF-kappa B in reproductive-aged healthy women. In a randomized, single-blind, crossover, placebo-controlled design, nine healthy women were randomly assigned oral salsalate (1,500 mg, twice daily) or placebo treatments for 5 days. Subjects underwent graded perfusion with the endothelium-dependent agonist acetylcholine (ACh, 10(-10) to 10(-1) M, 33 degrees C) alone and in combination with 15 mM N-G-nitro-l-arginine methyl ester [l-NAME; nonselective nitric oxide (NO) synthase inhibitor] through intradermal microdialysis. Laser-Doppler flux was measured over each microdialysis site, and cutaneous vascular conductance (CVC) was calculated as flux divided by mean arterial pressure and normalized to site-specific maximum (CVC%max; 28 mM sodium nitroprusside + 43 degrees C). The l-NAME sensitive component was calculated as the difference between the areas under the dose-response curves. During the placebo and salsalate treatments, the l-NAME sites were reduced compared with the control sites (both P < 0.0001). Across treatments, there was a significant difference between the control and l-NAME sites, where both sites shifted upward following salsalate treatment (both P < 0.0001), whereas the l-NAME-sensitive component was not different (P = 0.94). These data demonstrate that inhibition of the transcriptional regulator NF-kappa B improves cutaneous microvascular function in reproductive-aged healthy women through non-NO-dependent mechanisms.