Gender Differences in the nNOS-mediated Forearm Blood Flow Response to Mental Stress

Introduction. Neuronal nitric oxide synthase (nNOS) regulatesbasal microvascular flow in man and mediates avasodilatory response to mental stress1. We examined whether nNOS-mediated responses are influenced by gender(as are those to endothelial NOS2) and whether they are influenced by phosphodiesterase type 5 inhibition.

Methods. A randomised, single-blinded, placebo-controlled crossover study was performed in 28normotensive participants (13 men, mean age 32.0±11 years) receiving placebo and sildenafil 50mg on two separate occasions.Following left brachial artery cannulation, bilateral forearm blood flow (FBF) was measured by strain gauge plethysmography during infusion of the nNOS specific inhibitor S-methyl L-thiocitrulline (SMTC, 0.05, 0.1 and 0.2μmol/min),and mental stress elicited by the Stroop test.

Results. Data are presented as mean ± SEM, percentage change in FBF from preceding baseline. P values denote significance of gender differences. Following placebo, SMTC reduced resting FBF to a similar degree in both genders: -12.8±3.4% in women and -17.1±6.6% in men (p=0.6).Women had a greater stress-induced increase in FBF than men: 77.9±15% vs. 32.8±9.2% in men (p=0.02). SMTC attenuated the stress-induced FBF to a greater degree in women compared to men (Figure 1a): reduction of -43.8±11.3% vs. -3.0±9.8% (p=0.01).Following sildenafil, SMTC reduced resting FBF to a greater extent in women compared to men: -27±5.2% vs. -9.9±5.5%, respectively (p=0.03).However, sildenafil had a paradoxical effect to attenuate stress-induced FBF in women by-33.4±17.4%, but to potentiateit in men by 30.6±22.4% (p=0.01, Figure 1b).

Figure 1a) Percentage increase from preceding baseline in FBF (ΔFBF) after placebo +/- local intra-arterial SMTC. b) Comparison of ΔFBF in the control non-infused arm after placebo and sildenafil.

Conclusion. The nNOS pathway in the human forearm microcirculation is influenced by gender, with nNOS contributing a greater degree to stress-induced vasodilation in women compared to men. Phosphodiesterase 5 inhibition with sildenafil produces diverging effects on resting vascular tone and stress-induced vasodilation in men and women.

1 Seddon et al, Circulation, 2008. 117: p. 1991-1996

2 Orshal et al, Am J Physiol Regul Integr Comp Physiol, 2004. 286(2): p. R233-49