The human coronary vasodilatory response to acute mental stress is mediated by neuronal nitric oxide synthase

Mental stress-induced ischemia approximately doubles the risk of cardiac events in patients with coronary artery disease, yet the mechanisms underlying changes in coronary blood flow in response to mental stress are poorly characterized. Neuronal nitric oxide synthase (nNOS) regulates basal coronary blood flow in healthy humans and mediates mental stress-induced vasodilation in the forearm. However, its possible role in mental stress-induced increases in coronary blood flow is unknown. We studied 11 patients (6 men and 5 women, mean age: 58 +/- 14 yr) undergoing elective diagnostic cardiac catheterization and assessed the vasodilator response to mental stress elicited by the Stroop color-word test. Intracoronary substance P (20 pmol/min) and isosorbide dinitrate (1 mg) were used to assess endothelium-dependent and -independent vasodilation, respectively. Coronary blood flow was estimated using intracoronary Doppler recordings and quantitative coronary angiography to measure coronary artery diameter. Mental stress increased coronary flow by 34 +/- 7.0% over the preceding baseline during saline infusion (P < 0.01), and this was reduced to 26 +/- 7.0% in the presence of the selective nNOS inhibitor S-methyl-L-thiocitrulline (0.625 mu mol/min, P < 0.001). Mental stress increased coronary artery diameter by 6.9 +/- 3.7% (P = 0.02) and 0.5 +/- 2.8% (P = 0.51) in the presence of S-methyl-L-thiocitrulline. The response to substance P did not predict the response to mental stress (r(2) = -0.22, P = 0.83). nNOS mediates the human coronary vasodilator response to mental stress, predominantly through actions at the level of coronary resistance vessels.