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 (ET_AR) 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 (ET_AR 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 means ± 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). ET_AR contributes 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.NEW & NOTEWORTHY Endothelin-1 A receptors (ET_ARs) have been shown to reduce endothelial function independently and through increased production of superoxide. We show that independent ET_AR inhibition increases microvascular endothelial function in non-Hispanic Black young adults. However, administration of a superoxide dismutase mimetic alone and in combination with ET_AR inhibition had no effect on microvascular endothelial function suggesting that, in the cutaneous microvasculature, the negative effects of ET_AR in non-Hispanic Black young adults are independent of superoxide production.

Keywords: endothelin-1; endothelium; human; microdialysis; nitric oxide.