Decrease in endogenous CGRP release in nitroglycerin tolerance: role of ALDH-2.
In the present study, we tested whether the decreased release of calcitonin gene-related peptide (CGRP) observed in nitroglycerin tolerance is associated with the decrease in aldehyde dehydrogenase (ALDH-2) activity. We further investigated the possible involvement of reactive oxygen species in the decrease in ALDH-2 activity. Tolerance was induced by exposure of isolated rat thoracic aortas and human umbical vein endothelial cells (HUVEC) to nitroglycerin in vitro or by pretreatment with nitroglycerin for 8 days in vivo. Pretreatment with ALDH-2 inhibitors and nitroglycerin significantly attenuated vasodilator responses to nitroglycerin concomitantly with a decrease in the release of CGRP from the isolated thoracic aorta. Nitroglycerin produced a depressor effect concomitantly with an increase in plasma concentrations of CGRP, and the effect of nitroglycerin was attenuated after pretreatment with an inhibitor of ALDH-2 or nitroglycerin for 8 days. Exposure of HUVEC to nitroglycerin for 16 h increased reactive oxygen species production and decreased ALDH-2 activity as well as cGMP production in a time-and concentration-dependent manner. Pretreatment with an ALDH-2 inhibitor also significantly decreased the cGMP production. However, tolerance to nitroglycerin in HUVEC was restored in the presence of N-acetylcysteine or captopril. The present results suggest that nitrate tolerance is, at least partially, associated with a decrease in endogenous CGRP release via a decrease in ALDH-2 activity as a result of stimulation of reactive oxygen species production.
Chen
Yue-Rong
YR
Department of Pharmacology, School of Pharmaceautical Sciences, Central South University, Changsha 410078, China.
Nie
Sheng-Dan
SD
Shan
Wang
W
Jiang
De-Jian
DJ
Shi
Rui-Zheng
RZ
Zhou
Zhi
Z
Guo
Ren
R
Zhang
Zhe
Z
Li
Yuan-Jian
YJ
D000111:Acetylcysteine / Q000494:pharmacology; D000444:Aldehyde Dehydrogenase / Q000378:metabolism*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism*; D002216:Captopril / Q000494:pharmacology; D002460:Cell Line; D002697:Chloral Hydrate / Q000494:pharmacology; D003484:Cyanamide / Q000494:pharmacology; D006152:Cyclic GMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004361:Drug Tolerance; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D020030:Nitric Oxide Donors / Q000494:pharmacology; D005996:Nitroglycerin / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects
D000806:Angiotensin-Converting Enzyme Inhibitors; D020030:Nitric Oxide Donors; D017382:Reactive Oxygen Species; D002697:Chloral Hydrate; D003484:Cyanamide; D002216:Captopril; D000444:Aldehyde Dehydrogenase; D005996:Nitroglycerin; D006152:Cyclic GMP; D015740:Calcitonin Gene-Related Peptide; D000111:Acetylcysteine