PURPOSE: Response of myocardial blood flow (MBF) to sympathetic stimulation with cold is modulated by endothelium-related factors and is typically altered in the presence of coronary risk factors. Determinants of flow response to cold pressor testing (CPT) in normal volunteers at low risk for CAD remain less well defined, especially relative to baseline conditions such as hemodynamics and MBF, plasma substrate and lipid levels, and total pharmacologically stimulated vasodilator capacity. METHODS: In 50 normal volunteers (42+/-13 years; 31 women) without coronary risk factors, insulin resistance, or family history of diabetes/premature CAD, MBF was measured with (13)N-ammonia and PET at baseline, during CPT, and during pharmacologic hyperemia. RESULTS: Sympathetic stimulation with CPT raised heart rate and blood pressure and thus MBF (Delta MBF=0.23+/-0.09 ml/min/g). MBF response, defined in absolute flow units as the difference between CPT and baseline, was independent of age, gender, heart rate, and blood pressure and rate-pressure product (RPP) at baseline as well as plasma substrate and lipid levels with the exception of an association with HDL cholesterol (rho=0.40, p=0.005) but depended on the change in RPP from rest (rho=0.33, p=0.019). Finally, changes in coronary vascular resistance in response to CPT were associated with changes in pharmacologic vasodilation (rho=0.56, p<0.0001). CONCLUSION: MBF response to sympathetic stimulation with cold (NO-mediated endothelium-dependent vasomotion), reflecting the functional state of the coronary endothelium, was independent of gender, age, and resting heart conditions. It was modulated by HDL cholesterol levels, even in healthy volunteers, and also related to pharmacologically stimulated vasodilator capacity at the coronary vascular resistance level.