title: Endothelial nitric oxide synthase is a molecular vascular target for the Chinese herb Danshen in hypertension.
abstract: 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 two-kidney, one-clip renovascular hypertension model in hamsters. Oral tanshinone (50 microg/100 g body wt) reduced mean arterial pressure (MAP) from 161.2 +/- 6.9 to 130.0 +/- 7.8 mmHg (mean +/- SE; P < 0.05) in hypertensive hamsters. MAP in sham-operated hamsters was 114.3 +/- 9.2 mmHg. Topical tanshinone at 1 microg/ml and 5 microg/ml increased normalized arteriolar diameter from 1.00 to 1.25 +/- 0.08 and 1.57 +/- 0.11, respectively, and increased periarteriolar nitric oxide concentration from 87.1 +/- 11.3 to 146.9 +/- 23.1 nM (P < 0.05) at 5 microg/ml in hamster cheek pouch. N(G)-monomethyl-L-arginine inhibited tanshinone-induced vasodilation. 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-h 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-h 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 vasodilation and reduces blood pressure.
authors.affiliation: Department of Pharmacology and Physiology, UMDNJ-New Jersey Medical School, 185 South Orange Avenue, Newark, NJ 07101-1709, USA. kimda@umdnj.edu
authors.forename: David D
authors.initials: DD
authors.lastname: Kim
authors.forename: Fabiola A
authors.initials: FA
authors.lastname: Sánchez
authors.forename: Ricardo G
authors.initials: RG
authors.lastname: Durán
authors.forename: Takehito
authors.initials: T
authors.lastname: Kanetaka
authors.forename: Walter N
authors.initials: WN
authors.lastname: Durán
mesh_terms: D000818:Animals; D006224:Cricetinae; D016503:Drug Delivery Systems / Q000379:methods; D004365:Drugs, Chinese Herbal / Q000008:administration & dosage*; D006973:Hypertension / Q000188:drug therapy* / Q000503:physiopathology*; D008297:Male; D008647:Mesocricetus; D051379:Mice; D008810:Mice, Inbred C57BL; D008833:Microcirculation / Q000187:drug effects / Q000503:physiopathology*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III; D027561:Salvia miltiorrhiza; D016896:Treatment Outcome
chemical_list: D004365:Drugs, Chinese Herbal; C028972:dan-shen root extract; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse