Decrease in endogenous CGRP release in nitroglycerin tolerance: role of ALDH-2.

Abstract:

: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.

journal_name

Eur J Pharmacol

authors

Chen YR,Nie SD,Shan W,Jiang DJ,Shi RZ,Zhou Z,Guo R,Zhang Z,Li YJ

doi

10.1016/j.ejphar.2007.05.042

subject

Has Abstract

pub_date

2007-09-24 00:00:00

pages

44-50

issue

1

eissn

0014-2999

issn

1879-0712

pii

S0014-2999(07)00647-4

journal_volume

571

pub_type

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