Document Detail


Pyrrolidine dithiocarbamate down-regulates vascular matrix metalloproteinases and ameliorates vascular dysfunction and remodelling in renovascular hypertension.
MedLine Citation:
PMID:  21434884     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND AND PURPOSE: Mounting evidence implicates matrix metalloproteinase (MMP) in the vascular dysfunction and remodelling associated with hypertension. We tested the hypothesis that treatment with pyrrolidine dithiocarbamate (PDTC), which interferes with NF-κB-induced MMPs gene transcription, could exert antihypertensive effects, prevent MMP-2 and MMP-9 up-regulation, and protect against the functional alterations and vascular remodelling of two-kidney, one clip (2K1C) hypertension.
EXPERIMENTAL APPROACH: Sham-operated or hypertensive rats were treated with vehicle or PDTC (100 mg·Kg(-1) ·day(-1)) by gavage for 8 weeks. Systolic blood pressure (SBP) was monitored weekly. Aortic rings were isolated to assess endothelium-dependent relaxations. Quantitative morphometry of structural alterations of the aortic wall was carried out in haematoxylin/eosin sections. Formation of vascular reactive oxygen species (ROS), and inducible (i) NOS and phosphorylated-p65 NF-κB subunit expression were measured in the aortas. MMP-2 and MMP-9 aortic levels and gelatinolytic activity were determined by gelatin and in situ zymography and by immunofluorescence.
KEY RESULTS: Treatment with PDTC attenuated the increases in SBP and prevented the endothelial dysfunction associated with 2K1C hypertension. Moreover, PDTC reversed the vascular aortic remodelling, the increases in aortic ROS levels and in iNOS and phosphorylated-p65 NF-κB expression found in 2K1C rats. These effects were associated with attenuation of 2K1C up-regulation of aortic MMP-2 and MMP-9 levels and gelatinolytic activity.
CONCLUSION AND IMPLICATIONS: These findings suggest that PDTC down-regulates vascular MMPs and ameliorates vascular dysfunction and remodelling in renovascular hypertension, thus providing evidence supporting the suggestion that PDTC is probably a good candidate to be used to treat hypertension.
Authors:
S B A Cau; D A Guimaraes; E Rizzi; C S Ceron; L L Souza; C R Tirapelli; R F Gerlach; J E Tanus-Santos
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  British journal of pharmacology     Volume:  164     ISSN:  1476-5381     ISO Abbreviation:  Br. J. Pharmacol.     Publication Date:  2011 Sep 
Date Detail:
Created Date:  2011-09-02     Completed Date:  2012-04-16     Revised Date:  2013-06-30    
Medline Journal Info:
Nlm Unique ID:  7502536     Medline TA:  Br J Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  372-81     Citation Subset:  IM    
Copyright Information:
© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.
Affiliation:
Department of Pharmacology, Faculty of Medicine of Ribeirao Preto, SP, Brazil.
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MeSH Terms
Descriptor/Qualifier:
Animals
Antihypertensive Agents / pharmacology*
Aorta / drug effects,  physiology
Gene Expression Regulation / drug effects*
Hypertension, Renal / complications,  drug therapy*
Hypertrophy / drug therapy
Male
Metalloproteases / antagonists & inhibitors*,  metabolism
NF-kappa B / metabolism
Nitric Oxide Synthase Type II / metabolism
Pyrrolidines / pharmacology*
Rats
Rats, Wistar
Thiocarbamates / pharmacology*
Chemical
Reg. No./Substance:
0/Antihypertensive Agents; 0/NF-kappa B; 0/Pyrrolidines; 0/Thiocarbamates; 25769-03-3/pyrrolidine dithiocarbamic acid; EC 1.14.13.39/Nitric Oxide Synthase Type II; EC 3.4.-/Metalloproteases
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