Inhibition of NF-κB Activation Improves Non-Nitric Oxide-Mediated Cutaneous Microvascular Function in Reproductive-Aged Healthy Women

Abstract

PURPOSE: The human cutaneous circulation is used as an in vivo bioassay to examine mechanisms of systemic vascular function and dysfunction in health and disease. In cohorts of patients with accelerated cardiovascular disease risk, systemic interventions to investigate inflammatory mechanisms [e.g., oral salsalate; nuclear factor kappa-B (NF-κB) inhibitor] have been used to elucidate mechanisms underlying microvascular dysfunction. In healthy control subjects, inhibition of inflammatory mechanisms modestly reduces microvascular function. We hypothesize that inhibition of NF-κB activation may impair nitric oxide (NO)-mediated cutaneous microvascular function in reproductive-aged healthy women. METHODS: In a randomized, single-blind, placebo-controlled design, oral salsalate (1500mg/b.i.d./5 days) was used to assess the impact of systemic inflammation on cutaneous microvascular function. Two intradermal microdialysis fibers were placed into the ventral forearm skin of eleven healthy women [Mean (SEM): 34 (2) yrs]. Laser-Doppler flowmetry was used to measure cutaneous blood flow while increasing concentrations of acetylcholine (10−10 to 10−1 M; endothelium-dependent vasodilator) were perfused with a control (lactated Ringer’s) or a NO synthase inhibitor (15 mM NG-nitro-L-arginine methyl ester). Following the dose-response protocol, maximal cutaneous vasodilation was induced by increasing local skin temperature to 43°C and perfusing 28 mM sodium nitroprusside. Cutaneous vascular conductance (CVC) was calculated as the quotient of red blood cell flux over mean arterial pressure and normalized as a percentage of the site-specific maximum (%CVCmax). The NO-dependent contribution was calculated as the difference between the area under the dose-response curve (AUC) of the control and the NO synthase-inhibited sites. RESULTS: There was an overall main effect of salsalate treatment ( p < 0.001). Both the control and NO synthase-inhibited sites shifted upwards following salsalate treatment (Placebo - Control: 45.78 (8.81)% vs NO synthase inhibited: 33.62 (8.10)%; Salsalate - Control: 56.30 (8.48)% vs NO synthase inhibited: 41.57 (7.85)%; both p < 0.05). There was no change in the NO-dependent contribution between treatments (Placebo: 164.30 (35.40) AU vs Salsalate: 180.30 (51.17) AU; p=0.7028).CONCLUSION: Inhibition of NF-κB activation improved cutaneous microvascular function in reproductive-aged healthy women. This improvement was mediated via non-nitric oxide-dependent mechanisms. Supported by NIH Grant R01 HL161000 (LMA) and Diversity Supplement R01 HL161000-02S2 (VGC). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.