Danshen, a Chinese herb, reduces hypertension in Oriental Medicine. We hypothesized that Danshen acts partially through endothelial nitric oxide synthase (eNOS) signaling mechanisms. We tested the hypothesis using tanshinone II_A, an active ingredient of Danshen, and the 2-kidney-1-clip renovascular (2K1C) hypertension model in hamsters. Oral tanshinone (50 µg/100g of body weight) reduced mean arterial pressure (MAP) from 161.2±6.9 to 130.0±7.8 mmHg (mean±SEM; p<0.05) in hypertensive hamsters. MAP in sham-operated hamsters was 114.3±9.2 mmHg. Topical tanshinone at 1 µg/ml and 5 µg/ml increased normalized arteriolar diameter from 1.00 to 1.25±0.08 and 1.57±0.11, and increased periarteriolar nitric oxide concentration from 87.1±11.3 nM to 146.9±23.1 nM (p<0.05) at 5 µg/ml in hamster cheek pouch. N^G-monomethyl-L-arginine inhibited tanshinone-induced vasodilatation. Hypertension reduced eNOS protein relative to sham-operated control. Tanshinone prevented the hypertension-induced reduction of eNOS, and increased eNOS expression to levels higher than sham-operated control in hamster cheek pouch. Topical tanshinone increased normalized arteriolar diameter from 1.0 to 1.47±0.08 in the cremaster muscle of control mice and to 1.12±0.13 in cremasters of eNOS-knockout mice. In ECV 304 cells transfected with eNOS-green fluorescent protein, tanshinone increased eNOS protein expression 1.35±0.05 and 1.85±0.07 -fold above control after 5 min and 1 hr application, respectively. Tanshinone also increased eNOS phosphorylation 1.19±0.07 and 1.72±0.20 -fold relative to control after 5 min and 1 hr application. Our data provide a basis to understand the action of a Chinese herb used in alternative medicine. We conclude that eNOS stimulation is one mechanism by which tanshinone induces vasodilatation and reduces blood pressure.