Demethylbellidifolin prevents nitroglycerin tolerance via improved aldehyde dehydrogenase 2 activity.
The aim of this study was to investigate the effect of demethylbellidifolin (DMB), a major xanthone compound of Swertia davidi franch, on nitroglycerin (NTG) tolerance. In the in vivo portion of the study, pretreatment of Sprague-Dawley rats with NTG (10 mg/kg) for 8 days caused tolerance to the depressor effect of NTG. This was evident because the depressor effect of NTG (150 microg/kg, I. V.) was almost completely abolished in the tolerant rats. The tolerance could be diminished by treatment with DMB. In the in vitro study, the exposure of aortic rings of Sprague-Dawley rats to NTG (10 microM) for 30 min caused tolerance to the vasodilating effect of NTG. The tolerance is evident because of a substantial right shift of the NTG concentration-relaxation curves. This shift was reduced by pretreatment of the aortic rings with DMB. In cultured human umbilical vein endothelial cells (HUVECs), incubation of NTG for 16 h increased reactive oxygen species (ROS) production, attenuated cyclic guanosine monophosphate (cGMP) levels and decreased the activity of aldehyde dehydrogenase 2 (ALDH-2), the main enzyme responsible for NTG bioactivation. All the effects mentioned above were prevented by co-incubation with DMB. In conclusion, DMB prevents NTG tolerance via increasing ALDH-2 activity through decreasing ROS production.
Shi
Rui-Zheng
RZ
Department of Cardiovascular Medicine, Xiangya Hospital, Central South University, Changsha, P. R. China.
Li
Xiao-Hui
XH
Jia
Su-Jie
SJ
Fu
Qiong-Mei
QM
Chen
Yue-Rong
YR
Chen
Jia
J
Chen
An
A
Li
Shi-Xun
SX
Tan
Gui-San
GS
Li
Yuan-Jian
YJ
Zhang
Guo-Gang
GG
D000444:Aldehyde Dehydrogenase / Q000378:metabolism*; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000818:Animals; D000975:Antioxidants / Q000302:isolation & purification / Q000494:pharmacology*; D001011:Aorta; D006152:Cyclic GMP / Q000378:metabolism; D004361:Drug Tolerance; D042783:Endothelial Cells / Q000187:drug effects*; D041743:Herb-Drug Interactions; D006801:Humans; D008297:Male; D024101:Mitochondrial Proteins / Q000378:metabolism*; D005996:Nitroglycerin / Q000627:therapeutic use*; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D029967:Swertia / Q000737:chemistry*; D014471:Umbilical Veins; D014665:Vasodilator Agents; D014966:Xanthenes / Q000302:isolation & purification / Q000494:pharmacology*
D000975:Antioxidants; D024101:Mitochondrial Proteins; D010936:Plant Extracts; D017382:Reactive Oxygen Species; D014665:Vasodilator Agents; D014966:Xanthenes; C467829:demethylbellidifolin; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; C505112:Aldh2 protein, rat; D005996:Nitroglycerin; D006152:Cyclic GMP