Endothelium‐Independent, but Not Endothelium‐Dependent, Human Microvascular Vasodilation Differs Between Young, Healthy Females and Males

Abstract

Estrogen increases nitric oxide production, but a direct comparison of endothelium-dependent and endothelium-independent mechanisms of human microvascular vasodilation between females and males has not been completed. The purpose of this study was to examine endothelium-dependent and endothelium-independent mechanisms of human cutaneous microvascular vasodilation between young, healthy females and males. Females were grouped by menstrual cycle phase to assess the influence of female sex hormones. We hypothesized that females in menstrual cycle phases of elevated estrogen would have an increased endothelium-dependent vasodilation response compared to females in phases of decreased estrogen or males. Eighteen participants (7 males; 6 females in early follicular phase, F-EF; 5 females in luteal phase, F-L) were instrumented with two microdialysis fibers in the skin of the forearm. A dose-response was completed at each site: 1) acetylcholine (ACh; 10-10 – 10-1 M) to assess endothelium-dependent vasodilation, and 2) sodium nitroprusside (SNP; 10-10 – 10-1 M) to assess endothelium-independent vasodilation. Doses were perfused for 5 minutes. Maximal vasodilation was elicited by heating the skin to 43°C and infusing 54 mM SNP. Laser-Doppler flowmetry (LDF) provided an index of skin blood flow. Cutaneous vascular conductance (CVC) was calculated (LDF/mean arterial pressure) and normalized to maximal blood flow (%CVCmax). Data are presented as mean ± SD. There was no interaction between main effects of group and dose in %CVCmax response to ACh, but there was a main effect of dose (p < 0.0001). The ACh logEC50 was similar between all groups (males: -3.8 ± 0.76M; F-EF: -2.7 ± 1.00M; F-L: -4.0 ± 0.61M). There was a significant interaction between group and dose in %CVCmax response to SNP (p = 0.04). At 10-4 M SNP, F-L (20 ± 9%CVCmax) displayed a lower response compared to males (46 ± 19%CVCmax, p = 0.004). At 10-3 M SNP, F-EF (46 ± 25%CVCmax, p = 0.038) and F-L (36 ± 15%CVCmax, p = 0.002) displayed lower responses compared to males (64 ± 16%CVCmax). The response to 10-2 M and 10-1 M SNP were not statistically different between groups. The SNP logEC50 was not different between F-EF and F-L; however, the SNP logEC50 was lower in males (-4.6 ± 0.47M) compared to F-EF (-3.3 ± 0.64M, p = 0.02) and F-L (-2.8 ± 0.36M, p < 0.0001). There was no difference between groups or phase for maximal CVC responses (p > 0.05). Endothelium-dependent mechanisms of microvascular vasodilation were similar between males and females, regardless of menstrual cycle phase. Males displayed heightened endothelium-independent vasodilation in response to lower doses of SNP, but also appeared to exhibit tachyphylaxis at the higher concentrations, compared to females.