Sex Differences in the Effect of Acute Intermittent Hypoxia on Respiratory-Sympathetic Coupling in Humans

Background Sex-related differences in respiratory-sympathetic coupling have been described in preclinical models of intermittent hypoxia (IH) and have been implicated in the development of neurogenic hypertension. Based on sex disparities in the respiratory and blood pressure response to acute IH in humans as well as changes in respiratory-sympathetic coupling in clinical sleep apnea, we examined sex-related differences in respiratory modulation of muscle sympathetic nerve activity (MSNA) following acute IH in healthy humans. We hypothesized the magnitude of respiratory-sympathetic coupling would increase in both men and women following IH; however, the respiratory patterning of MSNA following IH would be sex-specific. Methods Heart rate, MSNA, and respiration were assessed in 21 healthy young men (30±1 yrs) and 10 healthy young women (28±1 yrs) during normoxic rest prior to and following IH. IH was achieved by alternating between a hypercapnic hypoxic (3% carbon dioxide, 5% oxygen) gas cylinder and room air (21% oxygen) to target 15 hypoxic events over 30-min. Respiratory modulation of MSNA was assessed by fitting polynomials to cross-correlation histograms constructed between sympathetic spikes and respiration. Results MSNA was elevated following IH in both men (34±2 to 41±3 bursts/100 heart beats) and women (30±4 to 35±5 bursts/100 heart beats) (p<0.01). When examining the normalized temporal profile of MSNA, both men and women exhibited changes in respiratory patterning of MSNA following IH; however, the pattern of MSNA differed by sex. Following IH, women exhibited more sympathetic activity during late expiration and less during post-inspiration (interaction of IH and time, p<0.01). In contrast, men exhibited greater sympathetic activity during post-inspiration following IH (interaction of IH and time, p<0.01). Conclusions Both men and women exhibit changes in respiratory patterning of MSNA following acute IH; however, this pattern differs by sex. These data support sex disparities in respiratory-sympathetic coupling and advance our understanding of sex-specific changes in sympathetic activation following IH which may have important implications for the development of neurogenic hypertension.