title: Bradykinin and matrix metalloproteinases are involved the structural alterations of rat small resistance arteries with inhibition of ACE and NEP.
abstract: OBJECTIVE
  Increased vascular resistance is a hallmark of hypertension and involves structural alterations, which may entail smooth muscle cell hypertrophy or hyperplasia, or qualitative or quantitative changes in extracellular matrix (ECM) proteins. Since the renin-angiotensin-aldosterone system modulates these changes, we investigated the effects of 8 weeks of treatment with an angiotensin-converting enzyme (ACE) inhibitor, ramipril (RAM), or a dual ACE and neutral endopeptidase (NEP) inhibitor, MDL-100240 (MDL), on mesenteric small artery structure and ECM proteins in mRen2-transgenic rats (TGRs), an animal model of hypertension with severe cardiovascular damage.
  
  
  METHODS
  Thirty-five 5-week-old rats were included in the study: six TGRs received RAM; five TGRs RAM + the bradykinin receptor inhibitor, icatibant; six TGRs, MDL; and five TGRs MDL + icatibant, while eight TGRs and five normotensive Sprague-Dawley controls were kept untreated. Mesenteric small arteries were dissected and mounted on a micromyograph. The media-to-lumen ratio (M/L) was then calculated. Vascular metalloproteinase (MMP) content was evaluated by zymography.
  
  
  RESULTS
  In untreated TGRs severe hypertension was associated with inward eutrophic remodelling of small arteries. Both RAM and MDL prevented the increase in blood pressure and M/L and decreased MMPs. Icatibant blunted the effect of MDL on BP, M/L and MMPs.
  
  
  CONCLUSIONS
  Changes in collagenase activity induced by ramipril and MDL are associated with prevention of small artery structural alterations in TGRs. Furthermore, MDL-induced enhancement of bradykinin could play a role in both the prevention of vascular structural alterations and in the stimulation of MMPs.
authors.affiliation: Department of Medical and Surgical Sciences, University of Brescia, DMCS - Clinica Medica 4, University of Padua, Italy. rizzoni@med.unibs.it
authors.forename: Damiano
authors.initials: D
authors.lastname: Rizzoni
authors.forename: Gian Paolo
authors.initials: GP
authors.lastname: Rossi
authors.forename: Enzo
authors.initials: E
authors.lastname: Porteri
authors.forename: Daniele
authors.initials: D
authors.lastname: Sticchi
authors.forename: Luigi
authors.initials: L
authors.lastname: Rodella
authors.forename: Rita
authors.initials: R
authors.lastname: Rezzani
authors.forename: Intissar
authors.initials: I
authors.lastname: Sleiman
authors.forename: Carolina
authors.initials: C
authors.lastname: De Ciuceis
authors.forename: Silvia
authors.initials: S
authors.lastname: Paiardi
authors.forename: Rossella
authors.initials: R
authors.lastname: Bianchi
authors.forename: G G
authors.initials: GG
authors.lastname: Nussdorfer
authors.forename: Enrico
authors.initials: E
authors.lastname: Agabiti-Rosei
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D030801:Animals, Genetically Modified; D001552:Benzazepines / Q000494:pharmacology*; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D065168:Bradykinin Receptor Antagonists; D004195:Disease Models, Animal; D004347:Drug Interactions; D006973:Hypertension / Q000139:chemically induced / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D007150:Immunohistochemistry; D008297:Male; D020782:Matrix Metalloproteinases / Q000032:analysis / Q000378:metabolism*; D008638:Mesenteric Arteries / Q000187:drug effects / Q000473:pathology* / Q000648:ultrastructure; D009213:Myography; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000494:pharmacology*; D017257:Ramipril / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000032:analysis; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000032:analysis; D014655:Vascular Resistance; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D001552:Benzazepines; D065168:Bradykinin Receptor Antagonists; D011725:Pyridines; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; C085683:MDL 100240; C065679:icatibant; D020782:Matrix Metalloproteinases; D015260:Neprilysin; D017257:Ramipril; D001920:Bradykinin