title: Pyrrolidine dithiocarbamate down-regulates vascular matrix metalloproteinases and ameliorates vascular dysfunction and remodelling in renovascular hypertension.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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: Department of Pharmacology, Faculty of Medicine of Ribeirao Preto, SP, Brazil.
authors: S B A
authors: SB
authors: Cau
authors: D A
authors: DA
authors: Guimaraes
authors: E
authors: E
authors: Rizzi
authors: C S
authors: CS
authors: Ceron
authors: L L
authors: LL
authors: Souza
authors: C R
authors: CR
authors: Tirapelli
authors: R F
authors: RF
authors: Gerlach
authors: J E
authors: JE
authors: Tanus-Santos
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects*; D006977:Hypertension, Renal / Q000150:complications / Q000188:drug therapy*; D006984:Hypertrophy / Q000188:drug therapy; D008297:Male; D045726:Metalloproteases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013859:Thiocarbamates / Q000494:pharmacology*
chemical_list: D000959:Antihypertensive Agents; D016328:NF-kappa B; D011759:Pyrrolidines; D013859:Thiocarbamates; C020972:pyrrolidine dithiocarbamic acid; D052247:Nitric Oxide Synthase Type II; D045726:Metalloproteases