An in vivo and in vitro study: High-dosage Danshen injection induces peripheral vascular endothelial cells injury

Danshen injection, a pharmaceutical dosage form of Danshen, has been widely used in the treatment of coronary heart diseases, myocardial infarction, and hypertension. With more and more adverse drug reactions linked with Danshen injection, its safety comes under suspicion. To evaluate its safety, mice were divided into four groups: vehicle, low-, middle-, and high-Danshen group, and each group was intravenously administered with Danshen injection at a dose of 0, 0.64, 1.55, and 5.76 g/kg/day for 5 days, respectively (the low dosage was the recommended clinical dosage, the middle dosage was the most commonly used higher dosage, and the high dosage was the highest dosage used in clinic). Peripheral vascular toxicity wasn't observed in the low-dosage group, elevated serum endothelin-1 (ET-1) was observed in the middle-dosage group; and more peripheral vascular toxicities like increased vascular leakage, elevated serum nitrate and ET-1, and vascular endothelial cells apoptosis were detected in the high-dosage group. In vitro study, low-concentration Danshen injection showed protective effect to human umbilical vein endothelial cells (HUVECs), while high concentration displayed strong cytotoxic effects, including increase in nitric oxide and ET-1 production, inhibition of cell viability, and apoptosis induction. Further, the HUVECs' apoptosis induced by high-concentration Danshen injection was found along with the induction of reactive oxygen species. In conclusion, these results suggest that Danshen injection is nontoxic in its recommended clinical dosage, and the 2.4-fold as the recommended clinical dosage might be the highest safety dosage in clinic treatment. In addition, Danshen injection is a potential vascular toxic drug in its high dosage and shouldn't be used far beyond its recommended dosage in clinic treatment.