Endothelin A receptor inhibition increases nitric oxide-dependent vasodilation independent of superoxide in non-Hispanic Black young adults

Abstract

Young non-Hispanic Black adults have reduced microvascular endothelial function compared with non-Hispanic White counterparts, but the mechanisms are not fully elucidated. The purpose of this study was to investigate the effect of endothelin-1 A receptor (ETAR) and superoxide on cutaneous microvascular function in young non-Hispanic Black (n=10) and White (n=10) adults. Participants were instrumented with four intradermal microdialysis fibers: 1) lactated Ringer's (control), 2) 500 nM BQ-123 (ETAR antagonist), 3) 10 μM tempol (superoxide dismutase mimetic), and 4) BQ-123 + tempol. Skin blood flow was assessed via laser-Doppler flowmetry (LDF), and each site underwent rapid local heating from 33°C to 39°C. At the plateau of local heating, 20 mM L-NAME [nitric oxide (NO) synthase inhibitor] was infused to quantify NO-dependent vasodilation. Data are mean ± standard deviation. NO-dependent vasodilation was decreased in non-Hispanic Black compared with non-Hispanic White young adults (p < 0.01). NO-dependent vasodilation was increased at BQ-123 sites (73 ± 10% NO) and at BQ-123 + tempol sites (71 ± 10 %NO) in non-Hispanic Black young adults compared with control (53 ± 13 %NO, p = 0.01). Tempol alone had no effect on NO-dependent vasodilation in non-Hispanic Black young adults (63 ± 14 %NO, p = 0.18). NO-dependent vasodilation at BQ-123 sites was not statistically different between non-Hispanic Black and White (80 ± 7 %NO) young adults (p = 0.15). ETAR contribute to reduced NO-dependent vasodilation in non-Hispanic Black young adults independent of superoxide, suggesting a greater effect on NO synthesis rather than NO scavenging via superoxide.

Inhibition of superoxide and iNOS augment cutaneous nitric oxide‐dependent vasodilation in non‐Hispanic black young adults

“…The plateau phase of the local heating response is largely mediated by NO derived from eNOS (~60%-80%) (Bruning et al, 2012;Choi et al, 2014;Kellogg Jr., Liu, et al, 1999;Kellogg Jr. et al, 2008, 2009Minson et al, 2001). Consistent with data from our lab and others (Akins et al, 2022;Hurr et al, 2018;Kim et al, 2018;Kim & Brothers, 2020;Miller et al, 2021;Patik et al, 2018;Turner, Hayat, et al, 2023;Wolf et al, 2020;Wong et al, 2020), we found there is both reduced microvascular endothelial-dependent vasodilation (plateau; Figures 1 and 2) and reduced NO-dependent vasodilation (Figures 3 and 4) to a standardized local heating protocol in non-Hispanic Black young adults. Reduced microvascular…”

“…endothelial function and NO-dependent vasodilation is observed whether local heating to 39°C is used, as in the current study (Akins et al, 2022;Hurr et al, 2018;Kim & Brothers, 2020;Miller et al, 2021;Patik et al, 2018;Turner, Hayat, et al, 2023;Wong et al, 2020), or to 42°C (Kim et al, 2018). The increase in microvascular endothelial function and NO-dependent vasodilation at tempol compared to control sites suggests superoxide negatively affects the microvascular endothelium in non-Hispanic Black young adults.…”

“…Since eNOS-derived NO is cardioprotective and the cutaneous vascular response is ~60%-80% dependent on eNOS, this represents an ideal stimulus to assess microvascular endothelial function. Data from our lab, and others, have shown reduced cutaneous vascular responses to local heating in non-Hispanic Black young adults (Akins et al, 2022;Hurr et al, 2018;Kim et al, 2018;Kim & Brothers, 2020;Miller et al, 2021;Patik et al, 2018;Turner et al, 2020;Turner, Hayat, et al, 2023;Wolf et al, 2020;Wong et al, 2020). We recently demonstrated this reduction is due, in part, to activity of inducible NO synthase (iNOS), which is upregulated under stress conditions, such as increased levels of superoxide, and has been shown to contribute to reduced cutaneous NO-dependent vasodilation in hypertensive humans (Massey et al, 2023;Miller et al, 2021;Putra et al, 2020;Smith et al, 2011;Tsai & Lein, 2021).…”

“…We recently demonstrated this reduction is due, in part, to activity of inducible NO synthase (iNOS), which is upregulated under stress conditions, such as increased levels of superoxide, and has been shown to contribute to reduced cutaneous NO-dependent vasodilation in hypertensive humans (Massey et al, 2023;Miller et al, 2021;Putra et al, 2020;Smith et al, 2011;Tsai & Lein, 2021). Previous data also indicates inhibition of superoxide and oxidative stress can improve NO-dependent vasodilation in non-Hispanic Black young adults (Hurr et al, 2018;Kim & Brothers, 2020;Patik et al, 2018;Turner, Hayat, et al, 2023;Wolf et al, 2020). Data in animal models suggests the iNOS inhibitor 1400 W may also attenuate oxidative stress, nitrosative stress, and proinflammatory cytokines in addition to its direct effects on iNOS (Massey et al, 2023;Putra et al, 2020).…”

Reply to Letter to the Editor in response to: Microvascular endothelial function following cessation of long‐term oral contraceptive pill use

“…Black young adults (Turner, Hayat et al, 2023) or naturally cycling women during menstruation (Turner, Stanhewicz, Nielsen, Otis et al, 2023), suggesting that there is a complex interplay in mechanisms that result in a given percentage of maximal CVC in response to a local heat stimulus. For these reasons, we would suggest that it is important to assess a general measure of endothelial function (i.e., plateau) in addition to the NO contribution.…”